dos Santos, DF;
Bairros de Pilger, DR;
Vandermeulen, C;
Khouri, R;
Mantoani, SP;
Goncalves Nunes, PS;
de Andrade, P;
... Kashima, S; + view all
(2020)
Non-cytotoxic 1,2,3-triazole tethered fused heterocyclic ring derivatives display Tax protein inhibition and impair HTLV-1 infected cells.
Bioorganic & Medicinal Chemistry
, 28
(22)
, Article 115746. 10.1016/j.bmc.2020.115746.
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Non-cytotoxic 1,2,3-triazole tethered fused heterocyclic ring derivatives display Tax protein inhibition and impair HTLV-1 infected cells.pdf - Accepted Version Download (4MB) | Preview |
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.
| Type: | Article |
|---|---|
| Title: | Non-cytotoxic 1,2,3-triazole tethered fused heterocyclic ring derivatives display Tax protein inhibition and impair HTLV-1 infected cells |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.bmc.2020.115746 |
| Publisher version: | https://doi.org/10.1016/j.bmc.2020.115746 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Physical Sciences, Biochemistry & Molecular Biology, Chemistry, Medicinal, Chemistry, Organic, Pharmacology & Pharmacy, Chemistry, HTLV-1, ATL, Compound screening, Cell proliferation, Apoptosis, Tax protein |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Lab for Molecular Cell Bio MRC-UCL |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10121841 |
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