Solid and Solution Phase Synthesis and Biological Evaluation of Combinatorial Sarcodictyin Libraries

Nicolaou, K. C.; Winssinger, Nicolas; Vourloumis, D.; Ohshima, T.; Kim, S.; Pfefferkorn, J.; Xu, J.-Y.; Li, T.

doi:10.1021/ja9823870

Scientific article

English

Solid and Solution Phase Synthesis and Biological Evaluation of Combinatorial Sarcodictyin Libraries

Contributors

Nicolaou, K. C.; Winssinger, Nicolas

; Vourloumis, D.; Ohshima, T.; Kim, S.; Pfefferkorn, J.; Xu, J.-Y.; Li, T.

Published in

Journal of the American Chemical Society, vol. 120, no. 42, p. 10814-10826

Publication date

1998

Abstract

Isolated from certain species of soft corals, the sarcodictyins, eleutherobin, and eleuthosides have become important synthetic targets due the their novel molecular architectures, important biological activities, and potential in medicine. Of particular interest is their Taxol-like mechanism of action involving disturbance of the tubulin−microtubule interplay resulting in tumor cell death. Their scarcity and biological profile prompted us to initiate a program directed at exploring their chemical synthesis and chemical biology. Herein we report (a) the first total synthesis of sarcodictyins A (7) and B (8) by a combination of solution and solid-phase methods through the attachment of the common precursors 18 or 20 on solid support, thus generating conjugates 23 and 24, followed by standard chemical manipulations; (b) the construction of a combinatorial library of sarcodictyins by solution and solid-phase chemistry modifying the C-8 ester, C-15 ester, and C-4 ketal functionalities, and, therefore, producing analogues of the general structures 33, 37, and 40; (c) the tubulin polymerization properties of all members of the library; and (d) the cytotoxic actions of a selected number of these compounds against a number of tumor cells including Taxol-resistant lines. Several of the synthesized analogues were identified to be of equal or superior biological activities (e.g. 60, 61, 63, 66−70, 73, 76, 85, 92) as compared to the natural products, setting the stage for further developments in the field of cancer chemotherapy.

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Not a UNIGE publication

Citation (ISO format)

NICOLAOU, K. C. et al. Solid and Solution Phase Synthesis and Biological Evaluation of Combinatorial Sarcodictyin Libraries. In: Journal of the American Chemical Society, 1998, vol. 120, n° 42, p. 10814–10826. doi: 10.1021/ja9823870

Article (Published version)

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PID : unige:24499
DOI : 10.1021/ja9823870

Journal ISSN

0002-7863

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Solid and Solution Phase Synthesis and Biological Evaluation of Combinatorial Sarcodictyin Libraries

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Citation (ISO format)

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