Syntheses and biological evaluation of vinblastine congeners

Martin E. Kuehne; William G. Bornmann; Istvan Markó; Yong Qin; Karen L. LeBoulluec; Deborah A. Frasier; Feng Xu; Tshilundu Mulamba; Carol L. Ensinger; Linda S. Borman; Anne E. Huot; Christopher Exon; Fred T. Bizzarro; Julia B. Cheung; Susan L. Bane

doi:10.1039/B209990J

Syntheses and biological evaluation of vinblastine congeners†

Martin E. Kuehne,*^a William G. Bornmann,^a Istvan Markó,^a Yong Qin,^a Karen L. LeBoulluec,^a Deborah A. Frasier,^a Feng Xu,^a Tshilundu Mulamba,^a Carol L. Ensinger,^a Linda S. Borman,^b Anne E. Huot,^c Christopher Exon,^d Fred T. Bizzarro,^d Julia B. Cheung^d and Susan L. Bane^e

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^a Department of Chemistry, University of Vermont, Burlington, VT 05405, USA

^b Department of Pharmacology and Vermont Regional Cancer Center, University of Vermont, Burlington, VT 05405, USA

^c Biomedical Technologies, University of Vermont, Burlington, VT 05405, USA

^d Hoffmann La Roche, Inc., Nutley, NJ 07110, USA

^e Department of Chemistry, SUNY, Binghamton, NY 13902, USA

Abstract

Sixty-two congeners of vinblastine (VLB), primarily with modifications of the piperidine ring in the carbomethoxycleavamine moiety of the binary alkaloid, were synthesized and evaluated for cytotoxicity against murine L1210 leukemia and RCC-2 rat colon cancer cells, and for their ability to inhibit polymerization of microtubular protein at <10⁻⁶ M, and for induction of spiralization of microtubular protein, and for microtubular disassembly at 10⁻⁴ M concentrations. An ID₅₀ range of >10⁷ M concentrations was found for L1210 inhibition by these compounds, with the most active 1000× as potent as vinblastine.

Organic & Biomolecular Chemistry

Syntheses and biological evaluation of vinblastine congeners†

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Syntheses and biological evaluation of vinblastine congeners

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