Design, synthesis, cytotoxicity and molecular modeling studies of some novel fluorinated pyrazole-based heterocycles as anticancer and apoptosis-inducing agents

Abstract

3,5-Diamino-4-(3-trifluoromethylphenyldiazenyl)-1H-pyrazole was used as a starting scaffold for the synthesis of new pyrazole-based heterocycles to study their effects on the proliferation of three human cancer cell lines; human liver carcinoma cell line (HepG-2), colon cancer cell line (HCT-116) and human breast cancer cell line (MCF-7) using MTT assay. The synthesized compounds were characterized on the basis of IR, H NMR,C NMR, mass spectral data and elemental analysis results. Cytotoxicity assay results revealed that some of the compounds showed potent growth inhibition against all the cell lines tested, with IC50 values in the range of 0.64-7.73 μg/mL. Breast cancer cells were used for further detailed studies to understand the mechanism of cell growth inhibition and apoptosis-inducing effect of the most active compounds. The results indicated that compounds 3a, 10b and 11a arrested MCF-7 cells at G2/M phase of the cell cycle and might induce apoptosis via caspase-3-dependent pathway. Molecular modeling and binding mode analysis of the most active compounds to caspase 3 active site further provide a synergistic mechanism for their pro-apoptotic effects. In order to explore the structural requirements controlling the observed cytotoxic properties, 3D pharmacophore model was generated.

Carboxamide appended quinoline moieties as potential anti-proliferative agents, apoptotic inducers and Pim-1 kinase inhibitors

“…Based on the above findings, and in continuation to our work on the synthesis of new compounds with biological activities [28][29][30][31][32][33][34], we have synthesized a new series of quinolone-3-carboxamide derivatives containing a series of biologically active moites that are expected to be strongly inhibitory for several human cell lines and PIM-1 inhibitors as a result of our commitment to search for new potential anticancer agents related to heterocyclic [35][36][37][38][39][40][41][42]. | P a g e…”

“…The PC-3 cells were planted into RPMI 1640 with a 10% fetal serum of bovine serum at 37 ° C, were stimulated by Caspase-3 compounds, and lysed with the cell extraction buffer. The lysate was diluted in the regular diluent tank over the test range and tested for human active Caspase-3 content (cells are plated in the density of 1.2-1.8 per 100 μL of cells per well in a 96 wave plate for 48 hours before the enzymes test) [36].…”

Synthesis of novel triazoloquinoxaline‐pyrazole hybrids as antiproliferatives, EGFR inhibitors, and apoptosis inducers

“…[2] Noteworthy, pyrazoles were proved to possess potent anticancer activity. [9][10][11] One of the reported anticancer pyrazoles which induced apoptosis via Caspase-3 activationdependent pathway was the reported phenyldiazenyl-1Hpyrazoles-3,5-diamine derivative B. [10] Based on these findings, we found that it is interesting to hybridize triazoloquinoxaline scaffold by pyrazole moieties (c.f.…”

“…reported that 1‐(4‐(1‐ethyl‐[1,2,4]triazolo[4,3‐ a ]quinoxalin‐4‐ylamino)phenyl)‐3‐(substitutedphenyl)prop‐2‐en‐1‐one A had antiproliferative characteristics with EGFR kinase inhibition (IC 50 = 0.039 μM) [2] . Noteworthy, pyrazoles were proved to possess potent anticancer activity [9‐11] . One of the reported anticancer pyrazoles which induced apoptosis via Caspase‐3 activation‐dependent pathway was the reported phenyldiazenyl‐1 H pyrazoles‐3,5‐diamine derivative B [10] …”

“…Noteworthy, pyrazoles were proved to possess potent anticancer activity [9‐11] . One of the reported anticancer pyrazoles which induced apoptosis via Caspase‐3 activation‐dependent pathway was the reported phenyldiazenyl‐1 H pyrazoles‐3,5‐diamine derivative B [10] …”