Chalcogenozidovudine derivatives with antitumor activity: Comparative toxicities in cultured human mononuclear cells

Abstract

Considering a novel series of zidovudine (AZT) derivatives encompassing selenoaryl moieties promising candidates as therapeutics, we examined the toxicities elicited by AZT and derivatives 50-(4-Chlorophenylseleno)zidovudine (SZ1); 50-(Phenylseleno)zidovudine (SZ2); and 50-(4-Methylphenylseleno)zidovudine (SZ3) in healthy cells and in mice. Resting and stimulated cultured human peripheral blood mononuclear cells (PBMCs) were treated with the compounds at concentrations ranging from 10 to 200 μM for 24 and/or 72 h. Adult mice received a single injection of compounds (100 μmol/kg, s.c.) and 72h after administration, hepatic/renal biomarkers were analyzed. Resting and stimulated PBMCs exposed to SZ1 displayed loss of viability, increased reactive species production, disruption in cell cycle, apoptosis and increased transcript levels and production of pro-inflammatory cytokines. In a mild way, most of these effects were also induced by SZ2. AZT and SZ3 did not cause significant toxicity towards resting PBMCs. Differently, both compounds elicited apoptosis and S phase arrest in stimulated cells. AZT and derivatives administration did not change the body weight and plasma biochemical markers in mice. However, the absolute weight and organ-to-body weight ratio of liver, kidneys and spleen were altered in AZT, SZ1-, and SZ2-treated mice. Our results highlighted the involvement of derivatives SZ1 and SZ2 in redox and immunological dyshomeostasis leading to activation of apoptotic signaling pathways in healthy cells under different division phases. On the other hand, the derivative SZ3 emerged as a promising candidate for further viral infection/antitumor studies as a new effective therapy with low toxicity for immune cells and after acute in vivo treatment.