ABSTRACT
Recent studies have shown that sulforaphane (SFN) selectively inhibits the growth of ALDH⺠breast cancer stem-like cells.Herein, a series of SFN analogues were synthesized and evaluated against breast cancer cell lines MCF-7 and SUM-159, and the leukemia stem cell-like cell line KG-1a. These SFN analogues were characterized by the replacement of the methyl group with heterocyclic moieties, and the replacement of the sulfoxide group with sulfide or sulfone. A growth inhibitory assay indicated that the tetrazole analogs 3d, 8d and 9d were significantly more potent than SFN against the three cancer cell lines. Compound 14c, the water soluble derivative of tetrazole sulfide 3d, demonstrated higher potency against KG-1a cell line than 3d. SFN, 3d and 14c significantly induced the activation of caspase-3, and reduced the ALDH⺠subpopulation in the SUM159 cell line, while the marketed drug doxrubicin(DOX) increased the ALDH⺠subpopulation.
Subject(s)
Acids, Heterocyclic/chemical synthesis , Acids, Heterocyclic/pharmacology , Anticarcinogenic Agents/chemical synthesis , Anticarcinogenic Agents/pharmacology , Acids, Heterocyclic/chemistry , Aldehyde Dehydrogenase/metabolism , Anticarcinogenic Agents/chemistry , Caspase 3/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Gene Expression Regulation/drug effects , Humans , Isothiocyanates/chemistry , MCF-7 Cells , SulfoxidesABSTRACT
Three novel series of 1,2,3-triazole and 1,3,4-oxadiazole derivatives of imatinib were prepared and evaluated in vitro for their cytostatic effects against a human chronic myeloid leukemia (K562), acute myeloid leukemia (HL60), and human leukemia stem-like cell line (KG1a). The structure-activity relationship was analyzed by determining the inhibitory rate of each imatinib analog. Benzene and piperazine rings were necessary groups in these compounds for maintaining inhibitory activities against the K562 and HL60 cell lines. Introducing a trifluoromethyl group significantly enhanced the potency of the compounds against these two cell lines. Surprisingly, some compounds showed significant inhibitory activities against KG1a cells without inhibiting common leukemia cell lines (K562 and HL60). These findings suggest that these compounds are able to inhibit leukemia stem-like cells.
