Design, synthesis, and antiproliferative activity of new 1H-pyrrolo[3,2-c]pyridine derivatives against melanoma cell lines

• Published in: European journal of medicinal chemistry Vol. 46; no. 8; pp. 3218 - 3226
• Main Authors: El-Gamal, Mohammed I., Jung, Myung-Ho, Lee, Woong San, Sim, Taebo, Yoo, Kyung Ho, Oh, Chang-Hyun
• Format: Journal Article
• Language: English
• Published: PARIS Elsevier 01.08.2011
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Benzenesulfonates - pharmacology; Biological and medical sciences; Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry, Medicinal; Drug Screening Assays, Antitumor; General aspects; Humans; Inhibitory Concentration 50; Life Sciences & Biomedicine; Medical sciences; Melanoma - drug therapy; Melanoma - pathology; Mice; Niacinamide - analogs & derivatives; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Phenylurea Compounds; Pyridines - chemical synthesis; Pyridines - pharmacology; Pyrroles - chemical synthesis; Pyrroles - pharmacology; Science & Technology; Skin Neoplasms - drug therapy; Skin Neoplasms - pathology; Structure-Activity Relationship; INTERLEUKIN-2; DIAGNOSIS; THERAPY; Antiproliferative activity; Melanoma; A375P; Pyrrolo[3,2-c]pyridine; Diarylurea; Diarylamide; Antineoplastic agent; Morpholine derivatives; Malignant melanoma; Ureas; Chemical synthesis; Tumor cell; Human; Rodentia; Malignant tumor; In vitro; Biological activity; Vertebrata; Mammalia; Cell line; Mouse; Carboxamide; Benzenic compound; Benzamide derivatives; Piperazine derivatives; Fluorine Organic compounds; Fibroblast; Cancer
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2011.04.031

Synthesis of a new series of diarylureas and diarylamides having 1H-pyrrolo[3,2-c]pyridine scaffold is described. Their in vitro antiproliferative activity against A375P human melanoma cell line was tested and the effect of substituents on pyrrolo[3,2-c]pyridine nucleus was investigated. The newly synthesized compounds, except three N-tolyl derivatives (8f, 9f, and 9h), generally showed superior activity against A375P to Sorafenib. Among all of these derivatives, compounds 8b, 8g, and 9a-e showed the highest potency against A375P with IC50 in nanomolar range. In addition, compounds 8d, 8e, 8h, 9g, 9i, and 9j were more potent than Sorafenib but with IC50 in micromolar range. Compounds 8b, 8g, 9b-d, and 9i demonstrated higher selectivity towards A375P compared with NIH3T3 fibroblasts. The most potent diarylurea 8g and diarylamide 9d were further tested and showed high potency over nine melanoma cell lines at the NCI. (C) 2011 Elsevier Masson SAS. All rights reserved.