New pyranopyrazole based derivatives: Design, synthesis, and biological evaluation as potential topoisomerase II inhibitors, apoptotic inducers, and antiproliferative agents.

A new series of pyranopyrazole-based derivatives were designed and synthesized. The synthesized compounds were assessed for their cytotoxic efficacy against A549 human lung carcinoma and MCF-7 human breast carcinoma cell lines. Three compounds (1b, 4b, and 7b) exhibited 1.3- to 2.3-fold more antiproliferative activity than that of doxorubicin against the A549 cell line. In comparison to doxorubicin, compounds 1d and 3b were 4.1- and 1.04-fold, respectively more powerful against MCF-7 cancer cells. All the synthesized compounds were found to be more selective toward A549 cancer cells than the normal human fibroblast BJ cells. Of interest, compounds 1b and 7b exhibited promising cytotoxicity and SIs of 27.72 and 25.30, respectively, towards A549 cancer cells, higher than that of doxorubicin (SI 4.81). The most potent compounds 1b, 1d, 3b, 4b, and 7b were then subjected to in vitro Topo II inhibition assay. They showed IC50 values in the range of 2.07 to 8.86 µM. Of particular interest, compound 7b (IC50 = 2.07 µM), exhibited higher Topo II inhibitory activity than that of doxorubicin (IC50 = 2.56 µM). The significant Topo II inhibition of compound 7b was explained by molecular docking simulations into the Topo II active site. Compound 7b halted the cell cycle in the S phase in A549 cancer cells. It induced total apoptosis and necrosis of 20.73- and 4-fold, respectively, greater than the control. This evidence was supported by a 3.59-fold increase in the level of apoptotic caspase-9 and a remarkable elevation of the Bax/BCL-2 ratio. The physiochemical parameters of compound 7b were aligned with Lipinski's rule of five.

Synthesis and Cytotoxicity Evaluation of Novel Indole Derivatives as Potential Anti-Cancer Agents.

BACKGROUND: Marine sponges and tunicates have been a wealthy source of cytotoxic compounds such as indole alkaloids. Most of the indole alkaloids show in vitro cytotoxic and antineoplastic activities against a wide range of cancer cell lines. OBJECTIVE: Three series of bioisosteres of marine indole alkaloids (meridianins) were synthesized and the compounds were tested for their in vitro anti-proliferative activity against HCT-116 cellline. In the design of the targeted analogues, the 2-aminopyrimidine ring of merdianins was replaced with 5-aminopyrazole, pyrazolo[1,5-a]pyrimidine and pyrazolo[3,4-b]pyridine rings. RESULTS: The cytotoxic screening of the synthesized compounds revealed that pyrazolo[1,5- a]pyrimidines (compounds 9c and 11a) had the most potent cytotoxic activity with IC50 = 0.31 µM and 0.34 µM respectively. Compounds 9c and 11a were further investigated for their kinase inhibitory potencies toward six kinases (CDK5/p25, CK1ð/ε, GSK-3α/ß, Dyrk1A, Erk2, and CLK1). They exhibited effective inhibition of GSK-3α/ß (IC50 = 0.196 µM and 0.246 µM, respectively) and Erk2 (IC50 = 0.295 µM and 0.376 µM, respectively). CONCLUSION: Meridianins emerged as promising lead structures that need further development to obtain more selective and potent cytotoxic agents. One of these modifications involved the replacement of 2-aminopyrimidinyl ring of meridianins with other heterocyclic rings. Both pyrazolo[ 1,5-a]pyrimidine and pyrazolo[3,4-b]pyridine rings showed promising cytotoxic activity compared to the five membered 5-aminopyrazole.