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A series of new 2-anilinoquinolines 6a-o possessing the substantial N-methylpicolinamide motif at C5 has been designed and synthesized as sorafenib analogs. The antiproliferative activities of the target compounds were preliminarily appraised against a panel of three human cancer cell lines (MCF-7, SK-BR3, and HCT116), and a selected array was further tested over a panel of approximately 60 cancer cell lines at NCI at 10 μM concentration. Interestingly, compounds 6c, 6d, 6j, 6k, and 6l showed promising selective anticancer activities (growth inhibition >80%) toward certain cancer cells at 10 μM testing dose. Compounds 6d and 6j were advanced to five-dose testing mode to determine their GI values and compared with our previously reported ureidoquinoline B and sorafenib as reference compounds. The 4-chloro-3-trifluoromethylaniline derivative 6j manifested superior potency than both compound B and sorafenib over eleven and eight cell lines, respectively. It showed GI values of 0.36, 0.66, 0.68, and 0.60 μM against the breast MDA-MB-468, renal A498, and melanoma SK-MEL-5 and UACC-62 cell lines, respectively. Moreover, both 6d and 6j exerted low cytotoxic effects against HFF-1 normal cell line. Furthermore, compounds 6d and 6j were tested against both B-Raf and C-Raf kinases and displayed modest inhibitory activities, which were justified by molecular docking study. Compound 6j could serve as a promising candidate for further development of potent anticancer chemotherapeutics.

Several thiophene featuring compounds are known for their promising antiproliferative activity. Prompted by the urgent need to identify new potent anticancer agents, 16 compounds of benzamides, benzylamines, and urea analogues incorporating a cyclohepta­[b]­thiophene scaffold were synthesized and biologically evaluated with a cell proliferation assay using the A549 nonsmall cell lung cancer cell line. Compound 17 demonstrated both potent and broad-spectrum anticancer activity with submicromolar 50% growth inhibition (GI50) values. It also showed superior antiproliferative activity (vs nocodazole) in OVACAR-4, OVACAR-5, CAKI-1, and T47D cell lines with GI50 values of 2.01 (vs 22.28), 2.27 (vs 20.75), 0.69 (vs 1.11), and 0.362 (vs 81.283) μM, respectively. Additionally, compound 17 displayed minimal cytotoxicity based on 50% lethal concentration (LC50) values toward all tested cell lines. Further cell-based mechanistic studies of compound 17 revealed its ability to induce cell cycle arrest of A549 cells as evidenced by dose dependent G2/M accumulation. Furthermore, induction of early apoptosis along with activation of caspase 3, 8, and 9 were confirmed in A549 cells treated with compound 17. Targeting tubulin polymerization may explain the mechanism of the antiproliferative activity of compound 17 based on cell cycle analysis, detected apoptosis, and in vitro inhibition of tubulin polymerization. In vitro data were further supported by in vivo antitumor efficacy studies of compound 17 in a CT26 murine model for which the results showed a reduction in the tumor growth compared to untreated mice. Overall, compound 17 has the potential to function as a promising candidate for further development of potent anticancer chemotherapeutics.

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