Synthesis, biological activity, structure activity relationship study and liposomal formulation development of some arylsulfonyl pyroglutamic acid derivatives

Abstract

In this study, we have synthesized some 4-biphenylsulphonyl-L(+)-pyroglutamic acid and pyroglutamines as we have already reported the corresponding glutamic acids and glutamines. The synthesized compounds were characterized and screened against human cancer cell lines (K562, Jurkat E6.1, U937 and MDA-MB-231) as well as normal human peripheral blood mononuclear cells (PBMCs) for their possible cytotoxic activity by MTT assay. All these synthesized compounds are cytotoxic towards leukemia cell lines (K562, Jurkat E6.1 and U937) and inactive against breast cancer cell line (MDA-MB-231) as well as normal human PBMCs. Two most active compounds in cytotoxicity study (compound 7 and compound 10) were further investigated by flow cytometric in-vitro apoptosis assay against Jurkat E6.1 and K562 cell lines. Compound 7 and compound 10 induced apoptosis significantly in both Jurkat E6.1 and K562 cell lines (p < 0.05) in a time dependent fashion. Mitochondrial membrane potential detection study as well as DNA deformation assay also confirmed apoptosis mediated cellular cytotoxicity. Compound 7 and compound 10 were encapsulated into liposomes (7a and 10a). Drug loaded liposomes, 7a and 10a are more than 8 fold cytotoxic in comparison with compound 7 and compound 10 against Jurkat E6.1 and K562 cell lines. In conclusion, compound 7 and compound 10 may be considered as potential lead molecules for the development of target specific anti-leukemic agents with minimal untoward events to normal human cells.