Thiopyrano[2,3-d]thiazole structures as promising scaffold with anticancer potential

Abstract

Seven chromeno[4',3':4,5]thiopyrano[2,3-d]thiazole derivatives were synthesized and screened for their cytotoxic effects on different lines of mammalian leukemia, breast adenocarcinoma, glioblastoma, and pseudo-normal and normal cells. The derivative 3 demonstrated toxicity towards tumor cells of Jurkat, K562, U251, HL-60, MCF-7, and MDA-MB-231 lines. At the same time, this compound possessed low toxicity (IC₅₀ > 100 μM) towards cells, used as control, representing non-tumor, somatic cells: HaCaT, HEK293 cells as well as murine Balb/c 3T3 and J774.2 cells, mink Mv1Lu cells, and normal mitogen-activated human blood lymphocytes. The derivative 3 induced apoptosis in human leukemia Jurkat T-cells and glioblastoma U251 cells via mitochondria-dependent pathway and inhibition of the DNA reparation enzyme PARP-1. This compound triggered pro-apoptotic morphological changes in Jurkat and U251 cells, namely chromatin condensation, nuclei fragmentation, and membrane blebbing. However, the DNA damaging effects of compound 3 were significantly lower in normal human lymphocytes, compared with such results in tumor Jurkat and U251 cells. The DNA damaging effects of compound 3 were unrelated to its DNA-binding and/or DNA-intercalating abilities. This compound induced the accumulation of endogenous reactive oxygen species (ROS), namely superoxide radicals, in human leukemia and glioblastoma cells. Our finding indicated that compound 3 inhibited the viability of human leukemia T-cells and glioblastoma cells via induction of DNA damage and apoptosis through ROS-mediated mitochondrial pathway.

Keywords: Anticancer activity; Apoptosis; Cytotoxicity; DNA damage; Heterocyclic compounds; ROS; Thiopyrano[2,3-d]thiazoles.