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Hemiasterlin analogues incorporating an aromatic, and heterocyclic type C-terminus: design, synthesis and biological evaluation

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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 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.

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Notes

  1. Scores are reported as obtained by the similarity analysis function implemented in the Spartan’06 software. The score is defined as [\((1-R2)/N\)], where R2 is the rms distance between template and molecule centers, and N is the number of similarity centers.

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Authors and Affiliations

  1. Dipartimento di Chimica, Università di Milano, via Golgi 19, Milan, 20133, Italy

    Giordano Lesma, Alessandra Silvani & Nadia Vaiana

  2. Dipartimento di Chimica, Materiali ed Ing.Chimica ‘Giulio Natta’, Politecnico di Milano, p.zza Leonardo da Vinci 32, Milan, 20133, Italy

    Alessandro Sacchetti

  3. Screening Technologies Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Frederick National Laboratory for Cancer Research, National Institutes of Health, Frederick, MD, 21702, USA

    Rouli Bai & Ernest Hamel

  4. Dipartimento di Salute della Donna e del Bambino, Università degli Studi di Padova, via Giustiniani 2, Padau, 35128, Italy

    Giuseppe Basso, Roberta Bortolozzi & Giampietro Viola

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  1. Giordano Lesma
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  2. Alessandro Sacchetti
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Correspondence to Alessandra Silvani.

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Lesma, G., Sacchetti, A., Bai, R. et al. Hemiasterlin analogues incorporating an aromatic, and heterocyclic type C-terminus: design, synthesis and biological evaluation. Mol Divers 18, 357–373 (2014). https://doi.org/10.1007/s11030-014-9507-9

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