Non-cytotoxic 1, 2, 3-triazole tethered fused heterocyclic ring derivatives display Tax protein inhibition and impair HTLV-1 infected cells. Issue 22 (15th November 2020)

• Record Type: Journal Article
• Authors: dos Santos, Daiane Fernanda; de Pilger, Denise Regina Bairros; Vandermeulen, Charlotte; Khouri, Ricardo; Mantoani, Susimaire Pedersoli; Nunes, Paulo Sérgio Gonçalves; de Andrade, Peterson; Carvalho, Ivone; Casseb, Jorge; Twizere, Jean-Claude; Willems, Luc; Freitas-Junior, Lucio; Kashima, Simone
• Is Part Of: Bioorganic & medicinal chemistry. Volume 28:Issue 22(2020)
• Publication Date: 2020-11-15
• Subjects: HTLV-1 -- ATL -- Compound screening -- Cell proliferation -- Apoptosis -- Tax protein; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2020.115746
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Highlights: 1, 2, 3-triazole tethered fused heterocyclic ring derivatives have been synthesized. 8 compounds decreased the metabolic activity of HTLV-1-infected cell line (MT-2). 02 induced S phase cell cycle arrest and 05, 06, 22 and 25 promoted apoptosis. 22 and 25 have also inhibited GFP expression in the inducible-tax reporter cell line. 3 non-cytotoxic active compounds against HTLV-1-infected cells have been discovered. Abstract: 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.