Design, synthesis and cytotoxic activity of molecular hybrids based on quinolin-8-yloxy and cinnamide hybrids and their apoptosis inducing property.

The present work aims at design and synthesis of a congeneric series of small hybrids 5 and 6a-i featuring the privileged quinoline scaffold tethered with 2-(arylamido)cinnamide moiety as potential anticancer tubulin polymerization inhibitors. Most of the synthesized hybrids 5 and 6a-i significantly inhibited the growth of the HepG2 cell line, with IC50 ranged from 2.46 to 41.31 µM. In particular, 2-(3,4,5-trimethoxybenzamido)-4-methoxycinnamide-quinoline hybrid 6e displayed potent IC50 value toward the examined cell line, and hence chosen for further mechanistic investigations. It is noteworthy that the antiproliferative action of compound 6e highly correlated well with its ability to inhibit tubulin polymerization. In addition, the most potent hybrid 6e demonstrated a significant modification in the cellular cycle distribution, in addition to provoke of apoptotic death within the tested HepG2 cell line. Furthermore, the mechanistic approach was confirmed by a substantial upregulation in the quantity of active caspase 9 by 5.81-fold relative to untreated control cells.

EGFR/VEGFR-2 dual inhibitor and apoptotic inducer: Design, synthesis, anticancer activity and docking study of new 2-thioxoimidazolidin-4one derivatives.

AIMS: EGFR and VEGFR-2 have emerged as promising targets for cancer management as they play a crucial role in tumor growth, angiogenesis and metastasis. A novel series of 2-thioxoimidazolidin-4-one derivatives were synthesized and evaluated as apoptotic inducers and EGFR/VEGFR-2 dual inhibitors. MAIN METHODS: The cytotoxic activities of all synthesized compounds were tested against MCF-7, HepG2 and A549 cell lines. The molecular mechanism of the most promising cytotoxic compounds was investigated via a series of assays including in vitro EGFR and VEGFR-2 inhibitory activity in MCF-7 cell line. Additionally, levels of p53, Bax, Bcl-2, caspase 7, 9 as well as cell cycle analysis were assessed in MCF-7 cell line to gain better understanding of their apoptotic activity. Molecular docking study was carried out to predict binding pattern of these compounds with EGFR and VEGFR-2 active sites. Finally, in silico ADME and drug-likeness profiling were calculated. KEY FINDINGS: Compounds 6 and 8a exhibited superior cytotoxic activity compared to sorafenib and erlotinib, against the three tested cell lines. In the same context, 6 and 8a showed better EGFR and VEGFR-2 inhibitory activity compared to the reference compounds. The later effect was further supported by the docking study. Furthermore, these compounds displayed potent apoptotic activity as evident by cell accumulation at pre-G1 phase and cell cycle arrest at G2/M phase together with increased p53, caspae-7 and caspase-9 levels and Bax/Bcl-2 ratio. Finally, synthesized compounds have acceptable drug likeness. SIGNIFICANCE: Compounds 6 and 8a act as potent dual EGFR/VEGFR-2 inhibitors with evident apoptotic activity.