Design and Synthesis of 4-O-Podophyllotoxin Sulfamate Derivatives as Potential Cytotoxic Agents.

4-O-Podophyllotoxin sulfamate derivatives were prepared using the natural lignan podophyllotoxin. The prepared compounds were afforded by reacting O-sulfonyl chloride podophyllotoxin with ammonia or aminoaryl/heteroaryl motif. Biological evaluation was performed in human breast cancer (MCF7), ovarian cancer (A2780), colon adenocarcinoma (HT29), and normal lung fibroblast (MRC5) cell lines. Compound 3 exhibited potent inhibitory activity and good selectivity margin. Compounds 2, 3, and 7 exerted apoptotic effect in MCF7 cells in a dose-dependent manner. The cytotoxicity of the verified compounds was inferior to that of podophyllotoxin.

Proapoptotic Activity of Achillea membranacea Essential Oil and Its Major Constituent 1,8-Cineole against A2780 Ovarian Cancer Cells.

Among the hundreds of reported Achillea species, A. membranacea (Labill.) DC. is one of the six that grow in Jordan. Many species of this genus are used in folk medicine to treat a variety of ailments and several biological and pharmacological activities have been ascribed to their essential oil (EO). For this study, the EO obtained from a specimen of A. membranacea grown in Jordan was analyzed by GC-MS. Ninety-six compounds were detected, of which oxygenated monoterpenes was the predominant class (47.9%), followed by non-terpene derivatives (27.9%), while sesquiterpenes represented 14.2% of the total composition. The most abundant compound in the EO was 1,8-cineole (21.7%). The cytotoxic activity of the EO was evaluated against three cancer cell lines (MCF7, A2780 and HT29), and one normal fibroblast cell line (MRC5) by MTT assay. Significant growth inhibition was observed in EO-exposed A2780 and HT29 cells (IC50 = 12.99 and 14.02 µg/mL, respectively), while MCF7 and MRC5 were less susceptible. The EO induced apoptosis and increased the preG1 events in A2780 cells. 1,8-Cineole, the major constituent of the EO, exhibited submicromolar cytotoxicity against A2780 cells, and was 42 times more selective against MRC5 cells. Its cytotoxicity against A2780 cells was comparable with that of doxorubicin, but 1,8-cineole was more selective for MRC5 normal cells. Interestingly, 1,8-cineole enhanced apoptosis in A2780, and caused a remarkable dose-dependent increase in preG1 events. Thus, 1,8-cineole has demonstrated promising cytotoxic and proapoptotic properties.

Molecular dynamics simulations reveal structural insights into inhibitor binding modes and mechanism of casein kinase II inhibitors.

Casein kinase-II, a member of protein kinase family, plays significant role in different cellular processes such as cell growth, differentiation, proliferation, gene expression, and embryogenesis. Being a potent suppressor of apoptosis, it serves as a significant link for its association with various types of malignancies such as colorectal and breast cancer. To overcome its pathological role in various cancerous diseases, CK-II procures great consideration as a therapeutic target. This study aimed at understanding the binding mechanism and structural properties of benzimidazole derivatives by utilizing various computational tools including docking simulation, three-dimensional quantitative structure activity relationships and molecular dynamic simulation. Structure-based 3D-QSAR techniques such as CoMFA and CoMSIA models, were established from the conformations gained by protein-ligand docking approach. The attained models have showed a good extrapolative power for internal as well as external validation. Moreover, MD simulation was carried out to explain the detailed binding mechanism and the comparison of inhibitor's binding mode with diverse biological activities. A good correlation was observed among docking studies, MD results, and contour map analysis. Interestingly new molecules were designed using detail structural information from MD simulation, showed higher potency of inhibition (pIC50 7.6-7.7) compare to the most active compound of the series.

Synthesis and in Vivo Lipid-Lowering Activity of Novel Imidazoles-5-carboxamide Derivatives in Triton-WR-1339-Induced Hyperlipidemic Wistar Rats.

A new series of imidazole-5-carboxamide derivatives were prepared and tested for their anti-hyperlipidemic activity in Triton-WR-1339-induced hyperlipidemic Wistar rats. The purpose of this research was to improve benzophenone carboxamides water solubility maintaining at the same time the antihyperlipidemic activity. Compounds 4, 6, 10, and 11 were synthesized through a coupling reaction between imidazoles-5-carbonyl chloride and amino benzophenones. The tested animals (n=48) were divided into six groups: the first group (hyperlipidemic control group; HCG) received an intraperitoneal injection (i.p.) of (300 mg/kg) Triton WR-1339. The second group received i.p. injection of Triton WR-1339 followed by an intra-gastric administration of bezafibrate (100 mg/kg) (bezafibrate; BF). The third, fourth, fifth, and sixth groups received i.p. injection of Triton WR-1339 followed by an intra-gastric administration of (30 mg/kg) of compounds 4, 6, 10, and 11, respectively. At a dose of 30 mg/kg body weight compounds 4, 6, 10, and 11 significantly (p<0.0001) decreased the plasma level of triglyceride (TG), low-density lipoprotein (LDL) and total cholesterol (TC) levels after 18 h of treatment. Additionally, compounds 4, 6, 11 and bezafibrate (100 mg/kg) significantly (p<0.0001) increased the plasma level of high-density lipoprotein (HDL) levels, which is known for its preventive role against atherogenesis. These results demonstrate the possibility of pharmacokinetic properties improvement maintaining the biological and pharmacological profile of these compounds.

Preparation and biological evaluation of metronidazole derivatives with monoterpenes and eugenol.

Two series of metronidazole derivatives (ester derivatives and ether derivatives) were prepared reacting metronidazole and its acetic acid oxidized form with menthol, thymol, carvacrol, and eugenol. Both series of compounds were tested in vitro against two strains of Helicobacter pylori (the ATCC 26695 and P12), and one strain of Clostridium (Clostridium perfringens). Most of the prepared compounds showed biological activity against the targeted bacteria. Compound 11 was highly active against all tested bacterial strains, especially against P12 with IC50 0.0011 µM/ml. Compound 6 was highly active against C. perfringens with MIC 0.0094 nM/ml. Viability test was conducted for compound 11 to test its selectivity for normal human fetal lung fibroblasts (MRC5), and it was found to be non-toxic with IC50 more than 50 µM/ml.

Atom and receptor based 3D QSAR models for generating new conformations from pyrazolopyrimidine as IL-2 inducible tyrosine kinase inhibitors.

In the current study, quantitative three-dimensional structure-activity-relationship (3D-QSAR) method was performed to design a model for new chemical entities by utilizing pyrazolopyrimidines. Their inhibiting activity on receptor IL-2 Itk correlates descriptors based on topology and hydrophobicity. The best model developed by ligand-based (atom-based) approach has correlation-coefficient of r2: 0.987 and cross-validated squared correlation-coefficient of q2: 0.541 with an external prediction capability of r2: 0.944. Whereas the best selected model developed by structured-based (receptor-based) approach has correlation-coefficient of r2: 0.987, cross-validated squared correlation-coefficient of q2: 0.637 with an external predictive ability of r2: 0.941. The statistical parameters prove that structure-based gave a better model to design new chemical scaffolds. The results achieved indicated that hydrophobicity at R1 location play a vital role in the inhibitory activity and introduction of appropriately bulky and strongly hydrophobic-groups at position 3 of the terminal phenyl-group which is highly significant to enhance the activity. Six new pyrazolopyrimidine derivatives were designed. Docking simulation study was carried out and their inhibitory activity was predicted by the best structure based model with predictive activity of ranging from 8.43 to 8.85 log unit. The interacting residues PHE435, ASP500, LYS391, GLU436, MET438, CYS442, ILE369, VAL377 of PDB 4HCT were studied with respect to type of bonding with the new compounds. This study was aimed to search out more potent inhibitors of IL-2 Itk.

Reprofiling of full-length phosphonated carbocyclic 2'-oxa-3'-aza-nucleosides toward antiproliferative agents: Synthesis, antiproliferative activity, and molecular docking study.

A series of phosphonated carbocyclic 2'-oxa-3'-aza-nucleosides were synthesized via 1,3 dipolar cycloaddition and evaluated for their in vitro antiproliferative activity against the growth of cancer cell lines (MCF-7, A2780, HCT116) and normal non-transformed fibroblast (MRC5) using MTT assay. Synthesized compounds exhibited antiproliferative activity in the micromolar range. Compounds 11b showed the highest activity against MCF-7 cells (IC50 of 0.2344 µm). Cell cycle analysis was performed for compound 11b on MCF7 cells showing arrest of cells in the S phase. Molecular docking of synthesized compounds confirmed high affinity of these compounds to two different receptors for anticancer nucleosides on dCK, namely the 1P5Z and 2ZIA, showing scores higher than the cognate ligand for all tested compounds. All synthesized compounds were evaluated according to the Lipinski, Veber, and Opera rules, and all of them passed the evaluation showing excellent features, superior to reference drugs. In addition, ADME for all the synthesized compounds was predicted through a theoretical kinetic study using the discovery studio 3.1 software.

Identification of potent virtual leads and ADME prediction of isoxazolidine podophyllotoxin derivatives as topoisomerase II and tubulin inhibitors.

Towards the design of new class of podophyllotoxin to target topoisomerase II and tubulin as substantial target in cancer therapy, a series of isoxazolidine podophyllotoxin derivatives were designed. Topoisomerase in complex with etoposide and four ß-tubulin in complex with zampanolide, taxol, vinblastine or colchicine were used as targets using GOLD5.2.2 as a docking module. The revealed key structural features of the highest fitness into tubulin domain have been explained as follows: (1) trans orientation of the lactone (ring D) with 5a-ß, 8a-α configuration; (2) dioxolane in ring A; (3) free rotation of ring E; (4) α (R) or ß (S) configuration has equal fitness in position 5; (5) 4'-OMe; (6) phosphoramide linkage; (7) ethylene bridge between the phosphate and isoxazolidine ring; (8) benzyl moiety at N2-position of isoxazolidine ring; and (9) position 5 of isoxazolidine ring accommodated with 6-bromo-9H-purine, 2-amino-6H-purin-6-one, or N-(2-oxopyrimidin-4-yl) acetamide. All of these structural features are applicable for compounds to fit properly into topoisomerase II, except (1) ß (S) configuration has a higher score fitness than α (R) in position 5; (2) 4'-OH; and (3) position 5 of isoxazolidine ring accommodated better with 6-bromo-9H-purine, 2-amino-6H-purin-6-one or 7H-purin-6-amine. Computational ADMET and toxicity studies were in consensus with the docking results. Compounds holding ethylene bridge between phosphate and benzyl moiety at N2-position of isoxazolidine ring have the optimal pharmacokinetic properties and were calculated to be non-toxic. The predicted solubility profile for most of 4'-OMe containing compounds was good. This accomplished our aim in identifying promising new hits as antitumor agent with improved activity and less toxicity.