Letters in Drug Design & Discovery - Volume 12, Issue 3, 2015

Saponins enhance the cytotoxicity of the type I ribosome-inactivating protein (RIP-I) saporin. In the present study, the synergistic cytotoxicity of nine newly isolated gypsogenin-containing saponins from Gypsophila trichotoma in combination with RIP-I was evaluated in vitro and used to derive a quantitative structure – activity relationship (QSAR). The QSAR model distinguished two important structural features of the studied saponins necessary for their cytotoxicity enhancing activity: the branched trisaccharide moiety attached to C-3 should contain one xylose residue instead of an arabinose and the branched tetrasaccharide at C-28 should contain one acetyl group attached to the glucose residue.

Novel disulfide analogues of isophosphoramide mustard (iPAM) were designed and synthesised. All compounds were hydrolytically stable and underwent reduction by L-glutathione with different kinetic parameters. Based on the HPLC-MS analysis a mechanism of activation by glutathione obtained disulfide analogues of iPAM was proposed. The compounds were tested for cytotoxic activity against human promyelocytic leukaemia HL-60, human lymphoblastic leukaemia MOLT-4, human lymphoblastic leukaemia CCRF/CEM, human bladder cancer HCV29T, murine melanoma B16-F0 and murine fibroblasts Balb3T3 cell lines. The most promising anticancer activity was exhibited by compound 4, which proved to be more active than the reference cisplatin against all cancer cell lines.

Several oncogenic pathways may lead to cancer. Pharmaceutical research develops efficacious compounds to inhibit these pathways. Current inhibitor drugs may block several pathways simultaneously but cause adverse and side effects. Therefore, we designed novel acyl thiourea derivatives containing pyrazole ring to selectively inhibit a kinase dependent pathway in cancer. In this study, breast and bone cancer cells were employed to monitor this selectivity. Since metastatic breast cancer spreads to bone, MCF-7 along with epithelial (Saos-2) and fibroblast (MG-63) human bone cancer cell lines were used to observe inhibitory effects of the synthesized compounds. It has been reported that Estrogen receptor α (ER-α) and Aurora kinase A and B are involved in different pathways at breast and bone cancer mechanism. Synthesized novel inhibitors presented in this work effectively and selectively bind to Aurora kinase A and B but do not interact with ER-α however; a generic inhibitor PHA-739358 binds to all three enzymes. This improved binding mode of the novel inhibitors may be a useful therapeutic strategy for the treatment of breast and bone cancer approaches and provides potency to personalized medicine.

By coupling nitric oxide (NO)-donating moieties with ATPT, an orally active AT1 receptor antagonist, a series of novel NO-releasing derivatives with N-phenylpyrrolyl-2-tetrazole moiety were designed and synthesized. The NOreleasing assay indicated that compound 4c had good maximum amount of NO release. Moreover the target compounds were evaluated for their antagonism of AT1 receptor with induced contraction in the rat thoracic aortic ring, and the results showed that compound 4c exhibited potent antagonistic activity of AT1 receptor, which was obviously superior to that of the control drug losartan. These results suggested that NO-donor ATPT hybrids may provide a promising approach for the search for novel antihypertensive agents.

The inhibition of glycosidases from bacteria and the liver of normal and diabetic rats by 2-(tetra-O-acetyl-β-Dglucopyranosylsulfanyl)- 5-(1-benzyl-1H-indol-2-yl)-1,3,4-oxadiazole BnM-3B; 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl)- 5-(1H-indol-2-yl)-1,3,4-oxadiazole- 2(3H)-thione MTB-4A; 3-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-Dglucopyranosyl)- 5-(1-benzyl-1H-indol-2-yl)-1,3,4-oxadiazole-2(3H)-thione BnN-5A has been investigated. In vitro treatment of hepatic α-amylase and β-glucuronidase from control and streptozotocin-induced diabetic rats by S- and Nglycosyl analogues from oxadiazolinethione derivatives exhibited a significant dose-dependent decrease on the specific activity of both α-amylase and β-glucuronidase. Moreover, these compounds also exhibited a significant decrease on the specific activity of α-amylase and α-glucosidase produced by Bacillus subtilis AH. The observed IC50 values of these compounds are much lower than that of ethanolamines, higher for α-glucosidase than α-amylase from bacteria and significantly lower for hepatic α-amylase and β-glucuronidase from diabetic rats. The obtained results suggest that these compounds are good inhibitors that act on glycosidases from bacteria and normal / diabetic rats in different mechanisms.

The overexpression of anaplastic lymphoma kinase (ALK) had been found in many types of cancers, especially the non-small-cell lung cancers (NSCLCs). So the discovery of novel ALK inhibitor had attracted a great deal of interest in anticancer drugs research area. Presently, a combined study of 3D-quantitative structure-activity relationship (3DQSAR) and molecular docking was undertaken to explore the structural insights of 36 2-acyliminobenzimidazoles compounds influencing the ALK inhibitory activities. Both the ligand-based resultant comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) models exhibited good predictability (CoMFA with R2, 0.995; q2, 0.534; CoMSIA with R2, 0.993; q2, 0.519;). 3D contour maps and docking results suggested different groups on the core parts of the componds could enhance the biological activities. Finally, 10 derivatives as potential candidates of ALK inhibitors with excellent predicted activities were designed.

A novel series of FtsZ-targeted phenylacrylamides were designed, synthesized and evaluated for their antibacterial activity and cell division inhibitory activity against various Gram-positive and -negative strains. Among them, some compounds displayed preferable or comparable antibacterial activity and cell division inhibitory activity in comparison with their parent cinnamic acid. In particular, the compounds bearing 2-methylbenzimidazolyl groups showed more potent antibacterial activity than the others against the tested strains. For instance, compound 12 exhibited over 32-fold more potent antibacterial activity than cinnamic acid against Staphylococcus epidermidis and compound 16 exerted over 32-fold better antibacterial activity against Staphylococcus aureus ATCC25923 and S. epidermidis than cinnamic acid. In contrast, against Bacillus subtilis ATCC9372, Escherichia coli ATCC25922 and Pseudomonas aeruginosa ATCC27853, the phenylacrylamides showed little or no antibacterial activity. In the cell division inhibitory activity, compounds 14-17 displayed more significant on-target activity against S. aureus ATCC25923 than the other tested strains. In particular, the most active compound 14 shared the minimum cell division concentration of 0.5 µg/mL, which had over 256-fold better activity than all the references.

4-isopropylcyclohexa-1, 3-dienecarboxylic acid (dehydrocumic acid) was prepared from β-pinene, and a series of acylthiourea derivatives was obtained. The structures of title compounds were characterized by FT-IR, NMR, and MS. The insecticidal activities against ostrinia furnacclis and bemisia tabaci were evaluated. The title compounds exhibited moderate larvicidal activity against ostrinia furnacclis. The preliminary study showed the introduction of orth and paro substitute displayed relatively good performance. The study promoted new application of β-pinene and its derivatives in pesticide management as botanical insecticide.