Discovery of antiproliferative and anti-FAK inhibitory activity of 1,2,4-triazole derivatives containing acetamido carboxylic acid skeleton.

Small molecule inhibitors of the focal adhesion kinase are regarded as promising tools in our armamentarium for treating cancer. Here, we identified four 1,2,4-triazole derivatives that inhibit FAK kinase significantly and evaluated their therapeutic potential. Most tested compounds revealed potent antiproliferative activity in HepG2 and Hep3B liver cancer cells, in which 3c and 3d were the most potent (IC50 range; 2.88 ~ 4.83 µM). Compound 3d possessed significant FAK inhibitory activity with IC50 value of 18.10 nM better than the reference GSK-2256098 (IC50 = 22.14 nM). The preliminary mechanism investigation by Western blot analysis showed that both 3c and 3d repressed FAK phosphorylation comparable to GSK-2256098 in HepG2 cells. As a result of FAK inhibition, 3c and 3d inhibited the pro-survival pathways by decreasing the phosphorylation levels of PI3K, Akt, JNK, and STAT3 proteins. This effect led to apoptosis induction and cell cycle arrest. Taken together, these results indicate that 3d could serve as a potent preclinical candidate for the treatment of cancers.

Potent combretastatin A-4 analogs containing 1,2,4-triazole: Synthesis, antiproliferative, anti-tubulin activity, and docking study.

A series of cis restricted 1,2,4-triazole analogs of combretastatin A-4 (CA-4) were designed and synthesized. The antiproliferative activity of these compounds was measured on hepatocellular carcinoma HepG2, leukemia HL-60, and breast cancer MCF-7 cell lines. The obtained results showed a substantial ability of the synthesized anilides to inhibit tumor growth. On HepG2 cells, 5o and 5r showed potent IC50 values of 0.10 and 0.04 µM, respectively. While on HL-60 cells, the IC50 values were 0.004 and 0.01 µM for 5b and 5i, respectively. The inhibitory activity of tubulin polymerization was evaluated on HepG2 cells. The anilide 5r showed a remarkable tubulin inhibition compared to CA-4. Moreover, flow cytometry studies showed that HepG2 cells treated with the most potent compounds 5b and 5r were arrested in the G2/M phase of the cell cycle. This effect was accompanied by cellular apoptosis and activation of caspase-3. Molecular modeling showed several hydrogen bonding and van der Waals interactions with several important amino acids inside the colchicine binding site of tubulin.

Targeted anticancer potential against glioma cells of thymoquinone delivered by mesoporous silica core-shell nanoformulations with pH-dependent release.

BACKGROUND AND PURPOSE: Glioma is one of the most aggressive primary brain tumors and is incurable. Surgical resection, radiation, and chemotherapies have been the standard treatments for brain tumors, however, they damage healthy tissue. Therefore, there is a need for safe anticancer drug delivery systems. This is particularly true for natural prodrugs such as thymoquinone (TQ), which has a high therapeutic potential for cancers but has poor water solubility and insufficient targeting capacity. We have tailored novel core-shell nanoformulations for TQ delivery against glioma cells using mesoporous silica nanoparticles (MSNs) as a carrier. METHODS: The core-shell nanoformulations were prepared with a core of MSNs loaded with TQ (MSNTQ), and the shell consisted of whey protein and gum Arabic (MSNTQ-WA), or chitosan and stearic acid (MSNTQ-CS). Nanoformulations were characterized, studied for release kinetics and evaluated for anticancer activity on brain cancer cells (SW1088 and A172) and cortical neuronal cells-2 (HCN2) as normal cells. Furthermore, they were evaluated for caspase-3, cytochrome c, cell cycle arrest, and apoptosis to understand the possible anticancer mechanism. RESULTS: TQ release was pH-dependent and different for core and core-shell nanoformulations. A high TQ release from MSNTQ was detected at neutral pH 7.4, while a high TQ release from MSNTQ-WA and MSNTQ-CS was obtained at acidic pH 5.5 and 6.8, respectively; thus, TQ release in acidic tumor environment was enhanced. The release kinetics fitted with the Korsmeyer-Peppas kinetic model corresponding to diffusion-controlled release. Comparative in vitro tests with cancer and normal cells indicated a high anticancer efficiency for MSNTQ-WA compared to free TQ, and low cytotoxicity in the case of normal cells. The core-shell nanoformulations significantly improved caspase-3 activation, cytochrome c triggers, cell cycle arrest at G2/M, and apoptosis induction compared to TQ. CONCLUSION: Use of MSNs loaded with TQ permit improved cancer targeting and opens the door to translating TQ into clinical application. Particularly good results were obtained for MSNTQ-WA.

One-pot synthesis of spiro(indoline-3,4'-pyrazolo[3,4-b]pyridine)-5'-carbonitriles as p53-MDM2 interaction inhibitors.

AIM: Inhibition of P53-mdm2 interaction will lead to cancer cell apoptosis. This strategy was achieved by reported spiro-oxindole derivatives. MATERIALS & METHODS: Spiro(indoline-3,4'-pyrazolo[3,4-b]pyridine)-5'-carbonitrile derivatives (4a-i and 9a, b) were synthesized and screened for their in vitro anticancer activity. The most active compounds were subjected to P53-MDM2 inhibitory activity, apoptotic and molecular docking studies. RESULTS & DISCUSSION: Compound 4d exhibited potent and broad spectrum of antiproliferative activity with full panel GI50 (MG-MID) value of 3.97 µM. Compounds 4d and 4i inhibited p53-MDM2 protein-protein interaction with IC50 = 52.1 and 95.2 nM, respectively. Compound 4d inhibits the expression of wild p53 in MCF-7 more than mutant p53 in MDA-MB231 at the molecular level. Molecular docking studies illustrated the possible interaction of the target spiro-oxindoles with the p53 binding site on MDM2.

Synthesis and biological evaluation of novel 5-chloro-N-(4-sulfamoylbenzyl) salicylamide derivatives as tubulin polymerization inhibitors.

A novel series of sulfonamide derivatives, coupled with a salicylamide scaffold, was designed and synthesized. The structures of the synthesized compounds were established using 1H NMR, 13C NMR and high-resolution mass spectroscopy. The synthesized compounds were tested in vitro against five types of human cell lines. Two were breast adenocarcinoma, including the hormone-dependent MCF-7 and the hormone-independent MDA-MB-231. The others were the colorectal adenocarcinoma Caco-2, the carcinoma HCT-116 and the immortalized retinal-pigmented epithelium, hTERT-RPE1. Nine sulfonamides were able to inhibit the growth of the four tested cancer cells. Compound 33 was the most active against the selected colon cancer (Caco-2 and HCT-116) subtypes, while compound 24 showed the best efficacy against the examined breast cancer (MCF-7 and MDA-MB-231) cells. The selectivity index introduced compounds 24 and 33 as having the best selectivity among the breast and colon subtypes, respectively. In vitro tubulin polymerization experiments and flow cytometric assays showed that compounds 24 and 33 led to cell cycle arrest at the G2/M phase in a dose-dependent manner by effectively inhibiting tubulin polymerization. Furthermore, the results of the molecular docking studies indicate that this class of compounds can bind to the colchicine-binding site of tubulin.

Synthesis, antitumour and antioxidant activities of novel α,ß-unsaturated ketones and related heterocyclic analogues: EGFR inhibition and molecular modelling study.

New α,ß-unsaturated ketones 4a,b; 5a-c; and 6a,b; as well as 4-H pyran 7; pyrazoline 8a,b; isoxazoline 9; pyridine 10-11; and quinoline-4-carboxylic acid 12a,b derivatives were synthesized and evaluated for in vitro antitumour activity against HepG2, MCF-7, HeLa, and PC-3 cancer cell lines. Antioxidant activity was investigated by the ability of these compounds to scavenge the 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) radical cation (ABTS•+). Compounds 6a, 6b, 7, and 8b exhibited potent antitumour activities against all tested cell lines with [IC50] ≅5.5-18.1 µΜ), in addition to significantly high ABTS•+ scavenging activities. In vitro EGFR kinase assay for 6a, 6b, 7, and 8b as the most potent antitumour compounds showed that; compounds 6b, and 7 exhibited worthy EGFR inhibition activity with IC50 values of 0.56 and 1.6 µM, respectively, while compounds 6a and 8b showed good inhibition activity with IC50 values of 4.66 and 2.16 µM, respectively, compared with sorafenib reference drug (IC50 = 1.28 µM). Molecular modelling studies for compounds 6b, 7, and 8b were conducted to exhibit the binding mode towards EGFR kinase, which showed similar interaction with erlotinib.

Azole-hydrazone derivatives: Design, synthesis, in vitro biological evaluation, dual EGFR/HER2 inhibitory activity, cell cycle analysis and molecular docking study as anticancer agents.

In this research, three series of azole-hydrazone derivatives namely, benzimidazole, benzoxazole and benzothiazole were designed and synthesized. Their structures were confirmed by elemental analysis and spectroscopic techniques. Stereochemical configuration of the synthesized compounds (Z/E) was determined. The new derivatives were tested in vitro against both human breast adenocarcinoma (MCF-7) and human hepatic adenocarcinoma (HepG2) cell lines. The most active compounds 3h (IC50 = 0.067 µM against MCF-7) and 3l (IC50 = 0.027 µM against HepG2) were further tested for Epidermal Growth Factor Receptor (EGFR) inhibitory activity. The most active 3h on EGFR was then screened for HER2 and VEGFR enzymes. Caspase-3/9 protein level expression were measured for the two compounds 3h and 3l. Cell cycle analysis showed pre G1 apoptosis and cell cycle arrest at G2/M phase. Up-regulation of Bax and down-regulation of Bcl-2 protein expression level confirmed apoptosis. Molecular docking analysis was performed for all the synthesized compounds inside the active site of EGFR.