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Article

Synthesis and Characterization of a Cobalamin−Colchicine Conjugate as a Novel Tumor-Targeted Cytotoxin

Supporting Info

Joshua D. Bagnato,^† Alanna L. Eilers,^‡ Robert A. Horton,^† and Charles B. Grissom*^†

Department of Chemistry, University of Utah, 315 S. 1400 E., Salt Lake City, Utah 84112-0850, and MantiCore Pharmaceuticals, Inc., 2401 Foothill Dr., Salt Lake City, Utah 84109-1405

J. Org. Chem., 2004, 69 (26), pp 8987–8996

DOI: 10.1021/jo049953w

Publication Date (Web): June 3, 2004

†

University of Utah.

‡

MantiCore Pharmaceuticals, Inc.

In papers with more than one author, the asterisk indicates the name of the author to whom inquiries about the paper should be addressed.

, grissomc@chemistry.utah.edu

Abstract

Colchicine was derivatized at C7 with p-alkoxyacetophenone and conjugated to cobalamin (vitamin B₁₂) through an acid-labile hydrazone linker. The cobalamin moiety leads to preferential uptake of the cobalamin−colchicine prodrug by cancer cells, whereupon the hydrazone linker undergoes hydrolysis in the lysosome to unmask colchicine, which acts as a potent cytotoxin by stabilizing microtubules and causing cell death. The bioconjugate is stable in cell culture media and at neutral pH but undergoes hydrolysis with a half-life of 138 min at pH 4.5. The colchicine−cobalamin bioconjugate exhibits nanomolar LC₅₀ values against breast, brain, and melanoma cancer cell lines in culture. Attachment of colchicine to cobalamin is expected to increase the therapeutic index of the drug by limiting the side effects caused by the current nonselective administration of tubulin-targeted chemotherapeutic drugs.

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