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  2. Development of Potent Microtubule Targeting Agent by Structural Simplification of Natural Diazonamide

Development of Potent Microtubule Targeting Agent by Structural Simplification of Natural Diazonamide

  • J Med Chem. 2024 Jun 13;67(11):9227-9259. doi: 10.1021/acs.jmedchem.4c00388.
Toms Kalnins 1 Viktorija Vitkovska 1 Mihail Kazak 1 Diana Zelencova-Gopejenko 1 Melita Ozola 1 Nauris Narvaiss 1 Marina Makrecka-Kuka 1 Ilona Domračeva 1 Artis Kinens 1 Baiba Gukalova 1 Nele Konrad 2 Riina Aav 2 Francesca Bonato 3 Daniel Lucena-Agell 3 J Fernando Díaz 3 Edgars Liepinsh 1 Edgars Suna 1
Affiliations

Affiliations

  • 1 Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga LV-1006, Latvia.
  • 2 Department of Chemistry and Biotechnology, Tallinn University of Technology, Akadeemia tee 15, Tallinn, Harju Maakon 12618, Estonia.
  • 3 Unidad BICS, Centro de Investigaciones Biologicas Margarita Salas, Consejo Superior de Investigaciones Cientificas, Ramiro de Maeztu 9, Madrid 28040, Spain.
Abstract

The marine metabolite diazonamide A exerts low nanomolar cytotoxicity against a range of tumor cell lines; however, its highly complex molecular architecture undermines the therapeutic potential of the natural product. We demonstrate that truncation of heteroaromatic macrocycle in natural diazonamide A, combined with the replacement of the challenging-to-synthesize tetracyclic hemiaminal subunit by oxindole moiety leads to considerably less complex analogues with improved drug-like properties and nanomolar antiproliferative potency. The structurally simplified macrocycles are accessible in 12 steps from readily available indolin-2-one and tert-leucine with excellent diastereoselectivity (99:1 dr) in the key macrocyclization step. The most potent macrocycle acts as a tubulin assembly inhibitor and exerts similar effects on A2058 cell cycle progression and induction of Apoptosis as does marketed microtubule-targeting agent vinorelbine.

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