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Solid and Solution Phase Synthesis and Biological Evaluation of Combinatorial Sarcodictyin Libraries
journal contribution
posted on 1998-10-09, 00:00 authored by K. C. Nicolaou, N. Winssinger, D. Vourloumis, T. Ohshima, S. Kim, J. Pfefferkorn, J.-Y. Xu, T. LiIsolated 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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analoguechemical synthesisBiological Evaluationsarcodictyinesterstructures 33solutioncombinatorial libraryconjugates 23cancer chemotherapytumor cellschemical biologytubulin polymerization propertiestumor cell deathcytotoxic actionsprecursors 18Combinatorial Sarcodictyin Librarieschemical manipulationsSolution Phase Synthesis
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