Design and Synthesis of a Fluoroindolocarbazole Series as Selective Topoisomerase I Active Agents. Discovery of Water-Soluble 3,9-Difluoro-12,13-dihydro-13-[6-amino-β-D-glucopyranosyll]-5H,13H-benzo[b] -thienyl[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione (BMS-251873) with Curative Antitumor Activity against Prostate Carcinoma Xenograft Tumor Model

Journal of Medicinal Chemistry

Volumn 47, Issue 7, 2004, Pages 1609-1612

  Balasubramanian, Balu N ^a   St Laurent, Denis R ^a   Saulnier, Mark G ^a   Long, Byron H ^a   Bachand, Carol ^a   Beaulieu, Francis ^a   Clarke, Wendy ^a   Deshpande, Milind ^a   Eummer, Jeffrey ^a   Fairchild, Craig R ^a   Frennesson, David B ^a   Kramer, Robert ^a   Lee, Frank Y ^a   Mahler, Mikael ^a   Martel, Alain ^a   Naidu, B Narasimhulu ^a   Rose, William C ^a   Russell, John ^a   Ruediger, Edward ^a   Solomon, Carola ^a   Stoffan, Karen M ^a   Wong, Henry ^a   Zimmermann, Kurt ^a   Vyas, Dolatrai M ^a   more..

^a BRISTOL MYERS SQUIBB PHARMACEUTICAL RESEARCH INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

3,9 DIFLUORO 12,13 DIHYDRO 13 (6 AMINO BETA DEXTRO GLUCOPYRANOSYL) 5H,13H BENZO[B]THIENYL[2,3 A]PYRROLO[3,4 C]CARBAZOLE 5,7(6H) DIONE; BMS 251873; CARBAZOLE DERIVATIVE; DNA TOPOISOMERASE INHIBITOR; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTINEOPLASTIC ACTIVITY; ARTICLE; CANCER MODEL; DRUG CYTOTOXICITY; DRUG DESIGN; DRUG EFFECT; DRUG EFFICACY; DRUG SELECTIVITY; DRUG SOLUBILITY; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME ACTIVITY; HUMAN; HUMAN CELL; MOUSE; NONHUMAN; PROSTATE CARCINOMA; REACTION ANALYSIS; STRUCTURE ANALYSIS; TUMOR XENOGRAFT;

ANIMALS; ANTINEOPLASTIC AGENTS; CARBAZOLES; DNA TOPOISOMERASES, TYPE I, EUKARYOTIC; GLUCOSIDES; MALE; MICE; NEOPLASM TRANSPLANTATION; PROSTATIC NEOPLASMS; SOLUBILITY; STRUCTURE-ACTIVITY RELATIONSHIP; WATER; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 12144288796     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm034197s     Document Type: Article

References (17)

1. (a) Wang, H.-K.; Morris-Natschke, S. L.; Lee, K.-H. Recent Advances in the Discovery and Development of Topoisomerase Inhibitors as Antitumor Agents. Med. Res. Rev. 1997, 17, 367-425 and references therein.
2. (b) Bailly, C. Topoisomerase I poisons and suppressors as anticancer drugs. Cur. Med. Chem. 2000, 7, 39-58 and references therein.
3. (a) Wall, M. E Camptothecin and taxol: discovery to clinic. Med. Res. Rev. 1998, 18, 299-314 and references therein.
4. (b) Bissery, M. C.; Vrignaud, P.; Lavelle, F.; Chabot, G. G. Experimental antitumor activity and pharmacokinetics of the camptothecin analog irinotecan (CPT-11) in mice. Anti-Cancer Drugs 1996, 7, 437-460 and references therein.
5. (a) Pindur, U.; Kim, Y.-S.; Mehrabani, F. Advances in indolo[2,3-a]carbazole chemistry: design and synthesis of protein kinase C and topoisomerase I inhibitors. Curr. Med. Chem. 1999, 6, 29-69.
6. (b) Long, B. H.; Balasubramanian, B. N. Non-camptothecin topoisomerase I active compounds as potential anticancer agents. Expert Opin. Ther. Pat. 2000, 10, 635-666.
7. Long, B. H.; Rose, W. C.; Vyas, D. M.; Matson, J. A.; Forenza, S. Discovery of antitumor indolocarbazoles: rebeccamycin, NSC 655649, and fluoroindolo-carbazoles. Curr. Med. Chem.: Anti-Cancer Agents 2002, 2, 255-266.
8. Ohkubo, M.; Nishimura, T.; Jona, H.; Honma, T.; Morishima, H. Practical synthesis of indolopyrrolo-carbazoles. Tetrahedron 1996, 52, 8099-8112.
9. (a) Bisagni, M.; Buu-Hoi, N. G.; Royer, R. Oxygen Heterocycles. Part III. The Reactivity of Benzofuran and 2-Alkylbenzofurans. J. Chem. Soc. 1955, 3688-3693.
10. (b) Adaptation using 2-(2-indolyl)benzofurans and benzothiophenes in conjunction with ref 5.
11. Gallant, M.; Link, J. T.; Danishefsky, S. J. A stereoselective synthesis of indolo-β-N-glycosides: an application to the synthesis of rebeccamycin. J. Org. Chem. 1993, 58, 343-349.
12. Ohkubo, M.; Kawamoto, H.; Ohno, T.; Nakano, M.; Morishima, H. Synthesis of NB-506, a new anticancer agent. Tetrahedron 1997, 53, 585-592.
13. Ohkubo, M.; Nishimura, T.; Jona, H.; Honma, T.; Ito, S.; Morishima, H. Synthesis of Dissymmetric Indolocarbazole Glycosides Using the Mitsunobu Reaction at the Glycosylation Step. Tetrahedron 1997, 53, 5937-50.
14. (a) The procedure for assaying compound-induced, topoisomerase I mediated single-strand breaks in DNA was essentially that described by Hsiang et al. in J. Biol. Chem. 1985, 260, 14873-14878.
15. 50, which is the drug concentration required to inhibit cell proliferation (i.e., absorbance at 450 nm) to 50% of that of untreated control cells.
16. Facompré, M.; Carrasco, C.; Vezin, H.; Chisholm, J. D.; Yoburn, J. C.; Van Vranken, D. L.; Bailly, C. Indolocarbazole Glycosides in Inactive Conformations. ChemBioChem 2003, 4, 386-395 and references therein (e.g., refs 1 and 9).
17. LCK (log of cell kill) is defined as the in vivo antitumor activity obtained against solid tumor implanted sc following iv, ip, or po administration of the agent and is calculated according to the guidelines described in Anti-Cancer Drugs 1996, 7, 437-460.