Novel synthetic bisbenzimidazole that targets angiogenesis in Ehrlich ascites carcinoma bearing mice.

Cancer is a leading cause of death in developed countries and second cause in developing countries. Herein we are reporting the synthesis of novel bisbenzimidazole derivatives and their anticancer properties. Among the newly synthesized bisbenzimidazoles, 3-(4-flurophenylsulfonyl)-1,7-dimethyl-2-propyl-1H,3H-2,5-bibenzo[d]imidazole (FDPB) presented as a potent antiproliferative agent against HeLa, HCT116 and A549 cells with selectivity over normal Vero cells (IC50 >50 µM). Additionally, we evaluated the efficacy of lead compound against Ehrlich ascites tumor (EAT) bearing mice for its antitumor and antiangiogenic properties. Our lead compound significantly reduced the cell viability, body weight, ascites volume and downregulated the formation of neovasculature and production of Vascular Endothelial Growth Factor (VEGF).

Synthesis of 1,2-benzisoxazole tethered 1,2,3-triazoles that exhibit anticancer activity in acute myeloid leukemia cell lines by inhibiting histone deacetylases, and inducing p21 and tubulin acetylation.

1,2,3-Triazole-based heterocycles have previously been shown to possess significant anticancer activity in various tumor models. In the present study, we attached a 1,2,3-triazole moiety to the third position of a 1,2-benzisoxazole heterocycle via copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) with various alkynes and established for the title compounds significant antiproliferative effect against human acute myeloid leukemia (AML) cells. Among the tested compounds, 3-(4-(4-phenoxyphenyl)-1H-1,2,3-triazol-1-yl)benzo[d]isoxazole (PTB) was found to be the most potent antiproliferative agent with an IC50 of 2 µM against MV4-11 cells using MTT assay. Notably, PTB induced cytotoxicity in MOLM13, MOLM14 and MV4-11 cells with selectivity over normal bone marrow cells (C57BL/6). Furthermore, PTB was found to induce cytotoxicity by increasing apoptosis of AML cells (MOLM13, MOLM14 and MV4-11) as well as sub-G1 cell population and apoptotic cells at submicromolar concentrations, as shown by flow cytometry and Annexin-V staining, respectively. On the protein level we suggested histone deacetylases (HDACs) as the potential protein target of those compounds in silico, and the predicted target was next experimentally validated by measuring the variations in the levels of p21, cyclin D and acetylation of histone H3 and tubulin. Molecular docking analysis of the title compounds with the second deacetylase domain of HDAC6 displayed high degree of shape complementarity to the binding site of the enzyme, forming multiple molecular interactions in the hydrophobic region as well as a hydrogen bond to the phenol side-chain of Tyr-782. Thus, 1,2,3-triazole derivatives appear to represent a class of novel, biologically active ligands against histone deacetylases which deserve to be further evaluated in their applications in the cancer field.

Synthesis, Characterization of 4-Anilino-6,7-Dimethoxy Quinazoline Derivatives as Potential Anti-Angiogenic Agents.

BACKGROUND: Quinazolines are a big family of heterocyclic compounds with anti-cancer properties. OBJECTIVE: The latest investigation was on synthesis, characterization of novel 4-anilinoquinazoline derivatives for their anti-angiogenic effect. METHOD: A series of novel 4-anilino-6,7-dimethoxy quinazoline derivatives were synthesized and characterized using 1H, 13C NMR, FT-IR and LC-MS techniques. Cytotoxicity assays were performed for all compounds against different cell lines such as Human colon carcinoma (HCT116), Human chronic myeloid leukemia (K562) and Human breast cancer (SKBR3) cell lines using 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyl tetrazolium Bromide (MTT), Trypan blue and Lactose dehydrogenase release assay. The selected compounds were evaluated for their anti-tumor and anti-angiogenic effect on EAC tumor model. The molecular docking studies were drawn using maestro 2D sketcher and energy minimize was compounded by OPLS 2005. RESULTS: Among all compounds, RB4 and RB7 showed moderate activity whereas RB1 showed most potent activity comparable with that of the standard drug cisplatin against all three cell lines. RB1 also inhibited the proliferation of tumor cells in three different cell lines. Further, in-vivo studies revealed that RB1 significantly reduced secretion of ascites, tumor cell proliferation and increased the life span of tumor bearing mice. The antiangiogenic effect of RB1 was revealed from the reduced vessel sprouting in the peritoneum region of treated mice and induced avascular zone in chorioallantoic membrane (CAM) model. The insilco molecular docking studies clearly demonstrate the dual inhibitory potential of RB1 against VEGFR-2 and EGFR from binding to the active site of its receptors. CONCLUSION: However these studies clearly show that RB1 might be a potent antitumor and anti-angiogenic agent representing a promising lead for further optimization and elucidation of the mechanism of action.

3,5-Disubstituted Isoxazole Derivatives: Potential Inhibitors of Inflammation and Cancer.

The products of arachidonic acid metabolism by lipoxygenase (LOX) and cyclooxygenase (COX) significantly contribute to inflammation and carcinogenesis. Particularly, overproduction of leukotrienes and prostaglandins contribute to tumor growth by inducing formation of new blood vessels that sustain tumor cell viability and growth. Hence, search for novel anticancer drug via inhibition of LOX and COX enzymes constitutes an impressive strategy till date. In this context, a series of isoxazole derivatives were synthesized and screened for their anti-inflammatory activity via LOX and COX inhibition. Among these, 3-(3-methylthiophen-2-yl)-5-(3,4,5-trimethoxyphenyl)isoxazole (2b) showed significant inhibitory activity toward LOX and COX-2. Additionally, 2b showed a good inhibition of tumor growth, peritoneal angiogenesis, and ascite formation in Ehrlich ascites carcinoma (EAC) cell mouse model. Further, the in silico molecular studies also revealed that the compound 2b binds to the catalytic domain of LOX and COX-1 and COX-2 strongly with high atomic contact energy (ACE) score compared to standard drug. These initial pharmacological data support the fact that the compound 2b serves as the basis in developing anti-inflammatory and anticancer agents.