Article
Non-cytotoxic 1,2,3-triazole tethered fused heterocyclic ring derivatives display Tax protein inhibition and impair HTLV-1 infected cells
Registro en:
SANTOS, Daiane Fernanda dos et al. Non-cytotoxic 1,2,3-triazole tethered fused heterocyclic ring derivatives display Tax protein inhibition and impair HTLV-1 infected cells. Bioorganic and Medicinal Chemistry, 2020.
0968-0896
10.1016/j.bmc.2020.115746
Autor
Santos, Daiane Fernanda dos
Pilger, Denise Regina Bairros de
Vandermeulen, Charlotte
Cunha, Antonio Ricardo Khouri
Mantoani, Susimaire Pedersoli
Nunes, Paulo Sérgio Gonçalves
Andrade, Peterson de
Carvalho, Ivone
Casseb, Jorge
Twizere, Jean-Claude
Willems, Luc
Freitas Junior, Lucio
Kashima, Simone
Resumen
Fundação de Amparo à
Pesquisa do Estado de São Paulo (FAPESP, n. 2015/11566-0 and n.
2016/17301-1) and Conselho Nacional de Desenvolvimento Científico e
Tecnológico (CNPq, n. 462290/2014-0). Human T cell lymphotropic virus type 1 (HTLV-1) is a human retrovirus that infects approximately 10–20
million people worldwide and causes an aggressive neoplasia (adult T-cell leukemia/lymphoma - ATL).
Therapeutic approaches for the treatment of ATL have variable effectiveness and poor prognosis, thus requiring
strategies to identify novel compounds with activity on infected cells. In this sense, we initially screened a small
series of 25 1,2,3-triazole derivatives to discover cell proliferation inhibitors and apoptosis inducers in HTLV-1-
infected T-cell line (MT-2) for further assessment of their effect on viral tax activity through inducible-tax reporter
cell line (Jurkat LTR-GFP). Eight promising compounds (02, 05, 06, 13, 15, 21, 22 and 25) with activity
≥70% were initially selected, based on a suitable cell-based assay using resazurin reduction method, and
evaluated towards cell cycle, apoptosis and Tax/GFP expression analyses through flow cytometry. Compound 02
induced S phase cell cycle arrest and compounds 05, 06, 22 and 25 promoted apoptosis. Remarkably, compounds
22 and 25 also reduced GFP expression in an inducible-tax reporter cell, which suggests an effect on Tax
viral protein. More importantly, compounds 02, 22 and 25 were not cytotoxic in human hepatoma cell line
(Huh-7). Therefore, the discovery of 3 active and non-cytotoxic compounds against HTLV-1-infected cells can
potentially contribute, as an initial promising strategy, to the development process of new drugs against ATL.