ROS-Mediated Antitumor Activity, Apoptosis, and Molecular Docking Studies of Platinum(II) Coordination Complexes Bearing 2-(Diphenylphosphino)pyridine Ligands.

Platinum-based drugs have been widely used in cancer treatment. However, their severe side effects have limited their use. So, researchers have been striving to find compounds with fewer side effects and greater efficacy, to overcome these drawbacks. Here, the cytotoxicity of platinum(II) complexes containing 2-(diphenylphosphino)pyridine ligands have been studied on human lung (A549), ovarian (SKOV3), breast (MCF-7) cancer, and normal breast (MCF-10A) cell lines. The most potent compound exhibits a marked cell growth-inhibitory effect against ovarian and lung cancer cells with IC50 values of 9.41 and 5.58 µM, respectively, which were significantly better than that observed for cisplatin (19.02, and 8.64 µM). Additionally, all complexes achieved significantly lower cytotoxicity towards MCF-10A. To investigate the interaction of complexes with DNA, an electrophoresis mobility shift assay was conducted, which indicated that complexes bind to DNA and affect its electrophoretic mobility. An analysis of apoptosis in A549 cells supported the conclusion that they inhibits cell proliferation via induction of apoptosis in a concentration-dependent manner. Molecular docking was also used to investigate the interactions of compounds with different DNA structures. These compounds have the ability to be a suitable pharmaceutical compound with further investigations in the field of cancer research.

Design, synthesis and evaluation of novel 1,2,4-triazole derivatives as promising anticancer agents.

Herein, we reported the synthesis of nineteen novel 1,2,4-triazole derivatives including 1,3-diphenyl-2-(1H-1,2,4-triazol-1-yl) propan-1-ones (7a-e), 1-(1,3-diphenylpropan-2-yl)-1H-1,2,4-triazole (8a-c) and 1,4-diphenyl-2-(1H-1,2,4-triazol-1-yl) butane-1,4-diones (10a-k). The structures of these derivatives were confirmed by spectroscopic techniques like IR, 1H-NMR, Mass spectroscopy and Elemental analysis. The cytotoxic activities of the synthesized compounds were evaluated against three human cancer cell lines including MCF-7, Hela and A549 using MTT assay. Compounds 7d, 7e, 10a and 10d showed a promising cytotoxic activity lower than 12 µM against Hela cell line. The safety of these compounds was also, evaluated on MRC-5 as a normal cell line and relieved that most of the synthesized compounds have proper selectivity against normal and cytotoxic cancerous cell lines. Finally, molecular docking studies were also, done to understand the mechanism and binding modes of these derivatives in the binding pocket of aromatase enzyme as a possible target.

Antiproliferative activity and DNA binding studies of cyclometalated complexes of platinum(II) containing 2-vinylpyridine.

The cytotoxic activity of four cyclometalated platinum(II) complexes [PtMe(vpy)(L)], containing 2-vinylpyridine (vpy) and the phosphine ligands (L) PMe2Ph (1a), PPh3 (1b), PMePh2 (1c), and P(c-Hex)3 (1d), were evaluated against human breast cancer (MDA-MB-231), human lung cancer (A549), human colon cancer (SW1116), and non-tumor epithelial breast (MCF-10 A) cell lines. The highest activity was found for 1c with IC50 values of 21.10 µM, 23.36 µM, and 12.96 µM, compared to cisplatin, which was 10.12 µM, 47.57 µM, and 19.50 µM against the A549, SW1116, and MDA-MB-231 cell lines, respectively. 1a-d showed a higher selectivity index (SI) than cisplatin. Docking studies confirmed interaction to the DNA minor groove for all complexes. Genotoxicity studies on 1c showed interactions with the genomic content of malignant cells. Compared with cisplatin as a positive control, a slight shift was found in the electrophoresis mobility, which was utilized further to study the direct interaction of 1c with DNA.

Novel Hydrazone Derivatives of 3-Bromopyruvate: Synthesis, Evaluation of the Cytotoxic Effects, Molecular Docking and ADME Studies.

A series of 3-bromopyruvate (3-BP) derivatives were synthesized to develop new potent anticancer agents. The chemical structures of the compounds were characterized using FT-IR, 1 H-, 13 C-NMR spectroscopy, and elemental analysis (CHN). Their cytotoxic activities were investigated against four cancer cell lines, including colon (SW1116), breast (MDA-MB-231), lung (A549), and liver (HepG2) cancer cell lines. Among the synthesized compounds, 3b showed promising cytotoxic activity compared to 3-BP, with IC50 values of 16.3 µM, 19.1 µM, 27.8 µM, and 14.5 µM against A549, MDA-MB-231, SW1116 and, HepG2 cell lines, respectively. Furthermore, the effect of these compounds on MCF-10A (a normal breast cell lines) was investigated to determine their selectivity between tumorigenic and non-tumorigenic cells. Since the 3-BP inhibits hexokinase II (HK II), molecular docking of 3-BP derivatives was carried out using AutoDock 4.2. The binding energies of these derivatives were greater than 3-BP, indicating that they had a higher affinity for HK II. For validation of docking, a 40 ns MD simulation was performed. SwissADME was used to predict pharmacokinetics, drug-likeness, and ADME parameters of the screened compounds. The results demonstrated that these derivatives are suitable candidates for developing orally potent HK II inhibitors.

Fluorinated Cycloplatinated(II) Complexes Bearing Bisphosphine Ligands as Potent Anticancer Agents.

A family of cationic cycloplatinated(II) complexes [Pt(dfppy)(P^P)]Cl, dfppy = 2-(2,4-difluorophenyl)pyridine, incorporating bisphosphine ligands, P^P = bis(diphenylphosphino)methane (1, dppm), 1,2-bis(diphenylphosphino)ethane (2, dppe) and 1,2-bis(diphenylphosphino)benzene (3, dppbz), was prepared. The complexes were characterized by means of several analytical and spectroscopic methods. These complexes displayed acceptable stability in the biological environments which was confirmed by NMR, HR ESI-MS and UV-vis techniques. The antiproliferative properties of these complexes were evaluated by National Cancer Institute (NCI) at National Institutes of Health (NIH) against 60 different human tumor cell lines such as leukemia, melanoma, lung, colon, brain, ovary, breast, prostate and kidney. These complexes showed higher cytotoxicity than cisplatin against a wide variety of cancer cell lines such as K-562 (leukemia), HOP-92 (lung), HCT-116 (colon), OVCAR-8 (ovarian), PC-3 (prostate), MDA-MB-468 (breast), and melanoma cancer cell lines. Complex 3 as the most potent compound in this study furnished an excellent anti-proliferative activity compared to the cisplatin against Hela, SKOV3, and MCF-7 cancer cell lines. The main mode of the interaction of 1-3 with DNA was also determined using molecular docking studies.

3-Hydroxypyrimidine-2, 4-dione Derivatives as HIV Reverse Transcriptase-Associated RNase H Inhibitors: QSAR Analysis and Molecular Docking Studies.

AIDS, as a lethal disease, is caused by infection with the HIV virus that affects millions of people. Three essential enzymes should be encoded for replication of HIV virus: protease, integrase and reverse transcriptase (RT). RT has two different activities including DNA polymerase and ribonuclease H (RNase H). However, all of the marketed RT inhibitors target only the DNA polymerase activity. Therefore, ribonuclease H activity may serve as a new target for drug discovery. In the present study, a series of 3-Hydroxypyrimidine-2, 4-dione derivatives as potent RT-associated RNase H inhibitors were applied to QSAR analysis. Two methods including multiple linear regressions (MLR) and partial least squared based on genetic algorithm (GA-PLS) were utilized to find the relationship between the structural feathers and inhibitory activities of these compounds. The best multiple linear regression equation was generated by GA-PLS method. A combination of 2D autocorrelations, topological, atom-centered, and geometrical descriptors were selected by GA-PLS as they had more effects on the inhibitory activity. Then, the molecular docking studies were carried out. The results showed that the important amino acids inside the active site of the enzyme responsible for essential interactions were Gln475, Asp549, Tyr501, Ser515, Trp534, Asp493, Tyr472, and Gln480 which took part in hydrogen bond formation. Furthermore, docking energy was plotted against pIC50 predicted by GA-PLS method. The result showed that there is a good correlation with R2=0.71. Consequently, these findings suggest that the better method, GA-PLS, could be applied to design new compounds and predict their inhibitory activity.

Binding mode of triazole derivatives as aromatase inhibitors based on docking, protein ligand interaction fingerprinting, and molecular dynamics simulation studies.

Aromatase inhibitors (AIs) as effective candidates have been used in the treatment of hormone-dependent breast cancer. In this study, we have proposed 300 structures as potential AIs and filtered them by Lipinski's rule of five using DrugLito software. Subsequently, they were subjected to docking simulation studies to select the top 20 compounds based on their Gibbs free energy changes and also to perform more studies on the protein-ligand interaction fingerprint by AuposSOM software. In this stage, anastrozole and letrozole were used as positive control to compare their interaction fingerprint patterns with our proposed structures. Finally, based on the binding energy values, one active structure (ligand 15) was selected for molecular dynamic simulation in order to get information for the binding mode of these ligands within the enzyme cavity. The triazole of ligand 15 pointed to HEM group in aromatase active site and coordinated to Fe of HEM through its N4 atom. In addition, two π-cation interactions was also observed, one interaction between triazole and porphyrin of HEM group, and the other was 4-chloro phenyl moiety of this ligand with Arg115 residue.

A Comparative QSAR Analysis, Molecular Docking and PLIF Studies of Some N-arylphenyl-2, 2-Dichloroacetamide Analogues as Anticancer Agents.

Dichloroacetate (DCA) is a simple and small anticancer drug that arouses the activity of the enzyme pyruvate dehydrogenase (PDH) through inhibition of the enzyme pyruvate dehydrogenase kinases (PDK1-4). DCA can selectively promote mitochondria-regulated apoptosis, depolarizing the hyperpolarized inner mitochondrial membrane potential to normal levels, inhibit tumor growth and reduce proliferation by shifting the glucose metabolism in cancer cells from anaerobic to aerobic glycolysis. In this study, a series of DCA analogues were applied to quantitative structure-activity relationship (QSAR) analysis. A collection of chemometrics methods such as multiple linear regression (MLR), factor analysis-based multiple linear regression (FA-MLR), principal component regression (PCR), and partial least squared combined with genetic algorithm for variable selection (GA-PLS) were applied to make relations between structural characteristics and cytotoxic activities of a variety of DCA analogues. The best multiple linear regression equation was obtained from genetic algorithms partial least squares, which predict 90% of variances. Based on the resulted model, an in silico-screening study was also conducted and new potent lead compounds based on new structural patterns were designed. Molecular docking as well as protein ligand interaction fingerprints (PLIF) studies of these compounds were also investigated and encouraging results were acquired. There was a good correlation between QSAR and docking results.