Discovery of Antitumor Indolocarbazoles: Rebeccamycin, NSC 655649, and Fluoroindolocarbazoles

ISSN: 1875-5992 (Online)
ISSN: 1871-5206 (Print)

Volume 16, 12 Issues, 2016

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Anti-Cancer Agents in Medicinal Chemistry

Formerly: Current Medicinal Chemistry - Anti-Cancer Agents

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Michelle Prudhomme
Universite Blaise Pascal - C.N.R.S
Aubiere Cedex

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Discovery of Antitumor Indolocarbazoles: Rebeccamycin, NSC 655649, and Fluoroindolocarbazoles

Anti-Cancer Agents in Medicinal Chemistry, 2(2): 255-266.

Author(s): Byron H. Long, William C. Rose, Dolatrai M. Vyas, James A. Matson and Salvatore Forenza.

Affiliation: K22-01, Pharmaceutical Research Institute, Bristol-Myers Squibb, Princeton, NJ, U.S.A


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 ca mptothecin. 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.


Antitumor Indolocarbazoles, Fluoroindolocarbazoles, fluoroindolocarbazoles (FICs), Rebeccamycin (RBM), Fluorotryptophan, 7-oxostaurosporine, 1,11-dideschloro-6-N-hydroxy RBM.

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Article Details

Volume: 2
Issue Number: 2
First Page: 255
Last Page: 266
Page Count: 12
DOI: 10.2174/1568011023354218
Price: $58

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