Hemiasterlin analogues incorporating an aromatic, and heterocyclic type C-terminus: design, synthesis and biological evaluation.
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 the A-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.
Dipartimento di Chimica, Università di Milano, via Golgi 19, Milan, 20133, Italy.
Giordano
G
Lesma
Alessandro
A
Sacchetti
Rouli
R
Bai
Giuseppe
G
Basso
Roberta
R
Bortolozzi
Ernest
E
Hamel
Alessandra
A
Silvani
Nadia
N
Vaiana
Giampietro
G
Viola
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D006571:Heterocyclic Compounds / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D055503:Protein Multimerization / Q000187:drug effects; D020836:Protein Structure, Quaternary; D014404:Tubulin / Q000737:chemistry; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D000970:Antineoplastic Agents; D006571:Heterocyclic Compounds; D009842:Oligopeptides; D014404:Tubulin; D050257:Tubulin Modulators; C467070:hemiasterlin