Synthesis, angiopreventive activity, and in vivo tumor inhibition of novel benzophenone–benzimidazole analogs

• Published in: Life sciences (1973) 2013-11, Vol.93 (23), p.904-911
• Main Authors: Ranganatha, V. Lakshmi, Vijay Avin, B.R., Thirusangu, Prabhu, Prashanth, T., Prabhakar, B.T., Khanum, Shaukath Ara
• Format: Article
• Language: English
• Subjects: Angiogenesis Inhibitors - chemical synthesis; Angiogenesis Inhibitors - chemistry; Angiogenesis Inhibitors - pharmacology; Angioprevention; animal models; Animals; antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; ascites; Benzimidazoles - chemical synthesis; Benzimidazoles - chemistry; Benzimidazoles - pharmacology; Benzophenones - chemical synthesis; Benzophenones - chemistry; Benzophenones - pharmacology; Benzophenone–benzimidazoles; carcinoma; Carcinoma, Ehrlich Tumor - blood supply; Carcinoma, Ehrlich Tumor - drug therapy; Carcinoma, Ehrlich Tumor - pathology; Cell Proliferation - drug effects; Chickens; chorioallantoic membrane; Chorioallantoic Membrane - blood supply; Chorioallantoic Membrane - drug effects; Cytotoxicity; Methoxy group; Mice; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - pathology; peritoneum; Peritoneum - blood supply; Peritoneum - drug effects; Structure-Activity Relationship; structure-activity relationships; therapeutics
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2013.10.001

The development of anticancer drugs with specific targets is of prime importance in modern biology. This study investigates the angiopreventive and in vivo tumor inhibition activities of novel synthetic benzophenone–benzimidazole analogs. The multistep synthesis of novel benzophenone–benzimidazole analogs (8a–n) allowing substitution with methoxy, methyl and halogen groups at different positions on the identical chemical backbone and the variations in the number of substituents were synthesized and characterized. The newly synthesized compounds were further evaluated for cytotoxic and antiproliferative effects against Ehrlich ascites carcinoma (EAC) cells. The potent lead compounds were further assessed for antiangiogenic effects in a CAM model and a tumor-induced vasculature in vivo model. The effect of angioprevention on tumor growth was verified in a mouse model. The cytotoxicity studies revealed that compounds 8f and 8n are strongly cytotoxic. Analyzing the structure–activity relationship, we found that an increase in the number of methyl groups in addition to methoxy substitution at the para position of the benzoyl ring in compound 8n resulted in higher potency compared to 8f. Furthermore, neovessel formation in in vivo systems, such as the chorioallantoic membrane (CAM) and tumor-induced mice peritoneum models, was significantly suppressed and reflected the tumor inhibition observed in mice. These results suggest the potential clinical application of compound 8n as an antiangiogenic drug for cancer therapy.