2. Academic Validation
  3. Identification of novel aza-analogs of TN-16 as disrupters of microtubule dynamics through a multicomponent reaction

Identification of novel aza-analogs of TN-16 as disrupters of microtubule dynamics through a multicomponent reaction

  • Eur J Med Chem. 2023 Jan 5;245(Pt 1):114895. doi: 10.1016/j.ejmech.2022.114895.
Arash Foroutan 1,  Marco Corazzari 2,  Ambra A Grolla 1,  Giorgia Colombo 1,  Cristina Travelli 3,  Armando A Genazzani 1,  Sewan Theeramunkong 4,  Ubaldina Galli 5,  Gian Cesare Tron 1
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, Università del Piemonte Orientale "Amedeo Avogadro", 28100, Novara, Italy.
  • 2 Department of Health Science (DSS), Center for Translational Research on Autoimmune and Allergic Disease (CAAD) & Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), Università del Piemonte Orientale "Amedeo Avogadro,", 28100, Novara, Italy.
  • 3 Department of Drug Sciences, Università degli Studi di Pavia, 27100, Pavia, Italy.
  • 4 Department of Pharmaceutical Sciences, Faculty of Pharmacy, Thammasat University Research Unit in Drug, Health Product Development and Application (DHP-DA), Thammasat University, Klong Luang, 12120, Pathum Thani, Thailand.
  • 5 Department of Pharmaceutical Sciences, Università del Piemonte Orientale "Amedeo Avogadro", 28100, Novara, Italy. Electronic address: ubaldina.galli@uniupo.it.
PMID: 36370553 DOI: 10.1016/j.ejmech.2022.114895
Abstract

Despite novel biological targets emerging at an impressive rate for Anticancer therapy, antitubulin drugs remain the backbone of numerous oncological protocols and their efficacy has been demonstrated in a wide variety of adult and pediatric cancers. In the present contribution, we set to develop analogs of a potent but neglected antitubulin agent, TN-16, originally discovered via modification of tenuazonic acid (3-acetyl-5-sec-butyltetramic acid). To this extent, we developed a novel multicomponent reaction to prepare TN-16, and then we applied the same reaction for the synthesis of aza-analogs. In brief, we prepared a library of 62 novel compounds, and three of these retained nanomolar potencies. TN-16 and the active analogs are cytotoxic on Cancer cell lines and, as expected from antitubulin agents, induce G2/M cell cycle arrest. These agents lead to a disruption of the microtubules and an increase in α-tubulin acetylation and affect in vitro polymerization, although they have a lesser effect in cellular tubulin polymerization assays.

Keywords

Anticancer compounds; Colchicine binding site; Multicomponent reactions; TN-16; Tubulin.

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