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-<scp>d</scp>-glucopyranosyl]-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.

Balasubramanian, Balu; Laurent, Denis R. St.; Saulnier, Mark G.; Long, Byron H.; Bachand, Carol; Beaulieu, Françis; Clarke, Wendy; Deshpande, M. P.; Eummer, Jeffrey; Fairchild, Craig R.; Frennesson, David B.; Krämer, Robert; Lee, Frank Y.; Mahler, Mikael; Martel, Alain; Naidu, B. Narasimhulu; Rose, William C.; Russell, John A.; Ruediger, E. H.; Solomon, Carola; Stoffan, Karen; Wong, H. N. C.; Wright, John; Zimmermann, Kurt; Vyas, Dolatrai M.

doi:10.1021/jm040089+

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“…The findings from this study are valuable because they can aid the design of novel Top1 poisons. 3,9-Difluorinated indolocarbazole glycosides have demonstrated efficacy in preclinical models and advanced to human clinical trials. , The 3-position substituents on the indenoisoquinoline and indolocarbazole scaffolds project toward Asn722 . This observation provides support for a universal structure–activity relationship for the Top1 poisons, and may therefore aid in the structure-based design and optimization of new and different Top1 poisons. − …”

Section: Discussionmentioning

confidence: 95%

Discovery of Potent Indenoisoquinoline Topoisomerase I Poisons Lacking the 3-Nitro Toxicophore

Beck

Abdelmalak

et al. 2015

J. Med. Chem.

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3-Nitroindenoisoquinoline human topoisomerase IB (Top1) poisons have potent antiproliferative effects on cancer cells. The undesirable nitro toxicophore could hypothetically be replaced by other functional groups that would retain the desired biological activities and minimize potential safety risks. Eleven series of indenoisoquinolines bearing 3-nitro bioisosteres were synthesized. The molecules were evaluated in the Top1-mediated DNA cleavage assay and in the National Cancer Institute's 60 cell line cytotoxicity assay. The data reveal that fluorine and chlorine may substitute for the 3-nitro group with minimal loss of Top1 poisoning activity. The new information gained from these efforts can be used to design novel indenoisoquinolines with improved safety.

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Section: Discussionmentioning

confidence: 95%

Discovery of Potent Indenoisoquinoline Topoisomerase I Poisons Lacking the 3-Nitro Toxicophore

Beck

Abdelmalak

et al. 2015

J. Med. Chem.

View full text Add to dashboard Cite

show abstract

Cited by 1 publication

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Discovery of Potent Indenoisoquinoline Topoisomerase I Poisons Lacking the 3-Nitro Toxicophore

Discovery of Potent Indenoisoquinoline Topoisomerase I Poisons Lacking the 3-Nitro Toxicophore

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