ABSTRACT
Twenty one novel (+)- usnic acid-based analogues belonging to three classes such as enamines, imines, and pyrazoles were synthesized. All the synthesized compounds were characterized by their spectral data (1H NMR, 13C NMR, IR, and HRMS). The synthesized compounds were evaluated for their antiproliferative activity against a panel of four human cancer cell lines including HeLa (cervix), MDA-MB-231 (breast), A549 (lung), and MiaPaca (pancreas) by employing SRB cell proliferation assay. Screening results indicated that all synthesized compounds showed enhanced activity than the parent compound. Most significantly, compounds 2e and 4a showed potent antiproliferative activity against all the cancer cell lines tested. Compounds 2e and 4a arrested the cell cycle in G2/M phase and induced apoptosis in HeLa cells. In view of significant antiproliferative activity, compounds 2e and 4a can be considered as lead molecules for further development.[Formula: see text].
Subject(s)
Antineoplastic Agents , Apoptosis , Benzofurans , Cell Line, Tumor , Cell Proliferation , Drug Screening Assays, Antitumor , Female , HeLa Cells , Humans , Molecular Structure , Structure-Activity RelationshipABSTRACT
A total of twenty-two novel coumarin triazole hybrids (4a-4k and 6a-6k) were synthesized from orcinol in good to excellent yields of 70-94%. The structures of all the synthesized compounds were elucidated by spectroscopic techniques such as 1H NMR, 13C NMR, and HRMS. The anti-inflammatory potential of synthesized compounds was investigated against the proinflammatory cytokine, TNF-α on U937 cell line and compounds 4d, 4j, and 6j were found to exhibit promising anti-inflammatory activity. These three compounds were further screened against TNF-α on LPS-stimulated RAW 264.7 cells, which confirm their anti-inflammatory potential. Furthermore, the above said active compounds were tested for their inhibitory effect on RANKL-induced osteoclastogenesis in RAW 264.7 cells by using tartrate resistant acid phosphatase (TRAP) staining assay at 10⯵M. Molecular mechanism studies demonstrated that compound 4d exhibited dose dependent inhibition of RANKL-induced osteoclastogenesis by suppression of the NF-kB pathway. Thus, compound 4d is a promising candidate for further optimization to develop as a potent anti-osteoporotic agent.
Subject(s)
Coumarins/pharmacology , NF-kappa B/antagonists & inhibitors , Osteogenesis/drug effects , Receptor Activator of Nuclear Factor-kappa B/antagonists & inhibitors , Resorcinols/pharmacology , Signal Transduction/drug effects , Triazoles/pharmacology , Animals , Cell Survival/drug effects , Coumarins/chemical synthesis , Coumarins/chemistry , Dose-Response Relationship, Drug , Humans , Mice , Molecular Structure , NF-kappa B/metabolism , RAW 264.7 Cells , Receptor Activator of Nuclear Factor-kappa B/metabolism , Resorcinols/chemistry , Structure-Activity Relationship , Triazoles/chemical synthesis , Triazoles/chemistry , U937 CellsABSTRACT
Ring-C of oleanolic acid was chemically modified by treating with NBS under a variety of experimental conditions. The structures of the synthesized compounds were established by spectral analysis ((1)H &(13)C NMR and Mass). All the compounds were evaluated against a panel of five human cancer cell lines by using MTT assay. Among the tested compounds, 2 and 7 showed significant activity against breast cancer cell line, MCF-7. Most significantly, compound 7 showed several folds enhanced activity against MCF-7 cancer cell lines (IC50: 2.96µM) than that of the parent (1) and the intermediate compound (6). Flow cytometric analysis revealed that these compounds arrested the cell cycle in G0/G1 phase and induced mitochondrial mediated apoptosis.
