Synthesis and Biological Evaluation of Novel 4‐(2‐Fluorophenoxy)‐2‐(1H‐tetrazol‐1‐yl)pyridines Bearing Semicarbazone Moieties as Potent Antitumor Agents

Abstract

A series of 4-(2-fluorophenoxy)-2-(1H-tetrazol-1-yl)pyridines bearing semicarbazone moieties were synthesized and evaluated for their in vitro antitumor potency. Some of the compounds (10b, 10c, 10e-10h, 10m-10p, 10r, and 11b) exhibited moderate to excellent antitumor activity as compared to sorafenib and PAC-1, as well as low levels of toxicity toward the human fetal lung fibroblast cell line WI-38. The most promising compound 10p (IC50 = 0.08, 0.36, 0.97 µM) was 45.1-, 6.1-, and 2.4-fold more active than sorafenib (IC50 = 3.61, 2.19, 2.32 µM), and 17, 3.2, and 2.9 times better than PAC-1 (IC50 = 1.36, 1.17, 2.83 µM) against three cancer cell lines (HT-29, H460, and MKN-45), respectively. In addition, further studies examining enzymatic activity suggested that the marked pharmacological activity observed might be ascribed to an inhibitory action against CRAf kinase.

Removal of Metabolic Liabilities Enables Development of Derivatives of Procaspase-Activating Compound 1 (PAC-1) with Improved Pharmacokinetics

“…8 PAC-1 has been shown to be cytotoxic against a diverse array of cancer cells in culture, including cell lines derived from hematopoietic tumors (lymphoma, 8, 36–43 leukemia, 8, 38, 42–47 and multiple myeloma 47 ), carcinomas of diverse origin (breast, 8, 38, 42–46, 48–50 renal, 8 adrenal, 8, 51 colon, 8, 42, 47, 49, 50, 52 lung, 8, 42–50, 52–55 cervical, 38, 47 gastric, 42, 43, 47, 49, 50, 52 ovarian, 47 liver, 42, 43, 47 prostate, 42, 43 and gallbladder 42, 43 ), and other solid tumor histologies (melanoma, 8, 38, 42, 43 osteosarcoma, 47 neuroblastoma, 8, 47, 49, 50 and glioblastoma 42, 43 ). PAC-1 and derivatives also induce apoptosis in patient-derived samples from colon cancer 8 and chronic lymphocytic leukemia, 18 and have anticancer efficacy in multiple murine tumor models 8, 42, 43, 48, 54–56 and in pet dogs with cancer.…”

“…Procaspase-activating compound 1 (PAC-1, 1 ; Figure ) was identified via a high-throughput screen for compounds that could enhance procaspase-3 enzymatic activity in vitro . PAC-1 is cytotoxic against a diverse array of cancer cells in culture, including cell lines derived from hematopoietic tumors (lymphoma, ,− leukemia, ,,− and multiple myeloma), carcinomas of diverse origin (breast, ,,− ,− renal, adrenal, , colon, ,,,,, lung, ,− ,− cervical, , gastric, ,,,,, ovarian, liver, ,, prostate, , and gallbladder , ), and other solid tumor histologies (melanoma, ,,, osteosarcoma, neuroblastoma, ,,, and glioblastoma , ). PAC-1 and its derivatives also induce apoptosis in patient-derived samples from colon cancer 8 and chronic lymphocytic leukemia, and have anticancer efficacy in multiple murine tumor models …”

Novel hydrazone moiety-bearing aminopyrimidines as selective inhibitors of epidermal growth factor receptor T790M mutant

“…The intermediate 6 was prepared via a regioselective coupling of the protected benzene-1,3-diamine 5 to the 4-position of 4 using a modified condition as previously reported [20]. Substitution of 6 with hydrazine hydrate led to the intermediate 7, which was reacted with an appropriate aromatic aldehyde or ketone under acid conditions to generate hydrazone 8 [21,22]. The key intermediate 9 was obtained by the deprotection of 8 in the presence of trifluoroacetic acid [20].…”

Anticancer agents incorporating the N‐acylhydrazone scaffold: Progress from 2017 to present

“…[13][14][15][16][17][18][19] Several studies on the chemistry and bioactivity of N-acylhydrazone lead scaffold have been published recently. This topic has gained significance over time for the development of novel, therapeutically effective bioactive N-acylhydrazone candidates as anticancer, [20][21][22][23] anti-inflammatory, [24][25][26][27][28][29][30][31] anti-Alzheimer, [32][33][34][35] antimicrobial agents, [36][37][38][39][40] and more. N-Acylhydrazones continue to be a prominent topic in therapeutic research, especially when it comes to the treatment of cancer.…”