Research Paper
Potent estrogen agonists based on carborane as a hydrophobic
skeletal structure
A new medicinal application of boron clusters
Yasuyuki Endo a Y*,Toru Iijima a,Yuko Yamakoshi a,Hiroshi Fukasawa a, Chisato Miyaura b,Masaki Inada b,Asako Kubo c,Akiko Itai c
a Graduate School of Pharmaceutical Sciences,University of Tokyo,7-3-1,Hongo,Bunkyo-ku,Tokyo113-0033,Japan
b School of Pharmacy,Tokyo University of Pharmacy and Life Science,1432-1,Horinouchi,Hachioji,Tokyo192-0392,Japan
c Institute of Medicinal Molecular Design,Key Molecular,Inc.,5-24-5,Hongo,Bunkyo-ku,Tokyo113-0033,Japan
Received30November2000;revisions requested12February2000;revisions received22February2001;accepted23February2001
First published online7March2001
Abstract
Background:Carboranes(dicarba-closo-dodecaboranes)are a class of carbon-containing polyhedral boron-cluster compounds having remarkable thermal stability and exceptional hydrophobi-city.Applications of the unique structural and chemical properties offered by icosahedral carboranes in boron neutron capture therapy have received increasing attention over the past30years. However,these features of carboranes may allow another application as a hydrophobic pharmacophore in biologically active molecules that interact hydrophobically with receptors. Results:We have designed candidate estrogen-receptor-binding compounds having carborane as a hydrophobic skeletal structure and synthesized them.The most potent compound bearing a carborane cage exhibited activity at least10-fold greater than that of17L-estradiol in the luciferase reporter gene assay.Estrogen receptor-K-binding data for the compound were consistent with the results of the luciferase reporter gene assay.The compound also showed potent in vivo effects on the recovery of uterine weight and bone loss in ovariectomized mice.
Conclusion:Further development of the potent carborane-containing estrogenic agonists described here,having a new skeletal structure and unique characteristics,should yield novel therapeutic agents,especially selective estrogen receptor modula-tors.Furthermore,the suitability of the spherical carborane cage for binding to the cavity of the estrogen receptor-K ligand-binding domain should provide a basis for a similar approach to developing novel ligands for other steroid receptors.?2001 Elsevier Science Ltd.All rights reserved.
Keywords:Carborane;Estrogen ligand;Hydrophobic interaction; Nuclear receptor
1.Introduction
The icosahedral carboranes(dicarba-closo-dodecabo-ranes),which were￠rst synthesized in the1960s,have un-usual properties,such as(1)high boron content,(2)re-markable thermal and chemical stability,(3)a hydrophobic surface,and(4)a spherical geometry[1]. The carboranes were utilized in medicinal chemistry in the￠eld of boron neutron capture therapy(BNCT)for incorporation of large numbers of boron atoms into tu-mor cells.Since the early applications of simple boron-containing compounds for BNCT,various compounds have been synthesized by adding carborane units to amino acids,nucleic acids,porphyrins,DNA binders and carbo-rane-containing antibodies[2,3].Among the properties of carboranes,the high boron content and chemical stability are useful for BNCT.However,their highly hydrophobic character prevents the incorporation of these molecules into tumor cells.Therefore,derivatization of carborane-containing molecules has been conducted to obtain water solubility[4].On the other hand,from the standpoint of receptor^ligand complexation,the exceptional hydropho-bic character of carboranes[5,6]may allow their use as a hydrophobic pharmacophore in biologically active mole-cules.This concept has been realized by the synthesis of several biologically active peptides,in which phenylalanine residues were replaced with(o-carboranyl)alanine[7^10].
1074-5521/01/$^see front matter?2001Elsevier Science Ltd.All rights reserved. PII:S1074-5521(01)00016-3
However,little attention has been paid to the possible use of carborane as a hydrophobic skeletal structure,in the ￠eld of drug design.We have been engaged in the design and synthesis of new nuclear receptor ligands[11,12]and signal transduction modulators[13,14],and have recog-nized the importance of hydrophobic interaction in recep-tor^ligand complexation.The di?erence of binding con-stants between a ligand having a suitable hydrophobic group and a ligand without such a group sometimes reaches100V10000times.To evaluate the utility of icosa-hedral carborane as a hydrophobic component for drug design[15^17],we focused on the design and synthesis of estrogen agonists bearing a carborane cage as a hydro-phobic skeletal structure[18].
The steroid hormone estrogen in￡uences the growth, di?erentiation,and functioning of many target tissues.Es-trogens play an important role in the female and male reproductive systems,and also in bone maintenance,in the central nervous system and in the cardiovascular sys-tem.The￠rst step in the appearance of these activities is mediated by the binding of hormonal ligands to the estro-gen receptors(ER)K[19]and L[20].The hormone-bound ER undergoes a conformational change,allowing the re-ceptor to dimerize.The dimer functions as a transcription factor that mediates biological response by binding to spe-ci￠c promoter elements of DNA to initiate gene https://www.doczj.com/doc/125830088.html,pounds that either induce or inhibit cellular es-trogen responses have potential value as biochemical tools and candidates for drug development.In this article,we describe the synthesis and biological evaluation of novel carborane-containing estrogenic agonists,which are more potent than17L-estradiol.
2.Results
2.1.Ligand design
Since the discovery of the non-steroidal estrogen dieth-ylstilbestrol[21],many stilbenes,triarylethylenes and other aromatic compounds have been synthesized and shown to possess estrogenic activity.Many estrogen agonists and antagonists[22]have been developed as agents for regu-lating fertility,preventing and controlling hormone-re-sponsive breast cancer,and post-menopausal hormone re-placement.Estrogenic activity has been found in a large range of structural prototypes,including non-steroidal compounds isolated from plants,such as￡avonoids[23]. On the other hand,the health risks of the estrogenic com-pounds that are either present in the environment or used as chemicals have become of interest in recent years[24]. One of the reasons for the estrogenic activity of such a wide variety of organic chemicals appears to be that ER binding is primarily the result of interaction between the receptor and a phenolic residue.Furthermore,the estro-genic activity is known to depend on the shape of the alkyl substituent in simple phenols having a bulky alkyl group at the4-position.Therefore,high binding a¤nity for ER and the appearance of substantial estrogenic activity re-quire an appropriate hydrophobic group adjacent to the phenolic ring,other than two hydrogen-bonding groups such as a phenolic hydroxyl group and another hydroxyl group located at a suitable position on the molecule.The C,D rings on the natural hormone,17L-estradiol(1),play an important role in stabilizing the ligand^receptor com-plex by hydrophobic interactions.The size of the carbor-ane cage seems to be appropriate for the hydrophobic skeletal structure in place of the C,D ring structure of 1.Substitution of the two carbon atoms of the carborane isomers should allow suitable￠xation of the direction of the functional groups.On the basis of these considera-tions,we designed the compound BE120(2c),which seems to contain all the essential molecular recognition compo-nents for ER.Fig.1shows a structural comparison of 17L-estradiol(1)and2c.As shown in Fig.1,we also de-signed compounds2a,2b and2d^f to evaluate the e?ects of substituents and of the distance of the aliphatic hydrox-yl group from the hydrophobic skeleton.In
icosahedral Fig.1.Structures of17L-estradiol(1)and designed compounds(2).(Bottom)Structural comparison of1and2c.
342Chemistry&Biology8/4(2001)341^355
cage structures throughout this paper,closed circles (b )represent carbon atoms and other vertices represent BH units.
2.2.Ligand synthesis
The designed molecules 2were synthesized from 1,12-dicarba-closo -dodecaborane (p -carborane,3)as shown in Fig. 2.1-(4-Methoxyphenyl)-1,12-dicarba-closo -dodeca-borane (4a ),which was prepared by coupling of the C-copper (I)derivative of 3with 4-iodoanisole in dimethoxy-ethane in the presence of pyridine in 60%yield [25],was demethylated with boron tribromide to a?ord compound 2a in 93%yield.The methoxyphenylcarborane 4a was converted to the C -methoxycarbonyl derivative 5by reac-tion of the lithiate of 4a with methyl chloroformate (91%).After reduction of 5with LiAlH 4,demethylation gave 1-hydroxymethyl-12-(4-hydroxyphenyl)-1,12-dicarba-closo -dodecaborane (BE120,2c )in 98%yield.1-Hydroxy-12-(4-hydroxyphenyl)-1,12-dicarba-closo -dodecaborane (2b )was prepared by oxidation of the lithiate of 4a with benzoyl peroxide [26]followed by demethylation (75%).Hydrolysis of the ester group of 5followed by demethylation a?orded 12-(4-hydroxyphenyl)-1,12-dicarba-closo -dodecaborane-1-carboxylic acid (2f )in 98%yield.The acid 4f was con-verted to the C-t -butoxycarbonylamino derivative (6)in
41%yield by means of the modi￠ed Curtius rearrangement [27]employing diphenylphosphoryl azide (DPPA),4-N,N -dimethylaminopyridine (DMAP)and tert -butanol.Depro-tection of the Boc group of 6followed by demethylation gave 1-amino-12-(4-hydroxyphenyl)-1,12-dicarba-closo -do-decaborane (2g )in a quantitative https://www.doczj.com/doc/125830088.html,pound 4a was converted to 4d by reaction of the lithiate of 4a with 2-(2-bromoethoxy)tetrahydro-2H -pyran followed by deprotec-tion of the THP group with p -toluenesulfonic acid (45%).Demethylation of the methoxy group gave 1-hydroxyeth-yl-12-(4-hydroxyphenyl)-1,12-dicarba-closo -dodecaborane (2d )in 88%yield.Similarly,introduction of a C3unit into 4a a?orded 1-hydroxypropyl-12-(4-hydroxyphenyl)-1,12-dicarba-closo -dodecaborane (2e ).
2.3.Transactivational properties and ER-binding a¤nity of
the designed carborane-containing molecules The estrogenic activities of the synthesized compounds were examined by the luciferase reporter gene assay [28],in which a rat ER K expression plasmid [29]and a reporter plasmid,which contains ￠ve copies of estrogen response elements,are transiently transfected into COS-1cells.17L -Estradiol at 1U 10310^1U 1038M induced the expression of luciferase in a dose-dependent manner.This activation by 17L -estradiol was dependent upon the expression of
ER
Fig.2.Synthetic route used for the preparation of the estrogen ligands bearing carborane.Key:(a)(1)n -BuLi,CuCl/DME,(2)p -iodoanisole/pyridine,re￡ux;(b)BBr 3/CH 2Cl 2;(c)(1)n -BuLi/benzene^Et 2O,(2)ClCOOCH 3;(d)LiAlH 4/THF;(e)KOH/H 2O^THF;(f)DPPA,Et 3N,DMAP/t -BuOH re-￡ux;(g)CF 3COOH/CH 2Cl 2;(h)(1)n -BuLi/benzene^Et 2O,(2)(C 6H 5COO)2/benzene^Et 2O;(i)(1)n -BuLi/benzene^Et 2O,(2)Br(CH 2)n OTHP;(j)p -TsOH W H 2O/MeOH.
Research Paper Estrogen agonists based on carborane Y.Endo et al.343
and was completely inhibited by estrogen antagonists (ta-moxifen and ICI 164,384).The results of the estrogenic activity assay of our carborane-containing molecules (2a ^g )are summarized in https://www.doczj.com/doc/125830088.html,pound 2a ,which is a simple phenol bearing p -carboranyl at the 4-position,exhibited potent transcriptional activity in the concentra-tion range of 1U 10310^1U 1038M;its potency is much higher than that of 4-alkylphenols.1-Phenyl-1,12-dicarba-closo -dodecaborane,which lacks the hydroxyl group,showed no activity.On the other hand,the activity of compound 2b ,which has a second hydrogen-bonding group on carbon of the carborane cage,was signi￠cantly increased.The potency of 2b was greater than that of 17L -estradiol.BE120(2c ),which has a hydroxymethyl group on the carborane cage,a?orded the most potent activity,being at least 10times more potent than 17L -estradiol.Further insertion of methylene units in the substituent on the carborane cage (2d and 2e )decreased the activity.The activity of 2g with an amino group on the carborane cage seemed to be somewhat stronger than that of 17L -estradiol,and 2f with a carboxylic acid moiety exhibited moderate activity.
ER K -binding assays were performed on the three active
compounds (2a ,2c and 2g )and 17L -estradiol to con￠rm that the gene-regulatory activity correlated with the bind-ing a¤nity for the ER K .The assays were done by mea-surement of inhibition of [6,7-3H]17L -estradiol binding (K d =0.4nM)to human recombinant ER K (PanVera),us-ing the nitrocellulose ￠lter binding assay method.The ER K -binding data for these compounds are consistent with the results of the luciferase reporter gene https://www.doczj.com/doc/125830088.html,-pounds 2a and 2g showed strong a¤nity for ER K ;their potency was almost the same as that of 17L -estradiol.The most active compound in the luciferase reporter gene as-say,2c ,also showed the highest a¤nity for ER K ,and its a¤nity was higher than that of 17L -estradiol.The K i val-ues of 2a ,2c ,and 2g for ER K were 0.40,0.10,and 0.65nM,respectively.
2.4.Structure^activity relations of the carborane-containing
estrogens To investigate the relation between the activity and the geometry and separation distance of the two hydroxyl groups on the phenylcarborane skeleton,we designed and synthesized compounds bearing a para -substituent on the carborane cage and a 3-hydroxyl group on the benzene nucleus (7a ^e ),compounds bearing a substituted meta -carborane cage and a 4-hydroxyl group on the ben-zene nucleus (8a ^e )and compounds bearing a substituted meta -carborane cage and a 3-hydroxyl group on the ben-zene nucleus (9a ^e ),in the same manner as described for 2a ^2e (Fig.4).The transcriptional activity of compounds 7,8,and 9is summarized in Fig.5.The activity of the compounds bearing a para -substituent on the carborane cage and a 3-hydroxyl group on the benzene nucleus (3)was somewhat weaker than that of 2,and showed the same tendency upon insertion of methylene groups as in the series of 2.However,the potency of 1-hydroxymethyl-12-(4-hydroxyphenyl)-1,12-dicarba-closo -dodecaborane 7c was still greater than that of 17L -estradiol.The
activity
Fig.3.Transcriptional activation by the estrogen ligands bearing car-borane (2a ^g ).COS-1cells were transfected with EREx5-pGL-TK and pCl-rER K and incubated with the compounds at the indicated concen-trations (10310^1038M).Results are shown as means tS.D.for tripli-cate
transfections.
Fig.4.Designed compounds for the structure^activity study of carbo-rane-containing
estrogens.
Fig.5.Transcriptional activation by the estrogen ligands bearing car-borane (7^9).COS-1cells were transfected with EREx5-pGL-TK and pCl-rER K and incubated with the compounds at the indicated concen-trations (10310^1038M).Results are shown as means tS.D.for tripli-cate transfections.
344Chemistry &Biology 8/4(2001)341^355
of the compounds bearing a meta-substituent on the car-borane cage and a4-hydroxyl group on the benzene nu-cleus(8)was weaker than that of7.Further,the activity of the compounds bearing a meta-substituent on the carbor-ane cage and a3-hydroxyl group on the benzene nucleus (9)was greatly decreased,being similar to that of the typical estrogenic alkylphenol4-tert-octylphenol.
2.5.E?ects of the carborane-containing estrogens on uterine
atrophy and bone loss in ovariectomized mice Estrogen de￠ciency results in uterine atrophy and a marked bone loss,and these phenomena can be restored by estrogen administration[30].Using ovariectomized (OVX)mice,we compared the e?ects of17L-estradiol and2c on the uterus.The uterine weight decreased mark-edly in OVX mice,indicating that the mice were estrogen-de￠cient as shown in Fig.6.As reported previously,17L-estradiol(100ng/day)restored the decreased uterine weight in OVX mice to a level higher than that of the sham-operated https://www.doczj.com/doc/125830088.html,pound2c(100ng/day)also re-stored the uterine weight of OVX mice,and its potency was similar to that of1(Fig.6A).This indicates that2c exhibits a potent estrogenic action in the uterus in vivo. To determine the e?ects of2c on bone mass,OVX mice were treated for4weeks with100ng/day of2c and the femurs were subjected to radiographic analysis.X-ray analysis showed a marked loss of mineralized cancellous bone,especially in the distal metaphysis of the femur,in OVX mice[31].Treatment with17L-estradiol or2c at100 ng/day markedly and similarly prevented the bone loss in the distal metaphysis in OVX mice(Fig.6B).The e?ects of 2c on bone mass were determined by measuring bone min-eral density(BMD)at a distal region of the femur.BMD was signi￠cantly reduced by OVX but recovered com-pletely on the administration of100ng/day of2c to the sham level.17L-Estradiol at the same dosage also restored the BMD,as reported previously.These results suggest that2c binds to estrogen receptor(s)present in uterus and bone,and exhibits estrogen-like e?ects in both tissues.
3.Discussion
Recent studies on the three-dimensional structure of the complex formed by17L-estradiol and the human ER K li-gand-binding domain(hER K LBD)have revealed the structural requirements for the appearance of estrogenic activity[32,33].17L-Estradiol is oriented in the hER K li-gand-binding pocket by two types of contacts:hydrogen bonding at both ends and hydrophobic van der Waals contacts along the body of the skeleton.The phenolic hydroxyl group is hydrogen-bonded to the glutamate (Glu-353)of hER K LBD and the17-L-hydroxyl group is hydrogen-bonded to the N-nitrogen of His-524.Docking simulations to this structure(1ERE:Fig.7A)would be
useful to clarify the relation between the three-dimensional structures and high activity of carborane-containing estro-gens.These simulations were performed using an auto-matic docking program(ADAM;not publicly distributed, only available for collaborators on contract basis)[34].
The most potent carborane-containing estrogen2c was well-￠tted to the cavity of the X-ray structure of hER K https://www.doczj.com/doc/125830088.html,pound2c is oriented in the cavity as shown in Fig.7B by two types of contacts:hydrogen bonding at both ends and hydrophobic van der Waals contacts along the body of the skeleton,as found for 17L-estradiol(1)in the X-ray https://www.doczj.com/doc/125830088.html,pound2b
, Fig.6.E?ects of1and2c on the uterine weight and bone mineral den-sity(BMD)of femurs in OVX mice.Mice were sham-operated or OVX, and some of the OVX mice were treated with1^100ng/day of2c or 100ng/day of1immediately after the operation.Numbers in parenthe-ses are doses of the test compounds per day(ng).At4weeks after the operation,uterine weight(A)and BMD of the distal femur(B)were measured.The upper panel in B shows soft X-ray radiograms of the fe-murs collected from animals of each group.Note that marked bone loss occurred in the femoral cancellous bone in OVX mice,and that the bone loss was completely prevented by the treatment with100ng/day of 2c or1.Data are expressed as the meanstS.E.M.of6^8mice. Research Paper Estrogen agonists based on carborane Y.Endo et al.345
with a hydroxyl group directly substituted on the carbor-ane cage,and the 3-hydroxy isomer 7c were also well-￠tted
to the cavity of hER K LBD (Fig.7C,D).Table 1shows the heteroatom^heteroatom distances of compounds 2a ,2b ,2c ,3b ,7c ,8c ,and 9c in the most stable docking models,and that in the crystal structure of 1.The relation between heteroatom^heteroatom distances and biological activity
suggested that three distances within 3.2A
?seem to
be Fig.7.The structure of the complex formed by 17L -estradiol (1)(A)and hER K LBD and the most stable docking models for 2c (B),2b (C),7c (D),2a (E),and 4-(1-adamantyl)phenol (F)to the hER K LBD.The colored cage represents the allowed region for carbon and boron atoms in ligands,calcu-lated from the protein structure.Intermolecular hydrogen bonds (distance less than 3.2A
?)are shown with yellow lines.346Chemistry &Biology 8/4(2001)341^355
e?ective for hydrogen bondings.However,the interactions of the ligands to the receptor cannot be explained only in terms of hydrogen bonding,but also hydrophobic interac-tion.The lack of one hydrogen bond might be compen-sated for by an e?ective hydrophobic interaction.The hy-drophobic interaction along the spherical carborane cage seems to produce a stronger interaction than that in the case of17L-estradiol.This may be the reason for the high activity of compound2a,which lacks a hydroxyl group for hydrogen bonding to the N-nitrogen of His-524(Fig.7E). Compound2a has signi￠cant potency compared to well-known estrogenic4-alkylphenols[35],4-cycloalkylphenols [36],and4-(1-adamantyl)phenol[36](Fig.7F).Therefore, use of this new hydrophobic and spherical component,the carborane cage,for molecular drug design should make it possible to develop a wide variety of biologically active molecules,especially nuclear receptor ligands.
In summary,we have developed novel carborane-con-taining molecules with potent estrogenic activity.The unique character of biologically active molecules contain-ing a carborane skeleton may give rise to unusual mem-brane transport characteristics and metabolism,compared with conventional active molecules.The superagonistic properties of the carborane-containing compounds raise the possibility that structure^function studies could lead to the development of more selective estrogen agonists and antagonists,which could be useful as therapeutic agents for a wide variety of conditions.
4.Signi￠cance
Carboranes(dicarba-closo-dodecaboranes)are a class of carbon-containing polyhedral boron-cluster compounds having remarkable thermal stability and exceptional hy-drophobicity.These features of carboranes may allow their use as a hydrophobic pharmacophore in biologically active molecules that interact hydrophobically with recep-tors.We therefore designed candidate estrogen-receptor-binding compounds having carborane as a hydrophobic moiety(2)and synthesized them.Their estrogenic activity was examined by the luciferase reporter gene assay using COS-1cells transfected with rat ER K expression plasmid and an appropriate reporter plasmid.The most potent compound bearing a carborane cage(BE120,2c)exhibited potent activity in the concentration range of1U10310^ 1U1038M;its potency is at least10-fold greater than that of17L-estradiol.In vitro ER K-binding data for these compounds were consistent with the results of the lucifer-ase reporter gene assay.These results con￠rm that the gene-regulatory activity of the carborane-containing com-pounds is correlated with their binding a¤nity for the ER. The most active compound in the luciferase reporter gene assay,BE120,also showed the highest a¤nity for ER K. The compound also showed potent in vivo e?ects on the recovery of uterine weight and bone loss in OVX mice. Development of the potent carborane-containing estrogen-ic agonists described here should yield novel candidate therapeutic agents,especially selective ER modulators. Furthermore,the suitability of the spherical carborane cage for binding to the cavity of ER K LBD should provide a basis for a similar approach to developing novel ligands for other steroid receptors.
5.Materials and methods
5.1.Synthesis
5.1.1.1-(4-Methoxyphenyl)-1,12-dicarba-closo-dodecaborane
(4a)
To a solution of1,12-dicarba-closo-dodecaborane(3,3.5g, 24.3mmol)in1,2-dimethoxyethane(95ml)was added dropwise a1.54M solution of n-BuLi in hexane(16.6ml,25.6mmol)at 03C under Ar.The mixture was stirred at room temperature for 30min,and CuCl(3.13g,31.6mmol)was added in one portion. Stirring was continued at room temperature for1h,then pyridine (14.7ml,183mmol)was added,and4-iodoanisole(5.97g,25.5 mmol)was further added in one portion,and the mixture was heated at1003C for48h.After cooling,the reaction mixture was diluted with Et2O and stirred at room temperature for3h.In-soluble materials were￠ltered o?through Celite.The￠ltrate was washed with2N HCl,aq.Na2S2O3,H2O,and brine,dried over Na2SO4,then concentrated.Puri￠cation by silica gel column chromatography(eluent:hexane to hexane/AcOEt,10:1)gave 4a(60%)and1,12-bis(4-methoxyphenyl)-1,12-dicarba-closo-do-
Table1
Heteroatom^heteroatom distances in A?(hydrogen bond distances)in the most stable docking models
Ligand Phenolic-OH/353Glu Phenolic-OH/349Arg Alcoholic-OH/524His E inter(kcal/mol)a
1 2.59 3.36 2.57354.67
2a 2.71 3.17^345.88
2b 2.80 3.24 2.91347.76
2c 2.64 2.89 2.82351.60
7b 3.41(4.59) 3.04345.63
7c 3.14(4.08) 2.80348.00
8c 2.97 3.32(5.05)349.17
9c 3.09(3.98) 2.93345.34
a E inter:interaction energy between protein and ligand in the most stable docking models.
Research Paper Estrogen agonists based on carborane Y.Endo et al.347
decaborane(13%).4a:colorless needles(hexane):mp102^1033C; 1H NMR(CDCl3)N1.50^3.30(10H,br m),2.75(1H,br s),3.74 (3H,s),6.68(2H,d,J=9.1Hz),7.11(2H,d,J=9.1Hz); HRMS calc.for C9H18B10O250.2361,found250.2374.
5.1.2.1-(4-Hydroxyphenyl)-1,12-dicarba-closo-dodecaborane(2a) To a solution of4a(100mg,0.399mmol)in CH2Cl2(1ml) was added dropwise a1M solution of BBr3in CH2Cl2(0.48ml) at3783C.The mixture was stirred at room temperature for2h, then poured into ice water,and extracted with CH2Cl2.The or-ganic layer was washed with brine,dried over Na2SO4,and con-centrated.Puri￠cation by silica gel￡ash column chromatography (eluent:hexane/AcOEt,10:1)gave2a(93%).2a:colorless needles (CH2Cl2^hexane);mp193^1943C;1H NMR(CDCl3)N1.40^3.20 (10H,br m),2.75(1H,br s),4.73(1H,br s),
6.61(2H,d, J=9.0Hz),
7.07(2H,d,J=9.0Hz);HRMS calcd for C8H16B10O236.2204,found236.2227.Anal.calcd for C8H16B10O:C,40.66;H,6.82.Found C,40.67;H,6.79.
5.1.3.1-Hydroxy-12-(4-hydroxyphenyl)-1,12-dicarba-closo-
dodecaborane(2b)
To a solution of4a(300mg,1.20mmol)in benzene/Et2O(2:1, 3ml)was added dropwise a1.54M solution of n-BuLi in hexane (1.56ml,2.40mmol)at03C under Ar.The mixture was stirred at room temperature for30min.The solution was cooled at03C and benzyl peroxide(145mg,0.601mmol)in benzene/Et2O(2:1, 3ml)was added dropwise,then the mixture was stirred at room temperature for2h.The reaction was quenched with10%aque-ous HCl and extracted with AcOEt.The organic layer was washed with brine,dried over Na2SO4,and concentrated.Puri￠-cation by silica gel￡ash column chromatography(eluent:hexane/ AcOEt,10:1)gave4b(75%)as a colorless solid:1H NMR (CDCl3)N1.60^3.40(10H,br m),2.87(1H,s),3.73(3H,s), 6.67(2H,d,J=8.6Hz),7.12(2H,d,J=8.6Hz);HRMS calcd for C9H18B10O2266.2310,found266.2304.2b was prepared from 4b by the same method as used for the preparation of2a.Puri-￠cation by recrystallization gave2b(95%).2b:colorless needles (CH2Cl2^hexane);mp181^1833C;1H NMR(CDCl3)N1.50^3.40 (10H,br m),4.70(1H,bs),6.60(2H,d,J=8.8Hz),7.07(2H, d,J=8.8Hz);HRMS calcd for C8H16B10O2252.2153,found 252.2173.Anal.calcd for C8H16B10O2W1/2H2O:C,36.77;H, 6.56.Found C,36.42,H,6.57.
5.1.4.1-Methoxycarbonyl-12-(4-methoxyphenyl)-1,12-dicarba-
closo-dodecaborane(5)
To a solution of4a(500mg,2.00mmol)in benzene/Et2O(2:1, 15ml)was added dropwise a1.54M solution of n-BuLi in hex-ane(1.56ml,2.40mmol)at03C under Ar.The mixture was stirred at room temperature for30min and cooled to03C,then methyl chloroformate(227mg,2.40mmol)was added dropwise and stirring was continued at room temperature for3h.The reaction was quenched with water and the whole was extracted with AcOEt.The organic layer was washed with brine,dried over Na2SO4,and concentrated.Puri￠cation by silica gel￡ash column chromatography(eluent:hexane/AcOEt,50:1)gave5(91%).5: colorless prisms(hexane);mp108^1093C;1H-NMR(CDCl3)N 1.60^3.40(10H,br m),3.65(3H,s),3.74(3H,s),6.68(2H,d, J=9.1Hz),7.08(2H,d,J=9.1Hz);Anal.calcd for C11H20B10O3:C,42.84;H,6.54.Found C,42.82;H,6.29.
5.1.5.1-Hydroxymethyl-12-(4-hydroxyphenyl)-1,12-dicarba-closo-
dodecaborane(2c)
To a suspension of LiAlH4(25.8mg,0.680mmol)in THF(3 ml)was added dropwise5(150mg,0.486mmol)in THF(2ml)at 03C,and the mixture was stirred at room temperature for2.5h. The reaction was quenched with2N HCl and the whole was extracted with AcOEt.The organic layer was washed with water and brine,dried over Na2SO4,then concentrated to give1-hy-droxymethyl-12-(4-methoxyphenyl)-1,12-dicarba-closo-dodeca-borane(4c)(99%).4c:colorless prisms(CH2CH2^hexane);mp 151^1523C;1H NMR(CDCl3)N1.50^3.30(10H,br m),3.55(2 H,s),3.74(3H,s),6.68(2H,d,J=9.2Hz),7.11(2H,d,J=9.2 Hz).Anal.calcd for C10H20B10O2:C,42.84;H,7.19.Found C, 42.94;H,6.96.2c was prepared from4c by the same method as used for the preparation of2a.Puri￠cation by silica gel￡ash column chromatography(eluent:hexane/AcOEt,4:1)gave2c (100%).2c:colorless needles(CH2Cl2^hexane);mp184^1853C; 1H NMR(CDCl3)N1.50^3.30(10H,br m),3.54(2H,s),4.87(1 H,br),6.61(2H,d,J=8.9Hz),7.06(2H,d,J=8.9Hz);HRMS calcd for C9H18B10O2266.2310,found266.2310.Anal.calcd for C9H18B10O2:C,40.59;H,6.81.Found C,40.30,H,6.81.
5.1.
6.1-Hydroxyethyl-12-(4-hydroxyphenyl)-1,12-dicarba-closo-
dodecaborane(2d)
To a solution of4a(200mg,0.80mmol)in benzene/Et2O(2:1, 7.5ml)was added dropwise a1.54M solution of n-BuLi in hexane(0.623ml,0.953mmol)at03C under Ar.The mixture was stirred at room temperature for30min and cooled to03C, then O-tetrahydropyranyl-2-bromoethanol(231mg,1.20mmol) was added dropwise and stirring was continued at room temper-ature for15h.The reaction was quenched with water and the whole was extracted with AcOEt.The organic layer was washed with brine,dried over Na2SO4,and concentrated.Puri￠cation by silica gel￡ash column chromatography(eluent:hexane/CH2Cl2, 2:1)gave the C-alkylated product(45%).1H NMR(CDCl3)N 1.45^1.82(6H,m),1.50^3.20(10H,br m),1.98(2H,t,J=7.0 Hz),3.17(1H,dt,J=9.9,7.6Hz),3.45^3.51(1H,m),3.55(1H, dt,J=10.1,7.6Hz),3.73(3H,s),3.80(1H,m),4.49(1H,m), 6.67(2H,d,J=9.2Hz),7.10(2H,d,J=9.2Hz).The compound (112mg,0.296mmol)was dissolved in MeOH/CH2Cl2(3:1,4 ml),and TsOH W H2O(5.6mg,0.0294mmol)was added.The mix-ture was stirred at room temperature for15h.The reaction was quenched with saturated aqueous NaHCO3,then the mixture was extracted with CH2Cl2.The organic layer was washed with brine, dried over Na2SO4,and concentrated to give4d(100%).1H NMR(CDCl3)N1.50^3.30(10H,br m),1.95(2H,t,J=7.0 Hz),3.48(1H,t,J=7.0Hz),3.73(3H,s),6.67(2H,d,J=9.0 Hz),7.10(2H,d,J=9.0Hz).2d was prepared from4d by the same method as used for the preparation of2a.Puri￠cation by silica gel￡ash column chromatography(eluent:hexane/AcOEt, 4:1)gave2d(88%).2d:colorless needles(CH2Cl2^hexane);mp 180^1813C;1H NMR(CDCl3)N1.30(1H,t,J=5.1Hz),1.50^
348Chemistry&Biology8/4(2001)341^355
3.30(10H,br m),1.95(2H,t,J=7.0Hz),3.48(1H,dt,J=7.0, 5.1Hz),
4.75(1H,s),6.60(2H,d,J=9.0Hz),7.06(2H,d, J=9.0Hz).HRMS calcd for C10H20B10O2280.2466,found 280.2462.Anal.calcd for C10H20B10O2:C,42.84;H,7.19.Found C,42.79;H,7.46.
5.1.7.1-Hydroxyethyl-12-(4-hydroxyphenyl)-1,12-dicarba-closo-
dodecaborane(2e)
4a(750mg,3.00mmol)was converted to4e(64%)in the same manner as used for the preparation of4d.1H NMR(CDCl3)N 1.17(1H,bs),1.40^3.30(10H,br m),1.46(2H,m),1.78(2H, m),3.50(2H,m),3.73(3H,s),6.67(2H,d,J=9.0Hz),7.10(2 H,d,J=9.0Hz).2e was prepared from4e by the same method as used for the preparation of2a.Puri￠cation by silica gel￡ash column chromatography(eluent:hexane/AcOEt,4:1)gave2d (92%).2d:colorless needles(CH2Cl2^hexane);mp185^1863C; 1H NMR(CDCl3)N1.10^3.30(10H,br m),1.45(2H,m), 1.77(2H,m),3.50(2H,t,J=6.1Hz),4.70(1H,bs),6.60(2 H,d,J=9.0Hz),7.06(2H,d,J=9.0Hz).Anal.calcd for C11H22B10O2:C,44.88;H,7.53.Found C,44.58,H,7.32.
5.1.8.1-Hydroxycarbonyl-12-(4-hydroxyphenyl)-1,12-dicarba-
closo-dodecaborane(2f)
To a solution of5(260mg,0.843mmol)in THF(3ml)was added1N KOH(4.22ml),and the mixture was stirred at room temperature for17h.The reaction was quenched with2N HCl and the whole was extracted with AcOEt.The organic layer was washed with water and brine,dried over Na2SO4,then concen-trated to give1-hydroxycarbonyl-12-(4-methoxyphenyl)-1,12-di-carba-closo-dodecaborane(4f)(quant.).1H NMR(DMSO-d6)N 1.60^3.40(10H,br m),3.69(3H,s),6.78(2H,d,J=9.1Hz), 7.08(2H,d,J=9.1Hz),14.06(1H,br).2f was prepared from4f by the same method as used for the preparation of2b(quant.). 2f:colorless needles(AcOEt^CH2Cl2^hexane);mp249^2523C; 1H NMR(DMSO-d6)N1.60^3.40(10H,br m),6.57(2H,d, J=8.8Hz),6.94(2H,d,J=8.8Hz),9.58(1H,s),14.04(1H, br);HRMS calcd for C9H16B10O3280.2102,found280.2114. Anal.calcd for C9H16B10O3:C,38.56;H, 5.75.Found C, 38.39,H,5.82.
5.1.9.1-tert-Butoxycarbonylamino-12-(4-methoxyphenyl)-1,12-
dicarba-closo-dodecaborane(6)
A mixture of4f(140mg,0.476mmol),Et3N(144mg,1.42 mmol),4-dimethylaminopyridine(11.6mg,0.0949mmol)and diphenylphosphoryl azide(196mg,0.712mmol)in t-BuOH(8 ml)was re￡uxed for24h,then concentrated.The residue was taken up in AcOEt,washed with water and brine,dried over Na2SO4,then concentrated.Puri￠cation by silica gel￡ash column chromatography(eluent:hexane/AcOEt,20:1)gave6(41%).6: colorless needles(hexane);mp148^1493C;1H NMR(CDCl3)N 1.39(9H,s),1.60^3.40(10H,br m),3.73(3H,s),4.89(1H,s), 6.67(2H,d,J=9.0Hz),7.11(2H,d,J=9.0
Hz).
Fig.8.Synthetic route used for the preparation of the estrogen ligands bearing carborane(7).Key:(a)(1)n-BuLi,CuCl/DME,(2)m-iodoanisole/pyri-dine,re￡ux;(b)BBr3/CH2Cl2;(c)(1)n-BuLi/benzene^Et2O,(2)ClCOOCH3;(d)LiAlH4/THF;(e)(1)n-BuLi/benzene^Et2O,(2)(C6H5COO)2/benzene^ Et2O;(f)n-BuLi/benzene^Et2O,(2)Br(CH2)n OTHP;(g)p-TsOH W H2O/MeOH.
Research Paper Estrogen agonists based on carborane Y.Endo et al.349
5.1.10.1-Amino-12-(4-hydroxyphenyl)-1,12-dicarba-closo-
dodecaborane(2g)
To a solution of6(62mg,0.170mmol)in CH2Cl2(2ml)was added TFA(0.4ml),and the mixture was stirred at room temper-ature for2.5h.The reaction was quenched with saturated aque-ous NaHCO3and the whole was extracted with CH2Cl2.The organic layer was washed with brine,dried over Na2SO4,then concentrated to give1-amino-12-(4-methoxyphenyl)-1,12-dicarba-closo-dodecaborane(100%)as colorless needles(CH2Cl2^hexane). mp155^1563C;1H NMR(CDCl3)N1.50^3.30(10H,br m),3.73 (3H,s),6.67(2H,d,J=9.0Hz),7.11(2H,d,J=9.0Hz).2g was prepared from the amine by the same method as used for the preparation of2a.The reaction mixture was poured into cold saturated aqueous NaHCO3and extracted with AcOEt.The or-ganic layer was washed with brine,dried over Na2SO4and con-centrated.Puri￠cation by silica gel￡ash column chromatography (eluent:hexane/AcOEt,5:1)gave2g(100%).2g:colorless needles (CH2Cl2^hexane);mp169^1713C;1H NMR(CDCl3)N1.50^3.30 (10H,br m),2.05(2H,br s),4.81(1H,s),6.59(2H,d,J=9.0 Hz),7.06(2H,d,J=9.0Hz);HRMS calcd for C8H17B10NO 251.2313,found251.2299.Anal.calcd for C8H17B10NO:C, 36.91;H,6.97;N,5.38.Found C,37.20;H,6.90;N,5.28. 5.1.11.1-(3-Methoxyphenyl)-1,12-dicarba-closo-dodecaborane
(10a)
Compound10a was prepared from1,12-dicarba-closo-dodeca-borane(3)and3-iodoanisole by the same method as used for preparation of4a(Fig.8).Puri￠cation by silica gel column chro-matography(eluent:hexane/AcOEt,100:1to10:1)gave10a (61%)and1,12-bis(3-methoxyphenyl)-1,12-dicarba-closo-dodeca-borane(10%).10a:colorless solid;1H NMR(CDCl3)N1.50^ 3.30(10H,br m),2.78(1H,br s),3.75(3H,s),6.73^6.76(2H, m),6.79(1H,m),7.08(1H,m).
5.1.12.1-(3-Hydroxyphenyl)-1,12-dicarba-closo-dodecaborane
(7a)
Compound7a was prepared from10a by the same method as used for preparation of2a.Puri￠cation by silica gel￡ash column chromatography(eluent:hexane/AcOEt,10:1)gave7a(100%). 7a:colorless needles(CH2Cl2^hexane);mp163^1643C;1H NMR (CDCl3)N1.50^3.30(10H,br m),2.78(1H,br s),4.67(1H,s), 6.66^6.69(2H,m),6.78(1H,m),7.03(1H,m).Anal.calcd for C8H16B10O:C,40.66;H,6.82.Found C,40.36;H,6.64.
5.1.13.1-Hydroxy-12-(3-hydroxyphenyl)-1,12-dicarba-closo-
dodecaborane(7b)
Compound10b was prepared from10a by the same method as used for preparation of4b.Puri￠cation by silica gel￡ash column chromatography(eluent:hexane/AcOEt,10:1)gave10b(65%)as colorless solid:1H NMR(CDCl3)N1.60^3.40(10H,br m),2.97 (1H,s),3.74(3H,s),6.72^6.77(2H,m),6.80(1H,ddd,J=1.0, 1.9,7.9Hz),7.07(1H,dt,J=0.9,7.9Hz).Compound7b was prepared from10b by the same method as used for preparation of 2b.Puri￠cation by silica gel￡ash column chromatography(elu-ent:hexane/AcOEt,5:1)gave7b(96%).7b:colorless needles (CH2Cl2^hexane);mp185^1863C;1H NMR(CDCl3)N1.50^3.40(10H,br m),4.70(1H,br),6.66^6.71(2H,m),6.78(1 H,br d)7.02(1H,t,J=8.0Hz).Anal.calcd for C8H16B10O2:C, 38.08;H,6.39.Found C,38.31;H,6.43.
5.1.14.1-Methoxycarbonyl-12-(3-methoxyphenyl)-1,12-dicarba-
closo-dodecaborane(11)
Compound11was prepared from10a by the same method as used for preparation of5.Puri￠cation by silica gel￡ash column chromatography(eluent:hexane/AcOEt,20:1)gave11(87%)as colorless solid:1H NMR(CDCl3)N1.60^3.50(10H,br m),3.65 (3H,s),3.75(3H,s),6.71^6.78(3H,m).
5.1.15.1-Hydroxymethyl-12-(3-hydroxyphenyl)-1,12-dicarba-
closo-dodecaborane(7c)
Compound7c was prepared from11by the same method as used for preparation of2c.Puri￠cation by silica gel￡ash column chromatography(eluent:hexane/AcOEt,4:1)gave7c(100%).7c: colorless needles(CH2Cl2^hexane);mp134^1353C;1H NMR (CDCl3)N1.50^3.30(10H,br m),1.58(1H,t,J=7.3Hz), 3.55(2H,d,J=7.3Hz),4.70(1H,s),6.67^6.69(2H,m), 6.77(1H,m),7.03(1H,m).Anal.calcd for C9H18B10O2:C, 40.59;H,6.81.Found C,40.35;H,6.51.
5.1.1
6.1-Hydroxyethyl-7-(3-hydroxyphenyl)-1,12-dicarba-
closo-dodecaborane(7d)
Compound10d was prepared from10a by the same method as used for preparation of4d(66%).10d:colorless solid;1H NMR (CDCl3)N1.28(1H,t,J=5.6Hz),1.50^3.30(10H,br m),1.95 (2H,t,J=7.0Hz),3.48(2H,dt,J=5.6,7.0Hz),3.74(3H,s), 6.73^6.79(3H,m),7.07(1H,m).Compound7d was prepared from10d by the same method as used for preparation of2d. Puri￠cation by silica gel￡ash column chromatography(eluent: hexane/AcOEt,3:1)gave7d(92%).7d:colorless needles (CH2Cl2);mp186^1873C;1H NMR(CDCl3)N1.30(1H,t, J=4.9Hz),1.50^3.30(10H,br m),1.95(2H,t,J=7.0Hz) 3.48(2H,dt,J=4.9,7.0Hz),4.74(1H,s),6.65^6.69(2H, m),6.76(1H,m),7.02(1H,m);HRMS calcd for C10H20B10O2 280.2466;found280.2466.Anal.calcd for C10H20B10O2W0.12O: C,42.56;H,7.21.Found C,42.39;H,6.95.
5.1.17.1-Hydroxypropyl-12-(3-hydroxyphenyl)-1,12-dicarba-
closo-dodecaborane(7e)
Compound10e was prepared from10a by the same method as used for preparation of4e(69%).10e:colorless solid;1H NMR (CDCl3)N1.14(1H,t,J=5.2Hz),1.40^3.30(10H,br m),1.45 (2H,m),1.78(2H,m),3.50(2H,dt,J=5.2,6.1Hz),3.74 (3H,s),6.72^6.80(3H,m),7.07(1H,m).Compound7e was prepared from10e by the same method as used for pre-paration of2e.Puri￠cation by silica gel￡ash column chro-matography(eluent:hexane/AcOEt,3:1)gave2e(99%).2e: colorless needles(CH2Cl2);mp211^2123C;1H NMR(DMSO-d6)N1.25(2H,m),1.40^3.20(10H,br m),1.73(2H,m)3.23 (2H,dt,J=5.1,5.7Hz),4.39(1H,t,J=5.1Hz),6.57^6.59 (2H,m),6.64(1H,m),7.01(1H,m),9.54(1H,s).Anal. calcd for C11H22B10O2:C,44.88;H,7.53.Found C,44.64;H, 7.24.
350Chemistry&Biology8/4(2001)341^355
5.1.18.1-(4-Methoxyphenyl)-1,7-dicarba-closo-dodecaborane
(13a)
To a solution of1,7-dicarba-closo-dodecaborane(12,3.5g, 24.3mmol)in1,2-dimethoxyethane(95ml)was added dropwise a1.54M solution of n-BuLi in hexane(16.6ml,25.6mmol)at 03C under Ar(Fig.9).The mixture was stirred at room temper-ature for30min,then CuCl(3.13g,31.6mmol)was added in one portion and stirring was continued at room temperature for1h. Pyridine(14.7ml,183mmol)was added,then4-iodoanisole(5.97 g,25.5mmol)was further added in one portion,and the mixture was heated at1003C for48h.After cooling,the reaction mixture was diluted with Et2O and stirred at room temperature for15h. Insoluble materials were￠ltered o?through Celite.The￠ltrate was washed with2N HCl,aq.Na2S2O3,H2O and brine,dried over Na2SO4,then concentrated.Puri￠cation by silica gel column chromatography(eluent:hexane to hexane/AcOEt,30:1)gave 13a(42%)and1,7-bis(4-methoxyphenyl)-1,7-dicarba-closo-dodec-aborane(17%).13a:colorless needles(hexane);mp100^1013C; 1H NMR(CDCl3)N1.50^3.70(10H,br m),3.04(1H,br s),3.77 (3H,s),6.76(2H,d,J=9.2Hz),7.33(2H,d,J=9.2Hz); HRMS calcd for C9H18B10O250.2361,found250.2361.
5.1.19.1-(4-Hydroxyphenyl)-1,7-dicarba-closo-dodecaborane(8a) Compound8a was synthesized from13a by the same method as used for preparation of2a.Puri￠cation by silica gel￡ash column chromatography(eluent:hexane/AcOEt,10:1)gave8a.8a:colorless needles(CH2Cl2^hexane);mp180^1813C;1H NMR (CDCl3)N1.50^3.70(10H,br m),3.04(1H,br s),4.81(1H,s),
6.69(2H,d,J=8.9Hz),
7.28(2H,d,J=
8.9Hz);HRMS calcd for C8H16B10O236.2204,found236.2206.Anal.calcd for C8H16B10O:C,40.66;H,6.82.Found:C,40.52;H,6.68.
5.1.20.1-Hydroxy-7-(4-hydroxyphenyl)-1,7-dicarba-closo-
dodecaborane(8b)
Compound13b was prepared from13a by the same method as used for preparation of4b.Puri￠cation by silica gel￡ash column chromatography(eluent:hexane/CH2Cl2,1:1)gave13b(41%)as colorless solid:1H NMR(CDCl3)N1.40^4.10(10H,br m),3.31 (1H,s),3.78(3H,s),6.76(2H,d,J=8.9Hz),7.32(2H,d, J=8.9Hz);HRMS calcd for C9H18B10O2266.2310,found https://www.doczj.com/doc/125830088.html,pound8b was prepared from13b by the same method as used for preparation of2b.Puri￠cation by silica gel ￡ash column chromatography(eluent:hexane/AcOEt,3:1)gave 8b(93%).8b:colorless needles(CH2Cl2^hexane);mp168^1693C 1H NMR(CDCl3)N1.40^4.00(10H,br m),4.80(1H,br),6.70 (2H,d,J=9.0Hz),7.28(2H,d,J=9.0Hz).Anal.calcd for C8H16B10O2:C,38.08;H,6.39.Found C,37.84;H,6.30.
5.1.21.1-Methoxycarbonyl-7-(4-methoxyphenyl)-1,7-dicarba-
closo-dodecaborane(14)
Compound14was prepared from13a by the same method as used for preparation of5.Puri￠cation by silica gel￡ash
column Fig.9.Synthetic route used for the preparation of the estrogen ligands bearing carborane(8).Key:(a)(1)n-BuLi,CuCl/DME,(2)p-iodoanisole/pyri-dine,re￡ux;(b)BBr3/CH2Cl2;(c)(1)n-BuLi/benzene^Et2O,(2)ClCOOCH3;(d)LiAlH4/THF;(e)(1)n-BuLi/benzene^Et2O,(2)(C6H5COO)2/benzene^ Et2O;(f)(1)n-BuLi/benzene^Et2O,(2)Br(CH2)n OTHP;(g)p-TsOH W H2O/MeOH.
Research Paper Estrogen agonists based on carborane Y.Endo et al.351
chromatography(eluent:hexane/AcOEt,20:1)gave14(82%). 14:colorless needles(hexane);mp47^483C;1H NMR(CDCl3) N1.50^3.70(10H,br m),3.76(3H,s),3.78(3H,s),6.77(2H,d, J=9.2Hz),7.33(2H,d,J=9.2Hz);HRMS calcd for C11H26B10O3308.2416,found308.2428.
5.1.22.1-Hydroxymethyl-7-(4-hydroxyphenyl)-1,7-dicarba-closo-
dodecaborane(8c)
Compound8c was prepared from14by the same method as used for preparation of2c.Puri￠cation by silica gel￡ash column chromatography(eluent:hexane/AcOEt,3:1)gave8c(79%).8c: colorless needles(CH2Cl2^hexane);mp173^1743C;1H NMR (CDCl3)N1.50^3.80(10H,br m),1.86(1H,br s),3.87(2H, s),4.83(1H,s),6.69(2H,d,J=8.9Hz),7.28(2H,d,J=8.9 Hz);HRMS calcd for C9H18B10O2266.2310,found266.2303. Anal.calcd for C9H18B10O2:C,40.59;H, 6.81.Found C, 40.57;H,6.88.
5.1.23.1-Hydroxyethyl-7-(4-hydroxyphenyl)-1,7-dicarba-closo-
dodecaborane(8d)
Compound13d was prepared from13a by the same method as used for preparation of4d(63%).13d:colorless solid;1H NMR (CDCl3)N1.20^3.30(10H,br m),2.28(2H,t,J=6.9Hz),3.67 (2H,t,J=6.9Hz),3.78(3H,s),6.76(2H,d,J=9.0Hz),7.32(2 H,d,J=9.0Hz).Compound8d was prepared from13d by the same method as used for preparation of2d.Puri￠cation by silica gel￡ash column chromatography(eluent:hexane/AcOEt,2:1) gave8d(90%).8d:colorless needles(CH2Cl2^hexane);mp156^ 1573C;1H NMR(CDCl3)N1.50^3.50(10H,br m),2.28(2H,t, J=6.9Hz),3.67(2H,t,J=6.9,Hz),4.79(1H,s),6.69(2H,d, J=8.9Hz),7.28(2H,d,J=8.9Hz);HRMS calcd for C10H20B10O2280.2466,found:280.2470.Anal.calcd for C10H20B10O2:C,42.84;H,7.19.Found C,42.53;H,6.75.
5.1.24.1-Hydroxypropyl-7-(4-hydroxyphenyl)-1,7-dicarba-closo-
dodecaborane(8e)
Compound13e was prepared from13a by the same method as used for preparation of4e(84%).13e:colorless solid;1H NMR (CDCl3)N1.20^3.40(10H,br m),1.25(1H,br s),1.67(2H,m), 2.12(2H,m),3.60(2H,t,J=6.1Hz),3.78(3H,s),6.75(2H,d, J=9.0Hz),7.32(2H,d,J=9.0Hz).Compound8e was prepared from13e by the same method as used for preparation of2e. Puri￠cation by silica gel￡ash column chromatography(eluent: hexane/AcOEt,2:1)gave8e(82%).8e:colorless needles (CH2Cl2^hexane);mp157^1583C;1H NMR(CDCl3)N1.23(1 H,t,J=5.1Hz),1.40^3.80(10H,br m),1.67(2H,m),2.11(2H, m)3.60(2H,dt,J=5.1,5.3Hz),4.81(1H,s),6.68(2H,d, J=8.9Hz),7.28(2H,d,J=8.9Hz).Anal.calcd for C11H22B10O2:C,44.88;H,7.53.Found C,44.61;H,7.24.
5.1.25.1-(3-Methoxyphenyl)-1,7-dicarba-closo-dodecaborane
(15a)
Compound15a was prepared from1,7-dicarba-closo-dodeca-borane(12)and3-iodoanisole by the same method as used for preparation of13a(Fig.10).Puri￠cation by silica gel column chromatography(eluent:hexane/AcOEt,100:1to50:1)gave 15a(39%)and1,7-bis(3-methoxyphenyl)-1,7-dicarba-closo-dodec-aborane(14%).15a:colorless solid;1H NMR(CDCl3)N1.50^ 3.70(10H,br m),3.05(1H,br s),3.79(3H,s),6.82(1H,dd, J=2.4,8.2Hz),6.96(1H,t,J=2.4Hz),7.01(1H,br d,J=8.2 Hz),7.16(1H,t,J=8.2Hz).
5.1.2
6.1-(3-Hydroxyphenyl)-1,7-dicarba-closo-dodecaborane(9a) Compound9a was synthesized from15a by the same method as used for preparation of2a.Puri￠cation by silica gel￡ash column chromatography(eluent:hexane/AcOEt,5:1)gave9a (100%).9a:colorless needles(CH2Cl2^hexane);mp140^1413C; 1H NMR(CDCl3)N1.40^3.80(10H,br m),3.05(1H,br s), 4.70(1H,s),6.75(1H,dd,J=2.4,8.1Hz),6.90(1H,t,J=2.4 Hz),6.99(1H,br d,J=8.1Hz),
7.11(1H,t,J=
8.1Hz).Anal. calcd for C8H16B10O:C,40.66;H,6.82.Found C,40.48;H, 6.56.
5.1.27.1-Hydroxy-7-(3-hydroxyphenyl)-1,12-dicarba-closo-
dodecaborane(9b)
Compound15b was prepared from15a by the same method as used for preparation of4b.Puri￠cation by silica gel￡ash column chromatography(eluent:hexane/CH2Cl2,1:1)gave15b(44%)as colorless solid:1H NMR(CDCl3)N1.60^4.00(10H,br m),3.30 (1H,s),3.79(3H,s),6.83(1H,dd,J=2.2,8.1Hz),6.95(1H,t, J=2.2Hz),7.00(1H,m),7.17(1H,t,J=8.1Hz).Compound9b was prepared from15b by the same method as used for prepara-tion of2b.Puri￠cation by silica gel￡ash column chromatography (eluent:hexane/AcOEt,3:1)gave9b(100%).9b:colorless needles (CH2Cl2^hexane);mp135^1363C;1H NMR(CDCl3)N1.40^4.00 (10H,br m),4.70(1H,br),6.76(1H,ddd,J=1.0,2.5,8.1Hz), 6.89(1H,t,J=2.5Hz),6.99(1H,ddd,J=1.0,2.5,8.1Hz),7.12 (1H,t,J=8.1Hz).Anal.calcd for C8H16B10O2:C,38.08;H, 6.39.Found C,37.79;H,6.37.
5.1.28.1-Methoxycarbonyl-7-(3-methoxyphenyl)-1,7-dicarba-
closo-dodecaborane(16)
Compound16was prepared from15a by the same method as used for preparation of5.Puri￠cation by silica gel￡ash column chromatography(eluent:hexane/AcOEt,20:1)gave16(76%)as colorless solid:1H NMR(CDCl3)N1.50^3.70(10H,br m),3.77 (3H,s),3.79(3H,s),6.84(1H,dd,J=2.4,8.2Hz),6.96(1H,t, J=2.4Hz),7.01(1H,br d,J=8.2Hz),7.17(1H,t,J=8.2Hz).
5.1.29.1-Hydroxymethyl-7-(3-hydroxyphenyl)-1,7-dicarba-closo-
dodecaborane(9c)
Compound9c was prepared from16by the same method as used for preparation of2c.Puri￠cation by silica gel￡ash column chromatography(eluent:hexane/AcOEt,3:1)gave9c(91%).9c: colorless needles(CH2Cl2^hexane);mp140^1413C;1H NMR (CDCl3)N1.50^3.80(10H,br m),1.91(1H,t,J=7.2Hz), 3.87(2H,d,J=7.2Hz),4.90(1H,s),6.76(1H,ddd,J=0.9, 2.2,8.0Hz),6.91(1H,t,J=2.2Hz),6.99(1H,ddd,J=0.9,2.2, 8.0Hz),7.11(1H,t,J=8.0Hz).Anal.calcd for C9H18B10O2:C, 40.59;H,6.81.Found C,40.33;H,6.81.
352Chemistry&Biology8/4(2001)341^355
5.1.30.1-Hydroxyethyl-7-(3-hydroxyphenyl)-1,7-dicarba-closo-dodecaborane (9d )
Compound 15d was prepared from 15a by the same method as used for preparation of 4d (52%).15d :colorless solid;1H NMR (CDCl 3)N 1.40(1H,t,J =5.4Hz),1.50^3.60(10H,br m),2.28(2H,t,J =6.9Hz),3.67(2H,dt,J =5.4,6.9Hz),3.79(3H,s),6.82(1H,dd,J =2.2,8.1Hz),6.95(1H,s),7.00(1H,br d,J =8.1Hz),7.16(1H,t,J =8.1Hz).Compound 9d was prepared from 15d by the same method as used for preparation of 2d .Puri￠cation by silica gel ￡ash column chromatography (eluent:hexane/AcOEt,3:1)gave 15d (100%).15d :colorless needles (CH 2Cl 2^hexane);mp 126^1273C;1H NMR (CDCl 3)N 1.42(1H,t,J =5.5Hz),1.30^3.60(10H,br m),2.28(2H,t,J =6.5Hz)3.68(2H,dt,J =5.5,6.5Hz),4.84(1H,s),6.75(1H,ddd,J =0.9,2.1,7.9Hz),6.89(1H,t,J =2.1Hz),6.98(1H,ddd,J =0.9,2.1,7.9Hz),7.11(1H,t,J =7.9Hz).Anal.calcd for C 10H 20B 10O 2:C,42.84;H,7.19.Found C,42.65;H,6.90.5.1.31.1-Hydroxypropyl-7-(3-hydroxyphenyl)-1,7-dicarba-closo-dodecaborane (9e )
Compound 15e was prepared from 15a by the same method as used for preparation of 4e (84%).15e :colorless solid;1H NMR (CDCl 3)N 1.24(1H,t,J =5.0Hz),1.50^3.50(10H,br m),1.67(2H,m),2.11(2H,m),3.60(2H,dt,J =5.0,6.0Hz),3.79(3H,s),6.82(1H,dd,J =2.4,8.2Hz),6.96(1H,t,J =2.4H),7.00(1H,br d,J =8.2Hz),7.16(1H,t,J =8.2Hz).Compound 9e was
prepared from 15e by the same method as used for preparation of 2e .Puri￠cation by silica gel ￡ash column chromatography (elu-ent:hexane/AcOEt,3:1)gave 9e (90%).9b :colorless needles (CH 2Cl 2^hexane);mp 106^1073C;1H NMR (CDCl 3)N 1.26(1H,t,J =5.1Hz),1.50^3.70(10H,br m),1.67(2H,m),2.11(2H,m),3.60(2H,dt,J =5.1,5.6Hz),4.87(1H,s),6.75(1H,ddd,J =0.7,2.1,8.1Hz),6.90(1H,t,J =2.1Hz),6.98(1H,ddd,J =0.7,2.1,8.1Hz),7.11(1H,t,J =8.1Hz).Anal.calcd for C 11H 22B 10O 2:C,44.88;H,7.53.Found C,44.58;H,7.35.5.2.Transfection and luciferase assays
The ER expression plasmid,pCI-rER K ,was constructed by inserting the rat uterus ER cDNA (pUCER6,which was obtained from the Health Science Research Resources Bank,Osaka,Ja-pan)into the expression vector pCI-neo (Promega).The reporter plasmid,EREx5-pGL-TK,was constructed by introducing ￠ve copies of the estrogen response element (ERE),caAGGTCAcccT-GACCTcc,and the herpes simplex virus thymidine kinase pro-moter into the Nhe I^Hin dIII sites of the pGL3-Basic luciferase reporter vector (Promega).The COS-1cells were obtained from the Japanese Cancer Research Resources Bank (JCRB)and were maintained in Dulbecco's modi￠ed essential medium (DMEM),supplemented with 5%fetal bovine serum (FBS).For the reporter gene assay,COS-1cells were seeded in 24-well tissue culture plates at 6U 104cells per well with 5%charcoal-stripped
FBS/
Fig.10.Synthetic route used for the preparation of the estrogen ligands bearing carborane (9).Key:(a)(1)n -BuLi,CuCl/DME,(2)m -iodoanisole/pyri-dine,re￡ux;(b)BBr 3/CH 2Cl 2;(c)(1)n -BuLi/benzene^Et 2O,(2)ClCOOCH 3;(d)LiAlH 4/THF;(e)(1)n -BuLi/benzene^Et 2O,(2)(C 6H 5COO)2/benzene^Et 2O;(f)(1)n -BuLi/benzene^Et 2O,(2)Br(CH 2)n OTHP;(g)p -TsOH W H 2O/MeOH.
Research Paper Estrogen agonists based on carborane Y.Endo et al.353
DMEM without phenol red.The cells were cultured at373C in 5%CO2overnight and allowed to attach to the plates.Then,the medium was removed and the transfection was performed with the cationic lipid transfection reagent Tfx-20(Promega).Lipo-somes were formed by incubating100ng of pCI-rER K,50ng of EREx5-pGL-TK,and100ng of the reference plasmid pCMV L (Clontech)with0.75W l of Tfx-20in phenol red-free DMEM (￠nal200W l)for10^15min at room temperature.These DNA/ Tfx-20mixtures were added to the cells and the culture plates were returned to the CO2incubator.After2h,800W l of DMEM supplemented with charcoal-stripped FBS(￠nal0.5%)and5W l of ethanol solution of ligands were added.After an additional18h of incubation,the cells were harvested,and the luciferase assay was performed with the Luciferase Assay System(Promega).The luciferase activities were normalized to L-galactosidase activities. Each condition was assayed in triplicate.
5.3.ER K ligand-binding assays
The ligand-binding activity of ER K was determined by the nitrocellulose￠lter binding assay method.ER K(0.5W g/tube,Pan-Vera Co.Ltd.)was diluted with a binding assay bu?er(20mM Tris^HCl pH8.0,0.3M NaCl,1mM EDTA pH8.0,10mM 2-mercaptoethanol,0.2mM phenylmethylsulfonyl￡uoride)and incubated with4nM[6,7-3H]17L-estradiol in the presence or absence of an unlabeled competitor at43C for16h.The incuba-tion mixture was absorbed by suction onto a nitrocellulose mem-brane that had been soaked in binding assay bu?er.The mem-brane was washed twice with bu?er(20mM Tris^HCl pH8.0,0.3 M NaCl)and then with25%ethanol in distilled water.Radio-activity that remained on the membrane was measured in Atom-light(NEN)using a liquid scintillation counter.
5.4.Animal studies
Eight-week-old female mice of the ddy strain were obtained from Japan SLC Inc.(Shizuoka,Japan).Mice were either sham-operated or OVX,and some of the OVX mice were sub-cutaneously administered either1^100ng/day of2c or100ng/day of17L-estradiol(1)dissolved in polyethyleneglycol300using a miniosmotic pump(Alza Co.),immediately after the surgery.At 4weeks after the surgery,the mice were killed and the weight of the uterus was measured,and the right and left femurs were removed to measure BMD.
5.5.Radiographic analysis of the femur
Radiographic photographs of the femurs were taken with soft X-rays(model CMB-2,SOFTEX).The BMD of the femurs was measured by dual X-ray absorptiometry(model DCS-600R,Alo-ka).The bone mineral content(BMC)of the mouse femur was correlated closely with the ash weight.BMD was calculated by dividing BMC of the measured area by the area.The scanned area was divided into three parts:proximal femur,midshaft,and distal femur.5.6.Docking simulation
The most stable docking models for all compounds were esti-mated using the automatic docking program ADAM version4.11 [34].Energy minimization of the docking models was done by the SANDER module of the AMBER5program package.Energy decomposition analyses of the￠nal docking models were done by the ANAL module of AMBER5[37].The structure of the hu-man ER K LBD was obtained from the crystal structure of the ER K LBD complex(PDB code1ERE A-chain)by removing the 17L-estradiol molecule.All hydrogen atoms that are missing in the crystal structure but should exist in the protein structure were computationally located at appropriate positions and optimized further by the AMBER program.
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Research Paper Estrogen agonists based on carborane Y.Endo et al.355
标准文献综述格式及范文 标准文献综述格式及范文一、文献综述的基本要求1. 毕业论文（设计）文献综述是指学生在毕业论文（设计）研究课题或研究题目（初步）确定后，通过搜集、整理、阅读国内外相关学术文献资料，就与该课题或题目直接相关的主要研究成果、学术意义、研究方法、研究动态、最新进展等问题进行归纳总结、综合分析后所做的简要评述。2. 毕业论文（设计）文献综述所评述的学术文献必须与学生所撰写论文保持大体上的一致，必须对可能影响所撰写论文主要论点、政策建议或反驳依据等主要学术结论的相关文献及其主要论断做出清晰、准确、流畅的说明，必须保证综述本身结构的完整性，能够反映学生的利用学术文献的综合能力。3. 毕业论文（设计）文献综述是学生撰写毕业论文（设计）过程的有机组成部分，必须在论文指导教师的指导下完成；文献综述必须按学校要求的基本规范撰写；论文类题目提交3000字左右的文献综述，设计类题目提交2000字左右的设计方案报告；文献综述的成绩综合纳入学生毕业论文（设计）成绩之中，未完成毕业论文（设计）文献综述的学生不得参加毕业论文（设计）答辩。文献综述是针对某一研究领域或专题搜集大量文献资料的基础上，就国内外在该领域或专题的主要研究成果、最新进展、研究动态、前沿问题等进行综合分析而写成的、能比较全面的反映相关领域或专题历史背景、前人工作、争论焦点、研究现状和发展前景等内容的综述性文章。“综”是要求对文献资料进行综合分析、归纳整理，使材料更精练明确、更有逻辑层次；“述”就是要求对综合整理后的文献进行比较专门的、全面的、深入的、系统的评述。1. 毕业论文（设计）文献综述是一篇相对独立的综述性学术报告，应该包括题目、前言、正文、总结等几个部分。题目：一般应采用《×××研究的文献综述》作为标题，经指导教师批准以所研究题目或主要论题加“文献综述”的方式作为标题。前言：点明毕业论文（设计）的论题、学术意义以及其与所阅读文献的关系，简要说明文献收集的目的、重点、时空范围、文献种类、核心刊物等方面的内容。正文：无固定格式，可以按文献的时空顺序，层次顺序，毕业论文（设计）的论点顺序等展开，总之要根据毕业论文（设计）的具体情况撰写，对毕业论文（设计）所采用的全部参考文献分类、归纳、分析、比较、评述，应特别注意对主流、权威文献学术成果的引用和评述，注意发现已有成果的不足。结论：对全文的评述做出简明扼要的总结，重点说明对毕业论文（设计）具有启示、借鉴或作为毕业论文（设计）重要论述依据的相关文献已有成果的学术意义、应用价值和不足，提出自己的研究目标。2. 文献综述所评述的文献应与毕业论文（设计）的论题相关，与毕业论文（设计）的参考文献数量一致，原则上不少于15篇，并且要有外文文献；重要论点、论据不得以教材、非学术性文献、未发表文献作为参考文献；一般不得以第二手资料作为参考文献。3. 文献综述中所涉及的文献如果在毕业论文（设计）参考文献中已有详细、清楚的说明，只需说明文献的作者和名称，在参考文献中无法说明的与文献的采用有直接关联的问题，如版本问题，翻译问题等，应在文献综述中加以说明。引用文献要加以标注。4. 文献综述的字体、字号、序号等应与毕业论文（设计）完全一致，引用图表、公式等资料的方式也应与毕业论文（设计）保持一致。1. 文献综述应始于选题，要根据指导教师的要求进行撰写，原则上要在毕业论文（设计）正式开题之前完成。2. 文献综述与毕业论文（设计）同为学生毕业资格审核的基本文献，为保存文档，学生应同时提供纸介和电子文档。摘要：民俗文化本身就带有稳定及和谐的特质，一直是维持社会和谐的不可缺少的因素，在建设和谐社会的过程中同样可以发挥更重要的作用。为此，对民俗文化的开发研究也成为我们急需努力探索的课题。现阶段，我们更应继承、保护和开发利用好我国的民俗文化资源，使之丰富和发展我国的文化建设。而针对当前我国民俗文化在发展过程中存在的诸如保护力度不够、保护方式不完善、开发方式不合理以及民俗精神淡化等一系列的问题，本文结合各家观点对我国的民俗文化开发研究进行了大量详实的文献综述。关键词：民俗文化；现状；保护；继承；科学开发Overview on our state folk cultural developmentAbstract：Folk custom culture
一、进入全文库 直接输入网址 二、检索方法 用户可以通过检索和浏览两条途径获取论文。 （一）检索途径 1.简单检索 (Simple Search) 单击页面左侧的“Search” 按钮，进入简单检索界面。 简单检索界面分为上下两个区，即检索策略输入区和检索结果的限定区。检索策略可在输入区中选择“Search in any field（所有字段）"、“Search in title only（文章标题）”、“Search in abstract field（文摘）”、“Author`s Name（作者）”、“Journal Title（期刊名）”等字段输入，再利用限定区，限定检索结果的出版时间、命中结果数及排序方式，而后点击“Search the Collections”按钮，开始检索。 检索结果有两类信息。一类是期刊题名，在题名下有该刊目次页（table of contents）的超链接和搜寻相关文件按钮；另一类是期刊论文题录，排在靠后的部分，显示论文标题、出处、作者、相关性排序分（“Score”）和搜寻相关文件按钮，通过搜寻相关文件按钮可检索到与该文内容类似的文章。 单击期刊题名下的“table of contents”按钮，可浏览目次信息；单击论文题录下的“Abstract”，按钮，可浏览该文章的标题、作者、作者单位、关键词、文摘等进一步信息；单击Article Full Text PDF ”按钮，即可看到论文全文（PDF格式）。 说明： 系统默认各检索字段间为“AND（与）”的关系。系统默认的显示结果数为50个，且按相关性排列，用户也可以自选。 作者姓名的输入方法为：姓，名例：Smith m。 在论文的文摘页下方，有一个“Get Citation Export”按钮，输出的数据主要供图书馆员参考。 2．高级检索（Expanded Search） 如果需要进行更详细的检索，在简单检索的界面或检索结果的界面中，点击左侧的“Expanded” 或“Expanded search Form”进入高级检索界面。 高级检索除增加了“ISSN（国际标准刊号）”、“PII（Published Item Identifier，出版物识别码）”、“Search in author keywords（作者关键词）”、“Search in text only（正文检索）”等检索字段外，还增加了学科分类、文章类型、语种等限定条件，可进行更精确的检索。 说明：“正文检索”字段指的是在正文中检索而不是在参考文献中进行检索。 论文类型（article type）的限定中，“Article”表示只显示论文；“Contents”表示只显示期刊题名；“Miscellaneous”表示只显示其他题材的论文。 3．检索式的构成： 在同一检索字段中，可以用布尔逻辑算符AND（与）、OR（或）、NOT（非）来确定检索词之间的关系。系统默认各检索词之间的逻辑算符为“AND”。
中小企业品牌战略研究综述 摘要：随着经济的发展,现代企业竞争已经不再单纯是规模与价格的竞争。如今的市场已经进入了品牌竞争时代,品牌在现代市场的营销和竞争中发挥着越来越重要的作用。品牌作为一种特殊的无形资产,甚至比有形资产的价值更高。本文对品牌、品牌战略的定义分类进行一些研究。 关键词：品牌、品牌战略 一、引言 1、品牌的起源、定义 品牌(BRAND)，来源于英文的本意是“烙印”的意思，是自然经济时代放牧主给自己的牲口打上的财产归属标记，以区分与他人的财物。现代品牌是19世纪资本主义制度确立之后出现的。资本主义经济的发展，生产规模的扩大，商品贸易的增长，需要一种能普遍用来辨认商品的标记，即需要在商品的自然名称之外起个名字，品牌由此广泛流行。现代品牌与早期品牌标记最重要的区别在于:它己不是一种单纯的品牌标记，而成为一种可以转让买卖的工业产权，是受到法律保护的无形财产。品牌作为无形资产与其他财产一样受法律保护。 “整合营销传播”之父唐舒尔兹在其《唐舒尔兹论品牌》一书中表述道“品牌是为买卖双方所识别并能够为双方带来价值的东西。”在唐舒尔兹的营销世界里“品牌”不过是所有者赖以赚钱的一种方式, 它可以是一种产品、一种服务、一件东西、一个观念、一个过程、一个国家、一个组织或者几乎任何东西。 美国著名品牌专家大卫阿诺德认为：“品牌就是一种类似成见的偏见。”“成功的品牌是长期、持续地建立产品定位及个性的成果, 消费者对它有较高的认同。一旦成为成功的品牌, 市场领导地位及高利润自然就会随之而来。”吉尼斯
公司前董事长安东尼特纳法认为：“从本质上讲，品牌是识别标志, 是区分你的产品和你的竞争对手产品的标牌。品牌也是一种简约的标识、用容易识别和记忆的方式描述产品的重要特征，如形象、用途和价格。 美国市场营销协会对品牌的定义如下：品牌是一种名称、术语、标记、符号或设计，或是他们的组合运用，其目的是借以辨认某个销售者或某群销售者的产品或服务，并使之同竞争对手的产品和服务区别开来 2、品牌的性质 从本质上来看,品牌是一种资本。它符合马克思在《资本论》中对资本的界定,即是一种“能带来剩余价值的价值”，具有流动性和赢利性等特征。同时，品牌又是一种特殊的资本，有着与其他类型的资本相区别的独特性： (1)非实物性。品牌不具有独立实体，只是表示企业拥有的特殊权利和获取超额利润的非实体资本。 (2)高价值性。品牌凝结了大量的劳动，具有很强的收益效用，因而价值都比较高。 (3)增值性。品牌产品由于具有强大的竞争力和垄断性，所以可以使自己占据较高的市场份额。 (4)重复使用性。品牌作为一种资本，在创造价值的过程中，本身不会发生有形磨损，相反使用次数越多，其价值也越大。基于品牌的上述本质和特征，可以从资本的角度将品牌定义为“企业使用的不具有实物形态而以知识形态存在的重要经济资源，能为其产权所有者或合法使用者提供权益或优势，并能带来经营收益的非货币性资产，其价值是依据已经耗费的资金和未来创造的收益估算的”。 二、国内外品牌战略学派理论 （一）品牌整合战略学派
轻松进入sciencedirect的方法(有问题联系：wmwman306@https://www.doczj.com/doc/125830088.html,) 这种方法很好进入sciencedirect，也无须验证代理的有效性。步骤如下： 1.代理 查找及设置 https://www.doczj.com/doc/125830088.html,/codeen/ （1）页面如图： （2）点击“status”,代理自动按照状态排序，选择“summary failed”的代理，如下图的第一个代理“139.19.142.3”，复制它.
（3）点击网页的“工具”--“internet 选项”--“连接”--“局域网设置”，选上“代理服务器”复选框，在“地址栏”输入刚才的代理“139.19.142.3”，在“端口”输入“3124”或“3127”或者“3128”，如下图我就输入“3128”。点击“确定”--“确定”，代理就这样设置完成了.
2.进入sciencedirect开始了，很关键，关键是网址变了 （1）在网页地址栏里的输入有三种选择好（呵呵，我只知道三种）： https://www.doczj.com/doc/125830088.html,/ 或者 https://www.doczj.com/doc/125830088.html,/ 或者 https://www.doczj.com/doc/125830088.html,/ （2）注意：初次进入可能进的不是sciencedirect主页，而是codeen介绍主页，这是你再输入刚才的网址刷新一下就好了 （3）进入主页如下图，有“Advanced Search ”字样的说明现在你能查阅它里边的文献了。点击“Advanced Search ”，就可以按照你的要求查阅相关文献了。
论《飘》中的现实主义 文献综述 引言 在20世纪的英美文学中，最具轰动效应的，莫过于美国女作家玛格丽特·米切尔（Margaret Mitchell,1900—1949）的长篇小说《飘》。该书自1936年问世以来，历经半个多世纪的考验，依然盛销不衰。小说以美国南北内战为背景，以战争的发展为线索，主要描写了女主人公斯嘉丽与维希礼和巴特勒之间的纠葛和恩怨。小说整体上是以女主人公斯嘉丽的爱情史为中心，虚写战争，实写战争对人类心灵的影响。此外，小说里还表现了对十九世纪中期美国南北文化的差异和矛盾，既是对当时南北战争中美国人的生活的生动刻画，也表现了当时战争中美国人勇敢和执着的精神。它是一部浪漫主义与现实主义创作手法相结合的优秀作品。尽管美国文坛一直有意贬低《飘》的文学价值,但它虽然未能进入文学经典的殿堂,却走进了千百万读者的心中。 一、国内对《飘》的相关评论 相对于西方而言，我国在《飘》的研究方面起步较晚，长期存在着接受与研究的严重脱节。即使是近年来这部小说获得越来越多的肯定评价，并正式进入文学史（以毛信德的《美国小说史纲》和王长荣的《现代美国小说》为代表），但对《飘》的研究也还是流于表面和简单。仅以中译本的序言水平就可见一斑：1990 年中国刮起了重译《飘》的旋风，一时出现沪本、京本、浙本三个版本的热闹场面，却没有一个本子的序言水平超过几十年前傅东华的译序。 《飘》作为一部富有争议的小说，吸引了许多文学工作者的目光。目前已有不少人从不同角度对《飘》进行了分析和欣赏。 张玉霞在《美国通俗小说经典〈飘〉研究综论》一文中认为，要对《飘》的持久魅力作出合理阐释，在整体的历史、文化的广阔视野关照下，必须回到细致的文本研究中去。张玉霞介绍了两个路径：1、把《飘》置于通俗文学发展进程中考察。从文类所属来看，它是历史小说与浪漫言情故事两个类型的交叉。偏重于形式要素的分析，得出的结论在于——优秀通俗小说的特征是“模式与模式突破”，即在内容和形式层面都具有承继、超越的双重性。而通俗小说的创作及接受两方面都受之影响。可以运用小说叙事学的研究方法进行具体的文本分析，并结合通俗小说类型研究来深入剖析《飘》的叙事结构特点。2、从创作流派及本土背景考察作为南方文学的《飘》，在解构与重建南方文化方面所具有的深刻内涵。 张淑英在《〈飘〉的流行与寂寞》一文中提到美国小说《飘》之所以能广泛流传的原因:一是艺术上的极高造诣,二是电影的推波助澜。然而,与小说的畅销和电影的火爆形成鲜明对照的是,一些文学史或文学手册中有关它的评论极少。很多人认为它是一部政治上反动的作品,这主要表现在小说对奴隶主和奴隶的阶级地位的描写,以及对南北战争有仇视情绪。 在王长荣的《现代美国小说史》中提到，《飘》是一部浪漫主义与现实主义创作手法相结合的优秀作品。他认为在人物塑造上，《飘》运用了浪漫主义的创作手法，女主人公斯嘉丽实际上成了表现南方神话的理想人物。从客观上讲，米切尔美化了正在崩溃的南方庄园经济，表现出对农奴主的同情。另一方面，在处理时代背景和人物对话时，米切尔却运用了现实主义的手法，使人读起《飘》来感到真切动人。
邻-碳硼烷合成路线综述 一．引言和背景 碳硼烷是由硼和碳形成的原子簇化合物。碳硼烷中研究和发展最为完全和充分的是二碳代-闭式-十二碳硼烷（closo-C2B10H12,dicarba-closo-dodecaborane）,它有3种异构体，即邻-碳硼烷(o-carborane)、间-碳硼烷(m-carborane)、对-碳硼烷(p-carborane)。由于碳硼烷具有高度对称的二十面体结构，2个C原子和10个B 原子都是六配位的，从而具有非常高的化学稳定性、热稳定性；其碳或硼原子上的氢具有可取代性，这使得以该化合物为基础可以合成许多结构新颖的衍生物。 六十年代中期邻-碳硼烷衍生物首先被美国军方合成并用于固体推进剂以获得高燃速及超高燃速，使得对碳硼烷的研究引起了人们的广泛关注。近几十年，碳硼烷衍生物的研究发展十分迅速，碳硼烷及其配合物，在分子识别、非线性光学、液晶显示材料、特殊聚合材料、以及作为模型化合物在研究金属有机催化反应、硼中子捕获疗法等方面均有重要应用。 一直以来，作为起始原料的邻-碳硼烷的合成受到整体反应收率低下的影响因而价格昂贵，制约了碳硼烷的应用。找到一条高效、简便、安全的合成路线将具有十分重大的意义，在这里将介绍邻-碳硼烷的典型合成路线及其所用初始反应原料[Et4N]2B10H10的合成；以及相关化合物具有启发性的合成路线的文献资料。二．邻-碳硼烷的典型合成路线： 1.1963年，T.L.Heying,etc.,Inorg.Chem,1963,2(6),1089-109 2. 步骤：十硼烷在1:1混合的正丙醚和二乙硫醚溶液中40℃反应12h，再升温至90℃，快速通入经过纯化的乙炔反应24h。产物经后处理纯化得邻-碳硼烷。收率：65-77%。 2.1968年,Charles R.Kutal,etc.,Inorganic Syntheses，1968,11,19-2 3. 步骤：十硼烷在苯中与二甲硫醚回流反应6h。冷却后加入1,4-二甲酰氧基-2-丁炔，待放热结束后，回流反应10h。加入甲醇搅拌5h后冷却至-10℃。加入冰水，析出黄色固体，过滤得粗产物1,2-二甲酰氧甲基-闭-1,2-二碳代十二硼烷。收率：75%。 1,2-二甲酰氧甲基-闭-1,2-二碳代十二硼烷和20%氢氧化钾水溶液在室温下搅拌5h，直到成为一混溶相，然后冰浴。在0-10℃下滴加高锰酸钾溶液，反应8h。产物处理后升华得邻-碳硼烷。收率：45%（以十硼烷计）。
超强酸-碳硼烷酸 碳硼烷酸H(CHB11Cl11) 为一种超强酸，是最强的单一分子酸，酸性为浓硫酸的一百万倍、氟磺酸的数百倍。 中文名碳硼烷酸 化学式 H(CHB11Cl11) 合成时间 2004年 合成地点加州大学河滨校区 合成团队 Chris Reed 团队 属性超强酸 碳硼烷酸分子结构图片 氢－白色氯－绿色硼－粉色碳－黑色 碳硼烷酸特性 造成碳硼烷酸强酸性的原因，是由于其共轭碱CHB11Cl11-非常稳定，而且具有高电负性的氯取代基，能有效分散负电荷。而外侧的氯包覆碳硼烷核心，使碳硼烷酸根非常稳定，不易与其他化学物质反应。 碳硼烷酸虽然酸性强，但不具强烈的腐蚀性与氧化性。混合酸，如魔酸、氟锑酸的酸性更强，但会生成氟离子造成副反应，生成的氢氟酸(HF)会腐蚀玻璃，造成使用上的困难。氟会攻击富勒烯(C60)，故H(CHB11Cl11)成为已知唯一能质子化富勒烯但不会将其分解的酸，能与富勒烯形成1：1的盐类。 碳硼烷酸具备令人吃惊的释放氢离子的能力，酸性是水的一百万亿倍。但由于碳硼烷酸中碳硼烷的结构十分稳定，释放氢离子后，由11个硼原子和一个碳原子排列而成的20面体结构没有发生任何变化，不发生进一步的化学反应，因此腐蚀性很低。 碳硼烷酸的应用十分广泛，可以用来制造“酸化”的有机分子，研究这些在自然界中短暂存在的有机分子有助于科学家了解物质发生变化的深层次机理，而目前科学家希望用碳硼烷酸酸化惰性气体氙，确定该气体的惰性强度。 碳硼烷酸历史 2004年，加州大学河滨校区（UC Riverside）的 Chris Reed 团队首先合成出碳硼烷酸。 人们对酸的认识是逐渐加深的。硫酸(H2SO4)、盐酸(HCl)、硝酸(HNO3)，被称为三大强酸，它们可以腐蚀我们日常生活中见到的很多物质。而王水是由浓硝酸和浓盐酸按1:3的比例混合而成，能够和化学性质极不活泼的金(Au)发生化学反应。所以在很长的一段时间内，人们认为王水就是酸中之王，是最强的酸了。 后来，奥莱教授和他的学生偶然发现了一种奇特的溶液，它能溶解不溶于王水的高级烷烃蜡烛，人们才知道其实王水并不是最强的酸，还有比它强的酸，这就是魔酸，又叫超强酸。自从奥莱教授和他的学生发现超强酸，人们又开始研究起强酸，相继找到了多种新的超强酸。 在碳硼烷酸出现之前，最强的酸性物质为氟乙酰氨硫酸(FCH2-CO-NH-SO3H)，这种酸腐蚀性极强，可以轻易穿透玻璃器皿，而碳硼烷酸则是已知超强酸中第一个可以在玻璃器皿中保存的超强酸性物质。
文献综述的写法 文献综述是对某一方面的专题搜集大量情报资料后经综合分析而写成的一种学术论文，它是科学文献的一种。文献综述是反映当前某一领域中某分支学科或重要专题的最新进展、学术见解和建议的它往往能反映出有关问题的新动态、新趋势、新水平、新原理和新技术等等。 要求同学们学写综述，至少有以下好处： ①通过搜集文献资料过程，可进一步熟悉科学文献的查找方法和资料的积累方法；在查找的过程中同时也扩大了知识面；②查找文献资料、写文献综述是科研选题及进行科研的第一步，因此学习文献综述的撰写也是为今后科研活动打基础的过程；③通过综述的写作过程，能提高归纳、分析、综合能力，有利于独立工作能力和科研能力的提高；④文献综述选题范围广，题目可大可小，可难可易。对于毕业设计的课题综述，则要结合课题的性质进行书写。 文献综述与“读书报告”、“文献复习”、“研究进展”等有相似的地方，它们都是从某一方面的专题研究论文或报告中归纳出来的。但是，文献综述既不象“读书报告”、“文献复习”那样，单纯把一级文献客观地归纳报告，也不象“研究进展”那样只讲科学进程，其特点是“综”，“综”是要求对文献资料进行综合分析、归纳整理，使材料更精练明确、更有逻辑层次；“述”就是要求对综合整理后的文献进行比较专门的、全面的、深入的、系统的论述。总之，文献综述是作者对某一方面问题的历史背景、前人工作、争论焦点、研究现状和发展前景等内容进行评论的科学性论文。 写文献综述一般经过以下几个阶段：即选题，搜集阅读文献资料、拟定提纲（包括归纳、整理、分析）和成文。 一、选题和搜集阅读文献 撰写文献综述通常出于某种需要，如为某学术会议的专题、从事某项科研、为某方面积累文献资料等等，所以，文献综述的选题，作者一般是明确的，不象科研课题选题那么困难。文献综述选题范围广，题目可大可小，大到一个领域、一个学科，小到一种算法、一个方法、一个理论，可根据自己的需要而定。 选定题目后，则要围绕题目进行搜集与文题有关的文献。关于搜集文献的有关方法，可以如看专著、年鉴法、浏览法、滚雪球法、检索法等等，在此不述。
常用国外数据库详细介绍（按国家分类） 一、美国 (1) Wiley InterScience(英文文献期刊) 主页：https://www.doczj.com/doc/125830088.html,/ 简介：Wiley InterScience是John Wiely & Sons 公司创建的动态在线内容服务，1997年开始在网上开通。通过InterScience，Wiley公司以许可协议形式向用户提供在线访问全文内容的服务。Wiley InterScience收录了360多种科学、工程技术、医疗领域及相关专业期刊、30多种大型专业参考书、13种实验室手册的全文和500多个题目的Wiley学术图书的全文。其中被SCI收录的核心期刊近200种。期刊具体学科划分为：Business, Finance & Management (商业、金融和管理)、Chemistry (化学)、Computer Science （计算机科学）、Earth Science （地球科学）、Education （教育学）、Engineering （工程学）、Law （法律）、Life and Medical Sciences （生命科学与医学）、Mathematics and Statistics （数学统计学）、Physics （物理）、Psychology （心理学）。 (2)美国IEEE (英文文献期刊) 主页：https://www.doczj.com/doc/125830088.html,/ 简介：IEEE（Institute of Electrical & Electronics Engineers）是电子信息领域最著名的跨国性学术团体，其会员分布在世界150多个国家和地区。据IEEE统计，IEEE会员总数2001年比2000年增加3.1%，达到377342人，其中学生会员为65669人，增长12.6%。 随着人们的信息越来越多地来自Internet，IEEE需要为会员提供更加完善和全面的电子信息产品和服务。IEEE应成为IEEE会员获得信息的首选之地。IEEE必须识别正确的信息，并提供对它们的访问方法。实现这个目标的重要一步是通过IEEE Xplore与IEEE/IEE Electronic Library (IEL)连接。IEL包括了1988年以来IEEE和IEE的所有期刊杂志和会议录，以及IEEE的标准，可以通过题目、关键词和摘要进行查阅。 (3)美国EBSCO(英文文献期刊) 主页：https://www.doczj.com/doc/125830088.html, 简介：EBSCO公司从1986年开始出版电子出版物，共收集了4000多种索引和文摘型期刊和2000多种全文电子期刊。该公司含有Business Source Premier （商业资源电子文献库）、Academic Search Elite（学术期刊全文数据库）等多个数据库。 Business Source Premier收录了三千多种索引、文摘型期刊和报纸，其中近三千种全文刊。数据库涉及国际商务、经济学、经济管理、金融、会计、劳动人事、银行等的主题范围，适合经济学、工商管理、金融银行、劳动人事管理等专业人员使用。数据库中有较著名"华尔街日报"（The Walls Street Journal）、"哈佛商业评论"（Harvard Business Review）、"每周商务"（Business Week）、"财富"（Fortune）、"经济学家智囊团国家报告" (EIU Country Reports)、American Banker、Forbes、The Economist等报刊。该数据库从1990年开始提供全文，题录和文摘则可回溯检索到1984年，数据库每日更新。 学术期刊集成全文数据库（Academic Search Premier，简称ASP）：包括有关生物科学、工商经济、资讯科技、通讯传播、工程、教育、艺术、文学、医药学等领域的七千多种期刊，其中近四千种全文刊。 EBSCO内含有两个免费数据库：
贵州大学人民武装学院2012 届本科毕业生 毕业论文 ( 设计 ) 文献综述撰写规范 为了培养学生独立从事学术研究的能力，特别是培养学生检索、搜集、整理、综合利用学术文献资料，根据所研究课题对文献资料进行有效的归纳、分析、总结的能力，提高独立工作能力和科研能力，并为科研活动奠定扎实的基础，本科毕业生在完成毕业论文（设计）的同时必须相应完成一篇文献综述。 一、文献综述的基本要求 1.毕业论文（设计）文献综述是指学生在毕业论文（设计）研究课题或研 究题目（初步）确定后，通过搜集、整理、阅读国内外相关学术文献资料，就与 该课题或题目直接相关的主要研究成果、学术意义、研究方法、研究动态、最新 进展等问题进行归纳总结、综合分析后所做的简要评述。 2.毕业论文（设计）文献综述所评述的学术文献必须与学生所撰写论文保持大体上的一致，必须对可能影响所撰写论文主要论点、政策建议或反驳依据等主要 学术结论的相关文献及其主要论断做出清晰、准确、流畅的说明，必须保证综述 本身结构的完整性，能够反映学生的利用学术文献的综合能力。 3.毕业论文（设计）文献综述是学生撰写毕业论文（设计）过程的有机组成部分，必须在论文指导教师的指导下完成；文献综述必须按学校要求的基本规范撰写；论文类题目提交 3000 字左右的文献综述，设计类题目提交 2000 字左右的设计方 案报告；文献综述的成绩综合纳入学生毕业论文（设计）成绩之中，未 完成毕业论文（设计）文献综述的学生不得参加毕业论文（设计）答辩。 二、文献综述的基本格式 文献综述是针对某一研究领域或专题搜集大量文献资料的基础上，就国内外在 该领域或专题的主要研究成果、最新进展、研究动态、前沿问题等进行综合分析而写成的、能比较全面的反映相关领域或专题历史背景、前人工作、争论焦点、研究 现状和发展前景等内容的综述性文章。“综”是要求对文献资料进行综合分析、归 纳整理，使材料更精练明确、更有逻辑层次；“述”就是要求对综合整理后的文献 进行比较专门的、全面的、深入的、系统的评述。
资料一 一、什么是文献综述 是对某一方面的专题搜集大量的情报资料后经综合分析而写成的一种学术论文，它是科学文献的一种。文献综述往往反映的是当前某一领域中某分支学科或重要专题的最新进展、学术见解和建议，反映有关问题的新动态、新趋势、新水平、新原理等等。 文献综述是作者对某一方面问题的历史背景、前人工作、争论焦点、研究现状和发展前景等内容进行归纳、整理并予以评论的科学性论文。 二、写文献综述的好处： 1、通过体验搜集文献资料的过程，可进一步熟悉科学文献的查找方法和资料的积累方法；在查找的过程中同时也扩大了知识面； 2、查找文献资料、写文献综述是科研选题及进行科研的第一步，因此，学习文献综述的撰写也是为今后科研活动打基础的过程； 3、通过文献综述的写作过程，能提高归纳、分析、综合的能力，有利于独立工作能力和科研能力的提高； 4、文献综述选题范围广，题目可大可小，可难可易。对于毕业设计的课题综述，则要结合课题的性质进行书写。 三、写文献综述常见的问题 1、根据已有的综述直译转抄 在写作综述论文时,可以借鉴他人已发表的综述启发思路,但切不可照抄照搬。也就是说,必须结合自己的工作体会写出有别于他文的特色,有自己的侧重点。要做到这一点,首先必须进行文献更新,补足与自己侧重点有关的和该课题最新发表的文献,然后按照自己的侧重点重新命题,将全文重新整理,综合分析,提出自己的见解。 2、洋洋大篇,只是资料的堆积 内容既无重点又不深入,层次不清,概念模糊,甚至有误，只是资料的堆积。 3、文献开列过多,引文不当 一般要求综述论文著录的文献应是作者亲自阅读过的原文,但也并不是所有读过的文献都统统列出,应选择最主要和最新近的文献: 1)综述论文论点和论据来自的文献; 2)为分析讨论提供有力依据的文献; 3)为理论和机制提供实验依据的文献; 4)注意引用知名度高的期刊; 5)以新近的文献代替旧的文献。 4、把综述写成讲座 讲座和综述的共同点是文章的综合性、新颖性和进展性。 一般认为,综述是专业人员写给同专业和相关专业人员看的,要求系统、深入;讲座是专业人员写给相关专业人员和非相关专业的"大同行"看的,一般在深度上不作太高要求。
文献综述 国外研究现状 国外的很多相关机构对内部控制的研究都取得了一定的研究成果。例如，2004年9月，COSO发布了《企业风险管理—整合框架》，它拓展了内部控制框架，更关注于企业风险管理这一更加宽泛的领域。按照COSO的设想，他们不打算，也的确没有用企业风险管理框架取代内部控制框架，而是将内部控制框架纳入其中，公司不仅可以借助这个企业风险管理框架来满足它们内部控制的需要，还可以借此转向一个更加全面的风险管理过程。《企业风险管理—整合框架》再一次强调了系统的概念，即在实施企业整体风险管理过程中，主体中的每个人都对企业风险管理负有责任：首席执行官（CEO）负有首要责任，并且应当成为主负责人，其他管理人员支持主体的风险管理理念，并在各自的责任范围内依据风险容限去管理风险。美国在2002年颁布了《萨班斯-奥克斯利法案》，这部法律扩充了长期持续的对公众公司保持内部控制制度的规定，要求管理当局证实、并由独立审计师鉴证这些制度。GAO发布了《联邦政府内部控制准则》，这个准则提供了一个综合的框架，以建立和维护内部控制、识别和确定那些面临着欺诈、浪费、滥用和管理不善的风险经营管理领域。该准则认为内部控制是一个企业管理的主要组成部分，为保护资产及发现错误和舞弊提供第一重防卫。准则将COSO报告关于内部控制5个要素的划分，变成了内部控制的5个具体准则，即控制环境、风险评估、控制活动、信息与沟通、监控。最高审计机关国际组织，简称（INTOSAI），将内部控制准则分为一般准则和详细准则两部分。一般准则包括：合理保证、支持态度、忠诚与能力、控制目标、执行之监控等，遵循一般准则可以为企业提供适当的控制环境。详细准则是达成控制目标的方法或程序，包括特定政策、程序、组织规划（含职务分工）。加拿大注册会计师公会所属的控制基准委员会，简称COCO，提出了一种更精简、更具动态的内部控制基本构架，从目的、承诺、能力、监督与学习4个方面提出20项控制基准。巴塞尔委员会发布《银行组织内部控制系统的框架》系统地提出了评价商业银行内部控制体系的13项指导原则，是商业银行内部控制研究历史性的突破。强调董事会和高级管理层对内控的影响，组织中的所有各级人员都必须参加内部控制过程，并会对内部控制产生影响。
贵州大学人民武装学院2017届本科毕业生 毕业论文(设计)文献综述撰写规范 为了培养学生独立从事学术研究的能力，特别是培养学生检索、搜集、整理、综合利用学术文献资料，根据所研究课题对文献资料进行有效的归纳、分析、总结的能力，提高独立工作能力和科研能力，并为科研活动奠定扎实的基础，本科毕业生在完成毕业论文（设计）的同时必须相应完成一篇文献综述。 一、文献综述的基本要求 1.毕业论文（设计）文献综述是指学生在毕业论文（设计）研究课题或研究题目（初步）确定后，通过搜集、整理、阅读国内外相关学术文献资料，就与该课题或题目直接相关的主要研究成果、学术意义、研究方法、研究动态、最新进展等问题进行归纳总结、综合分析后所做的简要评述。 2.毕业论文（设计）文献综述所评述的学术文献必须与学生所撰写论文保持大体上的一致，必须对可能影响所撰写论文主要论点、政策建议或反驳依据等主要学术结论的相关文献及其主要论断做出清晰、准确、流畅的说明，必须保证综述本身结构的完整性，能够反映学生的利用学术文献的综合能力。 3.毕业论文（设计）文献综述是学生撰写毕业论文（设计）过程的有机组成部分，必须在论文指导教师的指导下完成；文献综述必须按学校要求的基本规范撰写；论文类题目提交3000字左右的文献综述，设计类题目提交2000字左右的设计方案报告；文献综述的成绩综合纳入学生毕业论文（设计）成绩之中，未完成毕业论文（设计）文献综述的学生不得参加毕业论文（设计）答辩。 二、文献综述的基本格式 文献综述是针对某一研究领域或专题搜集大量文献资料的基础上，就国内外在该领域或专题的主要研究成果、最新进展、研究动态、前沿问题等进行综合分析而写成的、能比较全面的反映相关领域或专题历史背景、前人工作、争论焦点、研究现状和发展前景等内
碳硼烷 摘要： 自20世纪60年代以来，碳硼烷化学得到了空前发展。碳硼烷衍生物具有独特的结构和良好的热稳定性等特点，已经应用于众多领域，如生物医学、光学材料、超分子化学、催化材料、离子液体以及离子选择性电极等。 关键词：碳硼烷;合成；结构；反应机理 Abstract： Since the 1960s，the chemistry of closo-C2B10H12carborane has witnessed rapid development．The icosahedral closo-C2B10H12carboranes and their derivatives have attracted considerable attention due to their unique molecular skeleton，excellent thermal stability and especially the potential applications in many fields，including，e．g．biomedical science，optical materials，macromolecules，catalysis，ionic liquids，and ion—selective electrodes． Key Words：carborane；synthesis；structure；reaction mechanism.
正文： （一）硼烷发展史简介 硼烷化学是当今国际上一个引人注目的研究领域。从1912年开始，Stock制备和分离了B2H6，B4H10，B5H9，B5H11，B6H10，B10H14，其后硼烷经历了两次繁荣发展时期：第一时期始于1941年，人们发现了挥发性的铀硼氢U(BH4)4，并设想将其用于铀同位素的分离，引发了硼烷化学的研究热潮，这一时期（1941-1946）的主要成就主要是大规模合成了NaBH4和B2H6；在第二时期，由于硼烷具有很高的燃烧值，受到航空和火箭工作者的注视。美、英、前苏联等国将其（主要是液态B5H9和固态B10H14)列入高能火箭燃料研究计划，在10多年里，已经发展了一些经济的合成方法，进一步合成了许多硼烷及其阴离子，并用多种手段研究其结构。Brown由于发现不饱和键与硼烷的硼氢化反应而获得1979年的诺贝尔化学奖。Williams小组和Greenwood小组分别合成了碳硼烷和金属硼烷，Hawthorne等合成了金属碳硼烷——夹心型的[Fe(C2B9H11)2]2-。这些重要成果使硼烷化学进入了一个新的发展时期，并深入开展理论研究和寻找更多潜在应用提供了可能。 （二）碳硼烷的结构 自20世纪60年代发展至今的碳硼烷化学是硼烷化学的一个重要分支。碳硼烷(carborane)是指多面体硼簇化合物的一个或多个硼顶点被碳原子取代而形成的化合物。由于不同数目和不同位置的硼原子被碳原子取代，形成了大量的碳硼烷簇合物，其构型主要有闭式(closo)、巢式(nido)和网式(arachno)。在这三种构型的碳硼烷中，闭式碳硼烷数量最多，性质也最稳定。在碳硼烷化学中，具有二十面体构型的二碳代-闭式十二硼烷(dicarba-closo-dodecaborane，C2B10H12)最受关注。根据两个骨架碳原子所处的相对位置不同，二碳代-闭式十二硼烷有三种异构体：邻碳硼烷(D-C2B10H12)、间碳硼烷(m-C2B10H12)和对碳硼烷(p-C2B10H12)。在加热条件下，二碳代-闭式十二硼烷可发生原子重排，进行构型转化(Scheme 1)。 二碳代-闭式十二硼烷的三种异构体(未标记的顶点均为BH，下同) Scheme 1 二碳代-闭式十二硼烷三种异构体的转化
毕业设计（论文）文献综述 课题名称：基于地域文化的上海城市公园休闲空间 设计研究——以徐家汇公园为例 学院：旭日工商管理学院 专业：旅游管理 姓名：王玉__ 学号：090760211 指导教师：潘文焰 二〇一二年十二月十一日
摘要：随着生活水平的提高，人们的休闲时间明显增加，这对原有城市公共空间的数量和质量都提出了新的要求。目前我国面临的人们闲暇的需求与设施的供给矛盾日益突出，游憩场地的数量不足和休闲空间质量不高比较明显。如何在有限的城市公园范围内创造出与需求相适应、高质量的城市休闲空间环境是景观设计师所面临的重要问题；城市公园是城市景观重要的组成部分，更是承载城市文化、文明的重要场所。城市公园作为一种具有长久生命力的文化载体，是表达地域文化的重要场所。在现在的时代背景下，提出植根于地域文化的公园设计概念是十分必要。“只有民族的，才是世界的”；只有植根于城市文化的沃土中，公园才可能具有“此区别于彼”的独特面貌；只有具有鲜明的地域特征，城市景观才会有生命力。但是面对全球化的冲击，一些城市公园盲目追求“现代化”、“国际化”，相继出现了一批缺乏本国特色和地域特色的公园。地域文化特色的缺失使城市公园失去了持久的生命力。 关键词：城市公园，地域文化，休闲，公共空间，设计表达
城市公园的研究及现状 1.1.城市公园的研究及现状 1.1国外的相关研究 公园规划的内容早已包含在了最早的现代城市规划之中，最早的公园规划案例要数英国利物浦的博肯海德公园和法国的奥斯曼改造计划。从那时起，人们已经认识到城市公园有着改善城市卫生、健康环境、美化城市、提高工作效率、促进地产升值等多个方面的作用。随着城市规划理论的不断发展，人们越来越重视“人”休闲权益，而关于城市公园的研究也越来越多。 20世纪70、80年代，西方研究公园与休闲、公园设计的代表人物——阿尔伯特J·拉特利奇出版了一系列有关公园与休闲和公园设计方面的著作，其中《大众行为和公园设计》一书在1990年被翻译成中文，对我国公园设计产生了重大影响。该书从行为学的角度，认为人的行为习惯是城市公园设计中最核心的要素，并提出了一系列相关的评价标准、观察与调查方法以及规划程序。 此外，Alexander Adrew von Kursell、Sassan Seyed Kalal、Anne Farrell Peterson、Dana H.Taplin等人也从不同角度出发，通过一系列的案例，研究了城市公园再造的因素、政治和社会机制对城市公园分布和城市景观塑造的影响、城市公园的景观价值、公园在城市和社区生活中的角色、不同阶层居民对公园的使用要求、公园在设计过程中的问题以及解决方案等。对于城市公园的上述研究，使用的研究方法多为问卷调查、访谈法、现场观察等。 1.2国内的相关研究 我国关于城市公园的研究出现在1979年以后，研究的内容包括城市公园发展、功能分析、景观设计、规划设计、生态研究、休闲游憩行为研究、公园容量研究等多个方面。国内关于城市公园的研究方法与国外类似，也多采用案例分析法，国内研究城市公园的学者们大都从研究单个或多个公园入手，进而总结出普遍经验。总结国外研究经验并因地制宜运用到国内城市公园中也是学者们的重要研究内容之一。 目前针对公园系统的研究主要有：石金莲等(2005)运用POE(post occupancy evaluation)的研究方法，以北京玉渊潭公园为研究对象，得到了POE评价分析
基于多分类器的个人信用评估模型研究 文献综述 作者：XXX 【摘要】随着我国经济的快速发展，信用消费已逐步浮出水面，信用卡个人消费贷款的规模正在迅速扩大，各商业银行均把发展信用卡业务作为未来发展战略的重要组成部分。由于目前国内商业银行对信用卡业务的风险管理水平较低，管理方法比较落后，缺乏一套行之有效的个人信用评分方法也阻碍着信用卡业务的进一步发展。本文在基于前人研究的基础上，通过研究各种常用于建立个人信用评估并进行分析比较，并从中选择出一些适用、合理的方法来进行毕业设计的实验。 【关键词】个人信用;评估模型;逻辑回归;判别分析;人工神经网络 1.序论 随着经济的快速发展，我国个人信贷业务，包括住房贷款、汽车消费贷款、信用卡业务在内的各种零售类贷款业务的规模正在迅速扩大。银行业的发展和人民生活水平的提高，使得个人和银行业联系越来越紧密，个人通过个人消费贷款和个人信用贷款与银行发生直接的关系[1]。银行业积极适应变化的市场环境，将零售业务提高到战略高度，个人信用体系的建立势在必行。同时，受金融危机的启示，一个适合的信用评估体系能够有效减少银行风险。因此，如何有效对个人信用进行评估、对个人信用风险加强防范措施，便成为了商业银行在竞争市场上的有利武器。个人信用风险管理在国内，已经受到越来越多的关注。 2.研究背景 我国的个人信用制度建设是在“九五”末期国内市场出现疲软、内需不足的形势下提出并开始起步的，是随着商业银行个人消费信贷业务的增加而产生的客观要求[2]。近年来个人消费信贷业务在我国迅速发展，它在刺激消费需求、引导资金流向以及提高我国居民生活质量等方面都发挥着重要作用。然而我国个人信用体系建设起步较晚，与欧美等发达的信用体系相比，我国个人信用体系还不健全，发展程度较低，还没有形成相对完善的体系。首先，各家商业银行对个人信用等级的评估有各自不同标准，所以可能出现各评估机构对同一客户得出的不同评估结果，甚至完全相反的结果，这样既不利于个人信用体系在全国范围内推广，也不利于与国际的接轨；其次，我国个人信用评估指标体系的设计也存在不足，需要在以后的发展中逐步完善[3]。 目前，虽然建立我国个人信用制度的经济条件已基本达到，但另一项不容忽视的问题就在于我国法律体系的不完善。同时，在配套政策方面，目前我国社会保障制度、个人破产制度、个人账户制度、个人财产申报制度等尚未出台，导致个人及其家庭的收入状况不透明，不但隐藏着严重的法律与道德风险，同时也使个人资信评估难以向国家机关和企事业单位推广[4]。 专业人才的缺乏相对日益发展的信用管理行业以及个人信用体系所需的人才需求来说仍有很大的缺口。我国针对信用方面的立法仍有待完善。惩罚机制不健全且惩罚力度较小，不足以对社会的各种失信行为形成强有力的法律规范和约束。