2. Academic Validation
  3. Efficient synthesis and antitumor evaluation of 4-aminomethyl-N-arylpyrazoles: Discovery of potent and selective agents for ovarian cancer

Efficient synthesis and antitumor evaluation of 4-aminomethyl-N-arylpyrazoles: Discovery of potent and selective agents for ovarian cancer

  • Bioorg Med Chem. 2021 Jan 1:29:115835. doi: 10.1016/j.bmc.2020.115835.
Michael J V da Silva 1,  Andrey P Jacomini 1,  Mariana C Figueiredo 2,  Davi F Back 3,  Mary A Foglio 2,  Ana L T G Ruiz 4,  Fávero R Paula 5,  Fernanda A Rosa 6
Affiliations

Affiliations

  • 1 Departamento de Química, Universidade Estadual de Maringá (UEM), 87030-900 Maringá, PR, Brazil.
  • 2 Faculdade de Ciências Farmacêuticas, Universidade Estadual de Campinas (UNICAMP), 13083-859 Campinas, SP, Brazil.
  • 3 Departamento de Química, Universidade Federal de Santa Maria (UFSM), 97110-970 Santa Maria, RS, Brazil.
  • 4 Faculdade de Ciências Farmacêuticas, Universidade Estadual de Campinas (UNICAMP), 13083-859 Campinas, SP, Brazil; Centro Pluridisciplinar de Pesquisas Químicas, Biológicas e Agrícolas (CPQBA), Universidade Estadual de Campinas, 13083-970 Campinas, SP, Brazil.
  • 5 Departamento de Farmácia, Universidade Federal do Pampa (UNIPAMPA), 97500-970 Uruguaiana, RS, Brazil.
  • 6 Departamento de Química, Universidade Estadual de Maringá (UEM), 87030-900 Maringá, PR, Brazil. Electronic address: farosa@uem.br.
PMID: 33214037 DOI: 10.1016/j.bmc.2020.115835
Abstract

A new one-pot two-step sequential methodology for synthesis of novel 3-carboxyethyl 4-[(tert-butylamino)methyl]-N-arylpyrazole derivatives is reported. One-pot transformation of β-enamino diketones and arylhydrazines generated 4-iminium-N-arylpyrazole salt intermediates in situ, which were easily transformed into 4-[(tert-butylamino)methyl]-N-arylpyrazole derivatives by NaBH3CN. The products could be isolated in the free or hydrochloride salt forms. Also, it was possible to obtain the products in the zwitterionic form by ester group hydrolysis. Furthermore, all synthesised compounds were evaluated in vitro against a panel of eight human tumor cell lines. The 4-[(tert-butylamino)methyl]-N-arylpyrazole derivatives were much more powerful than the hydrochloride and zwitterionic forms. Moreover, the results suggest that the N-aryl group at the pyrazole ring is vital for modulating antiproliferative activity. The 3-carboxyethyl 4-[(tert-butylamino)methyl]-N-phenylpyrazoles 3a-g exhibited higher inhibitory activities against OVCAR-3, with GI50 values of 0.013-8.78 μM, and lower inhibitory activities against normal human cell lines. Molecular docking was performed to evaluate the probable binding mode of 3a into active site of CDK2.

Keywords

Amino(methyl)pyrazole; Antitumor; One-pot reactions; Ovarian cancer.

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