Targeting Colon Cancer Cells with Pyrazino-Imidazolinone Derivatives: Synthesis, Molecular Docking, and in Vitro Evaluation of Anti-Proliferative and Pro-Apoptotic Activities.

We report the synthesis, spectroscopic characterization, molecular docking and biological evaluation of nine pyrazino-imidazolinone derivatives. These derivatives were evaluated for their anticancer activity against three cancer cell lines: 518A2 melanoma, HCT-116, and HCT-116 p53 knockout mutant colon carcinoma. The MTT assay was employed to assess their effectiveness. Among the nine compounds tested, four compounds (5 a, 5 d, 5 g, and 5 h) exhibited promising antiproliferative activity specifically against HCT-116 p53-negative cells (IC50 0.23, 0.20, 2.07 and 58.75 µM, respectively). Interestingly, treatment with the 3,4-dimethoxyphenyl derivative 5a resulted in a significant increase (199 %) in caspase activity in HCT-116 p53-negative cells compared to untreated cells while the bromo-pyrazine derivative 5d demonstrated (190 %) increase. These findings suggest that compounds 5a and 5 d induce p53-independent apoptotic cell death. Additionally, in silico molecular docking studies with EGFR and tyrosinase proteins indicated that compounds 5 d and 5 e have the potential to bind to important anticancer drug targets.

A New Naphthopyran Derivative Combines c-Myb Inhibition, Microtubule-Targeting Effects, and Antiangiogenic Properties.

Based on the promising c-Myb inhibitor 1b, a series of 2-amino-4-aryl-4H-naphtho[1,2-b]pyran-3-carbonitriles (1a, 2a-q, 3a-g) were repurposed or newly synthesized via a three-component reaction of 1-naphthol, and various aryl aldehydes and malononitrile and screened for their c-Myb inhibitory activities. 1b also served as a lead compound for seven new naphthopyran derivatives (3a-f), which were cytotoxic with nanomolar IC50 values, to inhibit the polymerization of tubulin, and to destabilize microtubules in living cells. Especially, the alkyne 3f, originally made for intracellular localization studies using click chemistry, showed an overall high activity in all assays performed. A strong G2/M cell cycle arrest was detected, which resulted in a distinct increase in sub-G1 cells through the induction of effector caspases 3 and 7. Inhibition of angiogenesis was confirmed in vitro and in vivo. In summary, 3f was found to be a pleiotropic compound with high selectivity for cancer cells, combining c-Myb inhibitory, microtubule destabilizing, and antiangiogenic effects.

New Pyrano-4H-benzo[g]chromene-5,10-diones with Antiparasitic and Antioxidant Activities.

New pyranonaphthoquinone derivatives were synthesized and investigated for their activity against Trypanosoma brucei, Leishmania major, and Toxoplasma gondii parasites. The pentafluorophenyl derivative was efficacious against T. brucei with single digit micromolar EC50 values and against T. gondii with even sub-micromolar values. The 3-chloro-4,5-dimethoxyphenyl derivative showed an activity against amastigotes of Leishmania major parasites comparable to that of amphotericin B. In addition, antioxidant activities were observed for the bromophenyl derivatives, and their redox behavior was studied by cyclovoltammetry. Anti-parasitic and antioxidative activities of the new naphthoquinone derivatives appear uncorrelated.