Synthesis and structure guided evaluation of estrogen agonist and antagonist activities of some new tetrazolyl indole derivatives.

Several regioisomeric tetrazolyl indole derivatives with structurally modified alkyl substituents at the tetracyclic indole nitrogen containing N-ethyl amino tetrazole moiety have been synthesized and screened for their ER binding affinity, agonist (estrogenic), antagonist (antiestrogenic) and anti-implantation activities. N-2 regioisomers were found to be moderately antagonists and one compound showed 100% contraceptive efficacy at 10 mg/kg dose. Molecular docking studies carried out in comparison to estradiol and raloxifene showed different binding modes of the two regioisomers to the binding site.

[1]  S. Durani,et al.  Structure-activity relationship of antiestrogens. Studies on 2,3-diaryl-1-benzopyrans. , 1990, Journal of medicinal chemistry.

[2]  John A. Katzenellenbogen,et al.  The estradiol pharmacophore: Ligand structure-estrogen receptor binding affinity relationships and a model for the receptor binding site , 1997, Steroids.

[3]  H. Nakagawa,et al.  4-(4-alkylpiperazin-1-yl)phenyl group: a novel class of basic side chains for selective estrogen receptor modulators. , 2003, Bioorganic & medicinal chemistry letters.

[4]  William P. Purcell,et al.  A brief review and table of semiempirical parameters used in the Hueckel molecular orbital method , 1967 .

[5]  C. D. Jones,et al.  Molecular determinants of tissue selectivity in estrogen receptor modulators. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[6]  B. Katzenellenbogen,et al.  Antiestrogen basicity--activity relationships: a comparison of the estrogen receptor binding and antiuterotrophic potencies of several analogues of (Z)-1,2-diphenyl-1-[4-[2-(dimethylamino)ethoxy]phenyl]-1-butene (tamoxifen, Nolvadex) having altered basicity. , 1982, Journal of medicinal chemistry.

[7]  K. Hajela,et al.  Resolution, molecular structure and biological activities of the D- and L-enantiomers of potent anti-implantation agent, DL-2-[4-(2-piperidinoethoxy)phenyl]-3-phenyl-2H-1-benzopyran. , 1999, Bioorganic & medicinal chemistry.

[8]  P. Gmeiner,et al.  Cyanoindole derivatives as highly selective dopamine D(4) receptor partial agonists: solid-phase synthesis, binding assays, and functional experiments. , 2000, Journal of medicinal chemistry.

[9]  U. Singh,et al.  A NEW FORCE FIELD FOR MOLECULAR MECHANICAL SIMULATION OF NUCLEIC ACIDS AND PROTEINS , 1984 .

[10]  H. Nagaso,et al.  Tetrahydrobenzindoles: selective antagonists of the 5-HT7 receptor. , 1999, Journal of medicinal chemistry.

[11]  A. Koren,et al.  Alkylation and Related Electrophilic Reactions at Endocyclic Nitrogen Atoms in the Chemistry of Tetrazoles , 2000 .

[12]  Chris P. Miller,et al.  Design, synthesis, and preclinical characterization of novel, highly selective indole estrogens. , 2001, Journal of medicinal chemistry.

[13]  K. Hajela,et al.  Synthesis and biological activities of some new dibenzopyranones and dibenzopyrans: search for potential oestrogen receptor agonists and antagonists. , 2004, Bioorganic & medicinal chemistry.

[14]  R. J. Herr,et al.  5-Substituted-1H-tetrazoles as carboxylic acid isosteres: medicinal chemistry and synthetic methods. , 2002, Bioorganic & medicinal chemistry.

[15]  M. Meegan,et al.  Advances in the science of estrogen receptor modulation. , 2003, Current medicinal chemistry.

[16]  D. Goodsell,et al.  Automated docking of substrates to proteins by simulated annealing , 1990, Proteins.

[17]  E. von Angerer,et al.  The inhibitory effect of 5-acetoxy-2-(4-acetoxyphenyl)-1-ethyl-3-methylindole (D 16726) on estrogen-dependent mammary tumors. , 1985, European journal of cancer & clinical oncology.

[18]  G. Duncan,et al.  Mammalian antifertility agents. 3. 1-Aryl-2-phenyl-1,2,3,4-tetrahydro-1-naphthols, 1-aryl-2-phenyl-3,4-dihydronaphthalenes, and their derivatives. , 1966, Journal of medicinal chemistry.

[19]  S. Bräse,et al.  The recent impact of solid-phase synthesis on medicinally relevant benzoannelated nitrogen heterocycles. , 2002, Bioorganic & medicinal chemistry.

[20]  B. C. Sekhar.  Cyclic 1,3‐diones and their derivatives—As versatile reactive intermediates in the syntheses of condensed fused ring heterocyles , 2004 .

[21]  David S. Goodsell,et al.  Distributed automated docking of flexible ligands to proteins: Parallel applications of AutoDock 2.4 , 1996, J. Comput. Aided Mol. Des..

[22]  G. Duncan,et al.  Mammalian antifertility agents. IV. Basic 3,4-dihydronaphthalenes and 1,2,3,4-tetrahydro-1-naphthols. , 1967, Journal of medicinal chemistry.

[23]  Ming-Wei Wang,et al.  Benzothieno[3,2-b]indole derivatives as potent selective estrogen receptor modulators. , 2005, Bioorganic & medicinal chemistry letters.

[24]  B. S. Setty,et al.  Structure activity relationship of some 2,3-diaryl-2H-1-benzopyrans to their anti-implantation, estrogenic and antiestrogenic activities in rat. , 1994, Contraception.

[25]  Zbigniew Dauter,et al.  Molecular basis of agonism and antagonism in the oestrogen receptor , 1997, Nature.

[26]  A. Nishida,et al.  Solid-phase synthesis of 5-(3-indolyl)oxazoles that inhibit lipid peroxidation , 2000 .

[27]  N. Knebel,et al.  1-(aminoalkyl)-2-phenylindoles as novel pure estrogen antagonists. , 1990, Journal of medicinal chemistry.