Synthesis and evaluation of novel hybrids beta-carboline-4-thiazolidinones as potential antitumor and antiviral agents

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Barbosa, Valeria Aquilino ; Barea, Paula ; Mazia, Renata Sespede ; Ueda-Nakamura, Tania ; da Costa, Willian Ferreira ; Foglio, Mary Ann ; Goes Ruiz, Ana Lucia T. ; de Carvalho, Joao Ernesto ; Vendramini-Costa, Debora Barbosa ; Nakamura, Celso Vataru ; Sarragiotto, Maria Helena

• Document type: Journal article
• Source: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY; v. 124, p. 1093-1104, NOV 29 2016.
• Web of Science Citations: 16

Abstract

A series of novel hybrids beta-carboline-4-thiazolidinones were synthesized and evaluated for their in vitro antitumor activity against human cancer cell lines and for antiviral activity towards Herpes simplex virus type-1 (HSV-1). From the N'-(2-ylidene-4-thiazolidinone)-beta-carboline-3-carbohydrazide series (9-11), compounds 9c and 11d were the most active, showing growth inhibition 50% (GI(50)) values less than 5 mu M for all cell lines tested. Compound 9c, bearing the 4-dimethylaminophenyl group at C-1 of beta-carboline was selected for further investigation concerning cell death and cell cycle profile, focusing on the human renal adenocarcinoma cell line 786-0. Treatments with 25 mu M of compound 9c induced cell death after 15 h of treatment, characterized by phosphatidylserine exposure and loss of membrane integrity. Moreover, treatment with 12.5 mu M promoted a sub-G1 arrest, which indicates cell death. Derivatives of the N-(2-substituted-aryl-4-thiazolidinone)-beta-carboline-3-carboxamide series (18-23) showed a potent activity and high selectivity for glioma (U251) and ovarian (OVCAR-3) cancer cell lines. Also, some beta-carboline-4-thiazolidinone hybrids showed potent antiviral activity against Herpes simplex virus type-1. The N-(2-substituted-aryl-4-thiazolidinone)-carboxamide moiety in 18, 19 and 22 confer a potent anti-HSV-1 activity for these derivatives, which presented EC50 values of 0.80, 2.15 and 2.02 mu M, respectively. The assay results showed that the nature of 4-thiazolidinone moiety and of the substituent attached at the 3- and 1- position of beta-carboline nucleus influenced the antitumor and antiviral activities. (C) 2016 Elsevier Masson SAS. All rights reserved. (AU)

• FAPESP's process: 15/08338-6 - Active natural products: clinical study of standardized Arrabidaea chica Verlot herbal medicine for mucositis treatment of head & neck cancer patients
• Grantee: Mary Ann Foglio
• Support Opportunities: Regular Research Grants