Identification of novel aza-analogs of TN-16 as disrupters of microtubule dynamics through a multicomponent reaction.
Eur J Med Chem
; 245(Pt 1): 114895, 2023 Jan 05.
Article
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| MEDLINE
| ID: mdl-36370553
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.
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MEDLINE
Assunto principal:
Pirrolidinonas
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Moduladores de Tubulina
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Antineoplásicos
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article