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 5'-(4-Chlorophenylseleno)zidovudine (SZ1); 5'-(Phenylseleno)zidovudine (SZ2); and 5'-(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 72 h 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.

Selenium-Based Drug Development for Antioxidant and Anticancer Activity

“…cells was caused by a disparity in redox and immunological homeostasis initiated by the zidovudine derivatives 10 and 11 [41]. Ebselen (EBS) was demonstrated to be a glutathione peroxidase mimic and a peroxynitrite scavenger [42].…”

“…With good water solubility, cycloselenide 9 catalyzed the dielectronic reduction of H 2 O 2 to H 2 O and the oxidation of mercaptan (RSH) to disulfide (RSSR) through a catalytic cycle akin to the GPX [40]. The stimulation of the apoptotic signaling pathway in healthy cells was caused by a disparity in redox and immunological homeostasis initiated by the zidovudine derivatives 10 and 11 [41]. Ebselen (EBS) was demonstrated to be a glutathione peroxidase mimic and a peroxynitrite scavenger [42].…”

Discussions of Fluorescence in Selenium Chemistry: Recently Reported Probes, Particles, and a Clearer Biological Knowledge

“…The cell type was human peripheral blood mononuclear cells (PBMCs). Importantly, different aspects of the cellular responses were taken into account; apoptotic events were carefully gauged [35].…”

Toxicological evaluation of zidovudine and novel chalcogen derivatives in Drosophila melanogaster

“…[9] AZT derivatives with structural changes are relevant in the search for new drugs with less unwanted side effects than the original compound, thus potentially decreasing their toxicity and increasing the therapeutic effectiveness. [10,11] For instance, AZT derivatives containing organochalcogen moieties are potential therapeutic molecules with antitumoral and antioxidant activity. [10,12] In line with this, novel AZT organochalcogen derivatives are being synthesized and tested for their antiviral activity requiring the use of simple animal models to screen their toxicity.…”

“…[10,12] In line with this, novel AZT organochalcogen derivatives are being synthesized and tested for their antiviral activity requiring the use of simple animal models to screen their toxicity. [10,11] The use of nonmammalian alternative models has been instrumental in preclinical toxicological, pharmacological, and neurobehavioral studies. The Drosophila melanogaster, popularly known as the fruit fly, has several advantages: a short life cycle, large offspring, well-described anatomy and phenotypes, and a high degree of genetic conservation of essential signaling and structural protein networks when compared with vertebrates.…”