Synthesis and docking studies of novel antitumor benzimidazoles

• Published in: Bioorganic & medicinal chemistry 2012-12, Vol.20 (24), p.6989-7001
• Main Authors: Omar, Mohamed A., Shaker, Yasser M., Galal, Shadia A., Ali, Mamdouh M., Kerwin, Sean M., Li, Jing, Tokuda, Harukuni, Ramadan, Raghda A., El Diwani, Hoda I.
• Format: Article
• Language: English
• Subjects: 12-O-Tetradecanoylphorbol-13-acetate; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Benzimidazole; Benzimidazoles; Benzimidazoles - chemical synthesis; Benzimidazoles - chemistry; Benzimidazoles - pharmacology; Biological and medical sciences; Breast cancer; Breast Neoplasms - drug therapy; Carcinogenesis, carcinogens and anticarcinogens; Cell Line, Tumor; Chemical agents; Cytotoxicity; Docking study; Drug Screening Assays, Antitumor; Epstein–Barr virus early antigen (EBV-EA) activation; Herpesvirus 4, Human - drug effects; Herpesvirus 4, Human - physiology; Humans; Lung cancer; Lung Neoplasms - drug therapy; MCF-7 Cells; Medical sciences; Models, Molecular; natural products; oleanolic acid; Pharmacology. Drug treatments; Plasminogen activator (uPA) receptor; Pyrroles - chemical synthesis; Pyrroles - chemistry; Pyrroles - pharmacology; Structure-Activity Relationship; Tamoxifen; Tetracyclines - chemical synthesis; Tetracyclines - chemistry; Tetracyclines - pharmacology; TPA; Tumor cell lines; Tumors; uPA enzyme; Virus Activation - drug effects
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2012.10.010

In this work, the benzimidazole-pyrrole conjugates 6a–h and benzimidazole-tetracycles conjugates 12–14 were prepared. The cytotoxicity of the compounds 3, 4a–h, 6a–h, 8, 10 and 12–14 was tested against lung cancer cell line A549. Compound 6b exhibited higher activity than the bis-benzoxazole natural product (UK-1), the standard. The tested 4g,h, 6a–h, 10 and 12–14 exhibited remarkable cytotoxicity activity against breast cancer cell line MCF-7 with higher activity than tamoxifen. Furthermore, compound 4h was found to be also more potent than doxurubicin. The antitumor promotion activity of synthesized compounds 4g,h, 6a–h, 10 and 12–14 has been estimated by studying their possible inhibitory effects on EBV-EA activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA). Among the studied compounds, the inhibitory activities of compounds 8, 13 and 14 demonstrated strong inhibitory effects on the Epstein–Barr virus early antigen (EBV-EA) activation without showing any cytotoxicity on the Raji cells and their effects being stronger than that of a representative control, oleanolic acid. Moreover, the molecular docking of the new compounds into plasminogen activator (uPA) receptor has been in correlation with the antitumor activity. All synthesized compounds 3, 4a–h, 6a–h, 8, 10 and 12–14 were docked into same groove of the binding site of the native co-crystalized (4-iodobenzo[b]thiophene-2-carboxamidine) ligand (PDB code:1c5x) for activity explaination. Compounds 4h, 6b and 13, giving the best docking results, were further studied to estimate their effect on the level of uPA using AssayMax human urokinase (uPA) ELISA kit. In case of A549 cell line, compound 6 exhibited similar activity to MMC, and for MCF-7 cell line, compound 4h exhibited similar activity to doxorubicin, in inhibiting the expression of uPA.