title: Discovery of antitumor indolocarbazoles: rebeccamycin, NSC 655649, and fluoroindolocarbazoles.
abstract: A fermentation directed product search for potential anticancer drugs conducted by Bristol-Myers in the 1970s and early 1980s resulted in the identification of a novel indolocarbazole (IC) rebeccamycin (RBM) as a potential drug development candidate. Subsequently, an analog program designed to impart distal site in vivo antitumor activity resulted in the discovery of diethylaminoethyl analog of RBM (DEAE-RBM), which is presently undergoing clinical evaluation as NSC 655649 and BMY-27557. Strong DNA intercalation is the primary mechanism of action of DEAE-RBM resulting in the potent catalytic inhibition of both topoisomerases I and II. Precursor feeding fermentation experiments with fluorine-substituted tryptophans yielded novel fluoroindolocarbazoles (FICs). These FICs were identified as targeting topoisomerase (topo) I in a mechanism-based screen and their action on topo I was confirmed by production of topo I-mediated single-strand breaks in DNA at sites essentially identical to those induced by camptothecin. Topo I dependent cytotoxicity was demonstrated for specific FICs using a P388 and camptothecin-resistant P388/CPT45 pair of cell lines, the latter expresses little or no functional topo I. For example, topo I selectivity was greatest with 3,9-difluoro substituted FIC and was least significant and least cytotoxic with 4,8-difluoro substituted FIC. The review focuses on the discovery of the rebeccamycin class of compounds and their structure-activity relationships leading to the development of the clinical candidate BMY-27557 (NSC 655649), as well as the lead identification of the fluoroindolocarbazole class of compounds.
authors.affiliation: Pharmaceutical Research Institute, Bristol-Myers Squibb, Wallingford, CT 06492, USA. byron.long@bms.com
authors.forename: Byron H
authors.initials: BH
authors.lastname: Long
authors.forename: William C
authors.initials: WC
authors.lastname: Rose
authors.forename: Dolatrai M
authors.initials: DM
authors.lastname: Vyas
authors.forename: James A
authors.initials: JA
authors.lastname: Matson
authors.forename: Salvatore
authors.initials: S
authors.lastname: Forenza
mesh_terms: D000617:Aminoglycosides; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis / Q000494:pharmacology*; D002227:Carbazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D015195:Drug Design; D005960:Glucosides; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000494:pharmacology*; D009369:Neoplasms / Q000188:drug therapy; D013329:Structure-Activity Relationship
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D000903:Antibiotics, Antineoplastic; D002227:Carbazoles; D005960:Glucosides; D007211:Indoles; C053339:rebeccamycin; C093269:becatecarin