PI3Kδ and mTOR dual inhibitors: Design, synthesis and anticancer evaluation of 3-substituted aminomethylquinoline analogues.

Phosphatidylinositide-3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) have recently been identified as potential cancer targets. In our work, a new family of quinoline analogues was designed, developed, and evaluated as dual inhibitors of PI3Kδ/mTOR. The preliminary biological activity analysis led to the discovery of the lead compounds 5h and 5e. Compounds 5h and 5e exhibited excellent anti-tumor potency with IC50 of 0.26 µM and 0.34 µM against Ramos cells, respectively. Importantly, based on the enzymatic activity assay results, compounds 5h and 5e were identified as dual inhibitors of PI3Kδ and mTOR, with IC50 values of 0.042 µM and 0.056 µM for PI3Kδ and 0.059 µM and 0.073 µM for mTOR, respectively. Furthermore, these compounds showed superior selectivity for blocking PI3Kδ compared to other PI3K isoforms (α, ß, and γ), supporting the concept of developing inhibitors that specifically target PI3Kδ/mTOR. The most effective compound 5h was chosen for additional biological testing. At a low dose of 0.5 µM, a western blot investigation confirmed the anticancer effects by inhibiting the PAM cascade, which in turn reduced downstream biomarkers pAkt (Ser473), pAkt (Thr308), and pRPS6 (Ser235/236). Furthermore, it increased apoptosis at the early (10.03 times) and late (17.95 times) stages in the Annexin-V assay as compared to the standard. In addition, the expression of p53, caspase-3, caspase-9, and the Bax/BCl-2 ratio were all significantly increased by compound 5h in the ELISA assay. Based on these results, it appears that 5h may activate the intrinsic apoptosis pathway, which in turn triggers cell death. Furthermore, the anticancer effects could be attributed to the inhibition of PI3Kδ/mTOR, as shown by docking interactions. Lastly, it demonstrated improved in vitro metabolic stability and passed the in silico ADMET/drug-likeness test. This profile recommends 5h for future in vivo PK-PD and efficacy investigations in animal cancer models.

A novel class of pyrazole analogues as aurora kinase A inhibitor: design, synthesis, and anticancer evaluation.

Pyrazole, as a small molecule, was discovered for higher cytotoxicity and affinity towards Aurora-A kinase. Based on these facts, a novel pyrazole substituted at the 4th position was designed, synthesized, and evaluated against MCF-7, MDA-MB-23, and Vero (non-cancerous kidney cell) cell lines. Compounds5hand5eexhibited greater cytotoxicity in the series against MCF-7 and MDA-MB-231, with GI50 values of 0.12 µM and 0.63 µM, respectively, as compared to Imatinib (GI50 values of 16.08 µM and 10.36 µM). All of the compounds displayed selective cytotoxicity against cancer cells but not on normal Vero cells, supporting the design strategy to be a selective anticancer agent. Furthermore, compounds 5h and 5e inhibited Aurora-A kinase with IC50 values of 0.78 µM (4.70-fold) and 1.12 µM (2.84-fold), respectively, as compared to alisertib (IC50 = 3.36 µM). In addition, compound 5h significantly arrested the cell cycle at G2/M (34.89 %, 5.56-fold) and the apoptotic phase (25.04 %, 11.81-fold) compared to the control. It also triggered an increase in early (7.43 %) and late (14.89 %) phase apoptosis compared to vehicle (0.235 and 0.36 %, respectively), causing 37.89-fold higher total apoptosis in the annexin-V assay. These data imply that Aurora-A kinase inhibition may be linked to apoptosis induction and cell cycle arrest. Furthermore, their higher docking score in the study confirmed evidence of Aurora-kinase suppression. It was observed that fluorine and imidazole increased the H-bond and lipophilic interactions with the binding residue. Also, the substitution of electron-rich and lipophilic groups increased hydrophobic interactions. Moreover, the three-atom linkage (CH2NHCH2) expanded compound 5h to fill the cavity. Based on current findings, it is concluded that compounds 5h and 5e with strong Aurora-A kinase suppression may be promising anticancer agents.

6,7-Dihydrobenzo[f]benzo[4,5]imidazo[1,2-d][1,4]oxazepine derivatives as selective inhibitors of PI3Kα.

Twenty eight 6,7-dihydrobenzo[f]benzo[4,5]imidazo[1,2-d][1,4]oxazepine derivatives were synthesized and evaluated their biological activities as PI3K inhibitors. Biological evaluation against four human tumor cell lines revealed that most target compounds showed impressively better antiproliferative activities than that of LY294002. Among these compounds, compound 25 exhibited the most potent and selective activity for PI3Kα, with the IC50 value of 0.016µM, an approximately 30-fold increase in comparison with LY294002, it also has an increased potency of approximately 11-fold for PI3Kß. It indicated the potential of developing 6,7-dihydrobenzo[f]benzo[4,5]imidazo[1,2-d][1,4]oxazepine derivatives as the new PI3Kα selective inhibitors for tumor treatment.

Synthesis, biological evaluation and 3D-QSAR study of novel 4,5-dihydro-1H-pyrazole thiazole derivatives as BRAF(V6°°E) inhibitors.

Many reports implied that the BRAF serine/threonine kinase was mutated in various types of human tumors, which were related with cell growth, survival and differentiation. To provide new therapeutic opportunities, a series of novel 4,5-dihydro-1H-pyrazole derivatives (6a-10d) containing thiazole moiety as potential V600E mutant BRAF kinase (BRAF(V600E)) inhibitors were designed and synthesized. All compounds were evaluated in vitro for anticancer activities against WM266.4 human melanoma cell line and breast cancer MCF-7 cell line. Compound 10d displayed the most potential antiproliferative activity with an IC50 value of 0.12µM against cell line WM266.4 and 0.16µM against MCF-7 with positive control Sorafenib. Results of the inhibitory activity against BRAF(V600E) revealed that compound 10d was bearing the best bioactivity with IC50 of 0.05µM as well. On the basis of the result of flow cytometry, with the dose of compound 10d increasing, more and more cancer cell gradually encountered apoptosis or died, which indicated the compound 10d could induce remarkable apoptosis of MCF-7 and WM266.4 cells in a dose dependent manner. Furthermore, docking simulation of inhibitor analogues and 3D-QSAR modeling provided potential binding model and further knowledge of pharmacophore.

Schiff's base derivatives bearing nitroimidazole and quinoline nuclei: new class of anticancer agents and potential EGFR tyrosine kinase inhibitors.

New Schiff's base derivatives 5a-j have been synthesized by reaction between 2-phenoxyquinoline-3-carbaldehydes 3a-j and 2-(2-methyl-5-nitro-1H-imidazol-1-yl)acetohydrazide 4 in presence of nickel(II) nitrate as a catalyst in ethanol under reflux in good yield (78-92%). All compounds were tested for anticancer and inhibition of EGFR. Of the compounds studied, majority of the compounds showed effective antiproliferation and inhibition of EGFR and HER-2 activities. Compound 5h showed most effective inhibition (IC50=0.12±0.05 µM) by binding in to the active pocket of EGFR receptor with minimum binding energy (ΔGb=-58.3691 kcal/mol). The binding was stabilized by two hydrogen bonds, two π-cation and one π-sigma interactions. Compound 5d showed most effective inhibition (IC50=0.37±0.04 µM).

Design, synthesis and molecular modeling of biquinoline-pyridine hybrids as a new class of potential EGFR and HER-2 kinase inhibitors.

A new series of biquinoline-pyridine hybrids were designed and synthesized by a base-catalyzed cyclocondensation through one-pot multicomponent reaction. All compounds were tested for in vitro anticancer activities against two cancer cell lines A549 (adenocarcinomic human alveolar basal epithelial) and Hep G2 (liver cancer). Enzyme inhibitory activities of all compounds were carried out against EGFR and HER-2 kinase. Of the compounds studied, majority of the compounds showed effective anticancer activity against used cancer cell lines. Compound 9i (IC50=0.09 µM) against EGFR and (IC50=0.2 µM) against HER-2 kinase displayed the most potent inhibitory activity as compared to other member of the series. In the molecular modelling study, compound 9i was bound in to the active pocket of EGFR with four hydrogen bonds and two π-cation interactions having minimum binding energy ΔGb=-54.4 kcal/mol.

Bromodomain and BET family proteins as epigenetic targets in cancer therapy: their degradation, present drugs, and possible PROTACs.

Alteration in the pattern of epigenetic marking leads to cancer, neurological disorders, inflammatory problems etc. These changes are due to aberration in histone modification enzymes that function as readers, writers and erasers. Bromodomains (BDs) and BET proteins that recognize acetylation of chromatin regulate gene expression. To block the function of any of these BrDs and/or BET protein can be a controlling agent in disorders such as cancer. BrDs and BET proteins are now emerging as targets for new therapeutic development. Traditional drugs like enzyme inhibitors and protein-protein inhibitors have many limitations. Recently Proteolysis-Targeting Chimeras (PROTACs) have become an advanced tool in therapeutic intervention as they remove disease causing proteins. This review provides an overview of the development and mechanisms of PROTACs for BRD and BET protein regulation in cancer and advanced possibilities of genetic technologies in therapeutics.

New Promises to Cure Cancer and Other Genetic Diseases/Disorders: Epi-drugs Through Epigenetics.

All the heritable alterations in gene expression and chromatin structure due to chemical modifications that do not involve changes in the primary gene nucleotide sequence are referred to as epigenetics. DNA methylation, histone modifications, and non-coding RNAs are distinct types of epigenetic inheritance. Epigenetic patterns have been linked to the developmental stages, environmental exposure, and diet. Therapeutic strategies are now being developed to target human diseases such as cancer with mutations in epigenetic regulatory genes using specific inhibitors. Within the past two decades, seven epigenetic drugs have received regulatory approval and many others show their candidature in clinical trials. The current article represents a review of epigenetic heritance, diseases connected with epigenetic alterations and regulatory approved epigenetic drugs as future medicines.

Recent Developments of Metal and Metal Oxide Nanocatalysts in Organic Synthesis.

Recently, various nanomaterials have been used in many organic transformations as efficient catalysts. The development of new catalysts by nanoscale design has emerged as a fertile field for research and innovation. The ability of nanotechnology to enhance catalytic activity opens the potential to replace expensive catalysts with lower amounts of inexpensive nanocatalysts. Besides, development of efficient and environmentally friendly synthetic methodologies for the synthesis of compound libraries of medicinal scaffolds is an attractive area of research in both academic and pharmaceutical industry. According to above reports and needs, this review deals with applications of nanoparticles as catalysts in various organic syntheses. We detail the topic of organic transformations using nanoparticles: Metal Nanoparticles and Metal Oxide Nanoparticles. In the latter part, different Metal Oxide Nanoparticles, such as ZnO Nanoparticle, TiO2 Nanoparticle, and CuO Nanoparticle are discussed.

Design, synthesis and molecular modeling of pyrazole-quinoline-pyridine hybrids as a new class of antimicrobial and anticancer agents.

A new series of pyrazole-quinoline-pyridine hybrids were designed based on molecular hybridization technique and synthesized by a base-catalyzed cyclocondensation reaction through one-pot multicomponent reaction. All compounds were tested for in vitro antibacterial and anticancer activities. Enzyme inhibitory activities of all compounds were carried out against FabH and EGFR. Of the compounds studied, majority of the compounds showed effective antibacterial as well as anticancer activity against used strains and cancer cell lines respectively. Compound 7k (IC50 = 0.51 ± 0.05 µM) against EGFR and 7b displayed the most potent inhibitory activity with IC50 of 3.1 µM against FabH as compared to other member of the series. In the molecular modeling study, compound 7k was bound in to the active pocket of EGFR with three hydrogen bond and one π-cation interaction with minimum binding energy ΔGb = -54.6913 kcal/mol, as well as compound 7b was bound in to the active site of FabH with hydrogen bond and π-sigma interactions with minimum binding energy ΔGb = -45.9125 kcal/mol.