Benzenesulfonamide-based PPARγ Agonists as Anticancer Agents Targeting JNK and MAPK Cascades

In the current study, two series of thiazolidinone-benzenesulfonamides 4a-l and 5a-f were synthesized as PPARγ agonists-targeted anticancer agents. The target compounds 4a-l and 5a-f were tested for anticancer screening against of a NCI-60 panel of cancer cell lines at a one-dose assay (10 µM), and their growth inhibition % (GI%) values were determined. The 4-benzyloxy/(2-phenylethoxy)benzenesulfonamides 4a-l and the 3-benzyloxy/(2-phenylethoxy) analogues 5a-f revealed GI% values ranging from 1.52% to 19.81%, and from 4.66% to 139.42%, respectively. Compounds 5b, 5c, 5e and 5f showed potent anticancer activities with mean GI% = 139.42, 72.73, 45.89, and 41.56%, respectively. The 3-benzyloxythiazolidinone benzenesulfonamides 5b, 5c and 5e were selected and further tested for a five-dose assay, and showed potent anticancer activities against the leukemia cell lines with GI50 values 1.26 - 6.54 µM, 1.98 - 5.59 µM, and 11.90 - 16.60 µM, respectively. Compounds 5b, 5c and 5e showed cytotoxicity against A375 melanoma cell line, however they found non-toxic against the hFB skin fibroblast normal cell line. Moreover, the cJUN and MAPK1 genes expression for compounds 5b, 5c and 5e were determined in A375 cells at their half IC50 values. The 4-fluoro analogue 5c showed higher cJUN and MAPK1 genes expression levels than control. Compound 5c caused cell cycle arrest in G1 phase by 31.69% in A375 cells at 10 µM as well as induction of early, and late apoptosis by 4.97, and 17.24%, respectively. Moreover, compound 5c revealed enhancements in apoptotic markers; Bax, and caspases-3, and -9 gene expression levels, while, a decline in Bcl-2 expression in A375 cells.