Synthesis and anticancer activity studies of cyclopamine derivatives

Authors: ZHANG, JIANJUN - USU; GARROSSIAN, MASSOUD - LOGAN NATURAL PROD. INC; Gardner, Dale; GARROSSIAN, ARASH - USU; CHANG, YOUNG-TAE - NYU; KIM, YUN - NYU; CHANG, CHENG-WEI - USU

Submitted to: Bioorganic and Medicinal Chemistry Letters
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/3/2008
Publication Date: 1/9/2008
Citation: Zhang, J., Garrossian, M., Gardner, D.R., Garrossian, A., Chang, Y., Kim, Y.K., Chang, C.T. 2008. Synthesis and anticancer activity studies of cyclopamine derivatives. Bioorganic and Medicinal Chemistry Letters. Online 18(2008) 1359-1363.

Interpretive Summary: The chemical compound cyclopamine is found naturally in Veratrum californicum, also known as the Corn Lilly plant. Cyclopamine is responsible for the teratogenic effects of this plant in sheep, but more recently has been found to have potent anticancer activity. In efforts to manipulate the physiochemical and biological properties a number of chemical derivatives of cylopamine were synthetically prepared by combining a carbohydrate unit and an N-alkyl linker in sequence with cyclopamine. Chemical units were chosen to optimize solubility of cyclopamine along with retaining or enhancing anticancer activity. From the created derivatives, one compound was found to exhibit improved activity against a lung cancer cells in comparison to the original cyclopamine.

Technical Abstract: A diversity-oriented synthesis has been developed for facile construction of a library of carbohydrate-cyclopamine conjugates. The synthetic protocol is suitable for generating cyclopamine derivatives with various structural motifs for exploring the desired activity. From this initial library, we have observed one derivative that exhibits improved activity against lung cancer cell as compared to cyclopamine.