A representative series of structural analogs of the antimitotic tripeptides hemiasterlins have been designed and synthesized, as potential inhibitors of tubulin polymerization. Relying also on a computational approach, we aimed to explore unknown extensive changes at the C-fragment, by incorporating the conformationally required double bond into five- and six-membered rings. Key steps of the synthetic strategy are a dynamic resolution affording theA-fragment in 97 % ee and the preparation of six new cyclic C fragments, all potentially able to interact with tubulin by means of H bonds. Unexpectedly, biological evaluation of these analogs did not provide evidences neither for cytotoxic effect nor for inhibition of tubulin polymerization.
Hemiasterlin analogues incorporating an aromatic, and heterocyclic type C-terminus: design, synthesis and biological evaluation / G. Lesma, A. Sacchetti, R. Bai, G. Basso, R. Bortolozzi, E. Hamel, A. Silvani, N. Vaiana, G. Viola. - In: MOLECULAR DIVERSITY. - ISSN 1381-1991. - 18:2(2014), pp. 357-373. [10.1007/s11030-014-9507-9]
Hemiasterlin analogues incorporating an aromatic, and heterocyclic type C-terminus: design, synthesis and biological evaluation
G. LesmaPrimo
;A. Silvani
;
2014
Abstract
A representative series of structural analogs of the antimitotic tripeptides hemiasterlins have been designed and synthesized, as potential inhibitors of tubulin polymerization. Relying also on a computational approach, we aimed to explore unknown extensive changes at the C-fragment, by incorporating the conformationally required double bond into five- and six-membered rings. Key steps of the synthetic strategy are a dynamic resolution affording theA-fragment in 97 % ee and the preparation of six new cyclic C fragments, all potentially able to interact with tubulin by means of H bonds. Unexpectedly, biological evaluation of these analogs did not provide evidences neither for cytotoxic effect nor for inhibition of tubulin polymerization.Pubblicazioni consigliate
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