首页   按字顺浏览 期刊浏览 卷期浏览 Synthesis of Heterocyclic Analogues of Tamoxifen asPotential Antiestrogens
Synthesis of Heterocyclic Analogues of Tamoxifen asPotential Antiestrogens

 

作者: Natarajan Srikanth,  

 

期刊: Journal of Chemical Research, Synopses  (RSC Available online 1997)
卷期: Volume 0, issue 8  

页码: 274-275

 

ISSN:0308-2342

 

年代: 1997

 

DOI:10.1039/a701410d

 

出版商: RSC

 

数据来源: RSC

 

摘要:

Ph OH O Ph O X 1 3 4 5 Ph X OCH2CH2A Z-isomer (b) OCH2CH2A + Ph X E-isomer (a) Ph OH X OCH2CH2A 2a X = S, A = N(CH2CH2)2O b X = Se, A = N(CH2CH2)2O a X = S b X = Se 3 X = S, A = N(CH2CH2)2O 4 X = Se, A = N(CH2CH2)2O i ii 1 iii 274 J. CHEM. RESEARCH (S), 1997 J. Chem. Research (S), 1997, 274–275 J. Chem. Research (M), 1997, 1828–1849 Synthesis of Heterocyclic Analogues of Tamoxifen as Potential Antiestrogens Natarajan Srikanth, Choon-Hong Tan, Siu-Choon Ng, Teck-Peng Loh, Lip-Lin Koh and Keng-Yeow Sim* Department of Chemistry, National University of Singapore, 10 Kent Ridge Crescent, Singapore 119260 The synthesis of (E/Z)-1-aryl-2-phenyl-1-(2-thienyl/selenophen-2-yl)but-1-enes, derived from 2-phenyl-1-(2-thienyl/ selenophen-2-yl)butan-1-ones, is described; the key steps in the synthesis involve the reaction of the butan-1-ones with 4-(2-morpholinoethoxy)phenyl bromide, followed by dehydration of the resulting carbinols to give the target compounds which are separated by fractional recrystallisation. Non-steroidal antiestrogens of the triarylethylene type, notably Z-tamoxifen, have been widely used as the first line endocrine therapy drugs for the treatment of estrogendependent tumours.It is generally acknowledged that antiestrogens act by competitively inhibiting the binding of estradiol to the estrogen receptor.1 The clinical efficacy of tamoxifen in the treatment of breast cancer has attracted widespread interest in the synthetic and biological studies of antiestrogens.2 For this purpose it is essential that only the geometrical isomer of Z-configuration is used since the E-isomer has unwanted opposing estrogenic properties.3,4 The separation of the mixture of isomers that results from the synthesis is often not easy and the present separation methods of the E–Z mixture5,6 are usually by fractional recrystallisation from a suitable solvent. So far there has been only one report on the synthesis of triarylethylene analogues7 (1,2-diphenyl-1-pyridylbut-1-enes) in which one of the phenyl groups has been replaced by an aromatic heterocyclic ring (pyridine).An E:Z ratio of 1:1 was obtained and only the Z-isomer could be separated by fractional recrystallisation. We report herein the synthesis of (E/Z)-1-aryl-2-phenyl- 1-(2-thienyl/selenophen-2-yl)but-1-enes, derived from 2- phenyl-1-(2-thienyl/selenophen-2-yl)butan-1-ones. It is well known that selenium in the appropriate chemical form and concentration exhibits anticarcinogenic properties in numerous animal tumour model systems.8 The methodology used for the synthesis of (E/Z)-1-aryl- 2-phenyl-1-(2-thienyl/selenophen-2-yl)but-1-enes (3a, 3b, 4b) is depicted in the Scheme.The precursors, 2-phenyl- 1-(2-thienyl/selenophen-2-yl)butan-1-ones (1), were synthesised by the reaction of thiophene/selenophene with 2- phenylbutyric acid in trifluoroacetic anhydride.9 The products of electrophilic substitution at positions 2 and 3 of the 5-membered heterocycles can be differentiated by their 1H NMR data.10 The chemical shifts of 1a, d3 7.71, d4 7.05, d5 7.56 and coupling constants J34 3.83, J35 1.07, J45 4.92 Hz are consistent with the results reported for 2-substituted thiophenes10 (d3 7.80, d4 7.17, d5 7.80 and J34 3.74, J35 1.09, J45 5.07 Hz).Similarly the chemical shifts of 1b, d3 7.93, d4 7.29, d5 8.30 and coupling constants J34 3.98, J35 1.02, J45 5.50 Hz are consistent with the results reported for 2-substituted selenophene10 (chemical shifts d3 8.02, d4 7.43, d5 8.52 and coupling constants J34 3.96, J35 1.14, J45 5.54 Hz).The reaction of the 2-phenyl-1-(2-thienyl/selenophen-2-yl)butan-1-ones (1) with the 4-(2-morpholinoethoxy)phenyl bromide, followed by acid-catalysed dehydration of the tertiary alcohols 2 obtained furnished mixtures of geometric isomers 3 and 4. The E- and Z-isomers of the thiophene analogue, 3a and 3b (E:Z=1:2), could be separated by recrystallisation from methanol. However, only the Z-isomer for the selenium analogue 4b (E:Z=1:4) could be obtained in the pure state by recrystallisation.It is well known that the geometric isomers of the tamoxifen derivatives can be differentiated by their 1H NMR spectra.11 Thus the isomers with monosubstituted aromatic rings (1- and 2-phenyl groups) are readily identified on the basis of the chemical shifts of the AB quartet for the protons of the remaining disubstituted aromatic moiety. In the transisomer (Z-tamoxifen) the AB quartet is usually found at a higher field as a consequence of the combined shielding influence of the two adjacent phenyl rings.On this basis and assuming the heteroaromatic thiophene ring as being equivalent to a phenyl group, compound 3a, with an AB quartet at dH 6.57–6.85 (J 8.85 Hz) and other aromatic protons at dH 6.95–7.26, can be assigned as the E-isomer. Compound 3b, with an AB quartet at dH 6.94–7.23 (J 8.72 Hz) and other aromatic protons at dH 7.24–7.35, can be assigned as the Z-isomer. Further confirmation of these structures was obtained by comparing the chemical shifts of the ethyl and the OCH2 groups with those reported for the E/Z isomers of 1-[-4-(2-dimethylaminoethoxy)phenyl]-2-phenyl-1-(4-pyridyl) but-1-ene and other triarylethylene derivatives.7,12 Thus compound 3a, showing a triplet at dH 1.00 (CH3), a quartet at dH 2.67 (CH2) and a triplet at dH 3.99 (OCH2), is assigned the E-isomer.Compound 3b, showing a triplet at dH 0.87 (CH3), a quartet at dH 2.29 (CH2) and a triplet at dH 4.16 (OCH2), is assigned the Z-isomer. Similarly compound 4 was assigned the Z-configuration based on the above results. The struc- *To receive any correspondence. Scheme Reagents and conditions: i, TFAA, thiophene/ selenophene; ii, n-BuLi, p-BrC6H4OCH2CH2A, THF, µ78 °C; iii, H+, MeOH, room temperatureJ. CHEM. RESEARCH (S), 1997 275 tures of 3a,b have also been confirmed by X-ray diffraction analysis.The X-ray structures of the isomers 3a and 3b are shown in Figs. 1 and 2, respectively. The crystal structure of 3a has monoclinic symmetry. Each asymmetric unit contains one independent molecule. The thiophene ring is disordered to two sets by flipping over around the C(1)·C(1s) bond with site occupancy factors of 0.60 and 0.40. This is possibly due to the free rotation about the C(1)·C(1s) bond. The conformation at the C(1)�C(2) double bond is as follows: (1) bondings at both C(1) and C(2) are planar; (2) the thiophene ring is cis to the ethyl group and (3) the N(CH2CH2)2O ring has a chair conformation.The crystal structure of 3b has orthorhombic symmetry. The thiophene group is again disordered (0.65/0.35). The conformation at the C(1)�C(2) double bond is as follows: (1) bondings at both C(1) and C(2) are planar; (2) the thiophene ring is trans to the ethyl group and (3) the N(CH2CH2)2O ring has a chair conformation.Crystal Data for 3a.·C26H29O2NS, Mr=419.6, monoclinic, a=25.962 (5), b=5.7470 (10), c=31.424 (6) Å, b=97.34 (3)°, V=4650 (2) Å3, DC=1.199 mg mµ3, Z=8, F(000)=1792, m(Mo-Ka)=0.161 mmµ1, space group I2/a. Crystal Data for 3b.·C26H29O2NS, Mr=419.6, orthorhombic, a=30.604 (7), b=51.461 (11), c=5.8030 (10) Å, V=9139 (3) Å3, DC=1.220 mg mµ3, Z=16, F(000)=3584, m(Mo-Ka)=0.163 mmµ1, space group Fdd2. Crystallographic Analyses.·Data were collected on a Siemens R3m/V diffractometer and structures elucidated by direct methods13 and refined by full-matrix least-squares analysis.14 The final R value was 0.060 (Rw=0.089) for compound 3a and 0.039 (Rw=0.036) for compound 3b.A preliminary ligand-binding study of compound 3b (which has the same configuration as E-tamoxifen) on a Molt 4 cell line showed that it had a lower relative binding affinity than Z-tamoxifen. Studies on the bioactivities of the synthetic compounds are in progress.We thank the National University of Singapore for a grant in support of this research and for the award of a Research Scholarship to N. S. Techniques used: IR, 1H NMR, mass spec, elemental analyses, TLC and X-ray diffraction References: 14 Appendix: Tables of atomic coordinates and equivalent isotropic displacement coefficients, bond lengths and angles, anispic displacement coefficients, H-atom coordinates and isotropic displacement coefficients for 3a and 3b Received, 28th February 1997; Accepted, 25th April 1997 Paper E/7/01410D References cited in this synopsis 1 V.C. Jordan, Pharmacol. Rev., 1984, 36, 245. 2 R. A. Magarian, L. B. Overacre, S. Singh and K. L. Meyer, Curr. Med. Chem., 1994, 1, 61. 3 M. J. K. Harper and A. L. Walpole, Nature (London), 1967, 212, 87. 4 V. C. Jordan, B. Hablemann and K. E. Allen, Endocrinology, 1981, 108, 1353. 5 M. J. K. Harper, D. N. Richardson and A. L. Walpole, Br. Pat., 1 064 629, 1966. 6 L. Magdani, A.Hutak, E. Szatmari, I. Simoni, J. Halmos and F. Nemere, Belg. Pat., 892 662, 1982. 7 W. Schwarz, R. W. Hartmann and H. Schonenberger, Arch. Pharm. (Weinheim, Ger.), 1991, 324, 223. 8 G. N. Schrauzer, Selenium in Medicine and Biology, ed. J. Neve and A. Favier, Walter de Gruyter, Berlin, Germany, 1988, p. 251. 9 M. Jarman and R. McCague, J. Chem. Res., 1985, (S) 116; (M) 1342. 10 M. E. H. Nygaard, E. O. Pettersen, J. M. Dornish and R. Oftebro, Invest. New Drugs, 1987, 5, 259. 11 R. McCague, O. Tai Leung and M. Jarman, J. Chem. Soc., Perkin Trans. 2, 1988, 1201. 12 (a) R. McCague and G. Leclercq, J. Med. Chem., 1987, 30, 1761; (b) D. J. Collins, J. J. Hobbs and C. W. Emmens, J. Med. Chem., 1971, 14, 952. 13 G. M. Sheldrick, Crystallographic Computing, ed. G. M. Sheldrick, C. Kruger and R. Goddard, Oxford University Press, Oxford, 1985, 175. 14 G. M. Sheldrick, SHELX-76, A Program for X-ray Crystal Structure Determination, University of Cambridge, England, 1976. Fig. 1 X-Ray crystal structure of the E-isomer of 1[4-(2-morpholino- ethoxy)phenyl]-2-phenyl-1-(2-thienyl)but-1-ene Fig. 2 X-Ray crystal structure of the Z-isomer of 1-[4-(2-morpholino- ethoxy)phenyl]-2-phenyl-1-(2-thienyl)but-1-ene

 



返 回