Antitumor studies. Part 1: Design, synthesis, antitumor activity, and AutoDock study of 2-deoxo-2-phenyl-5-deazaflavins and 2-deoxo-2-phenylflavin-5-oxides as a new class of antitumor agents

• Published in: Bioorganic & medicinal chemistry 2007, Vol.15 (1), p.242-256
• Main Authors: Ali, Hamed I., Tomita, Keiichiro, Akaho, Eiichi, Kambara, Hiroto, Miura, Shinji, Hayakawa, Hiroyuki, Ashida, Noriyuki, Kawashima, Yutaka, Yamagishi, Takehiro, Ikeya, Hisao, Yoneda, Fumio, Nagamatsu, Tomohisa
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - classification; Antineoplastic Agents - pharmacology; Antitumor activity; AutoDock; Binding Sites; Cell Line, Tumor; Cell Proliferation - drug effects; Computer Simulation; Drug Design; Drug Screening Assays, Antitumor; Flavin analog; Flavins - chemical synthesis; Flavins - classification; Flavins - pharmacology; Humans; Ligands; Models, Molecular; Molecular Structure; Oxides - chemical synthesis; Oxides - classification; Oxides - pharmacology; Protein Conformation; Protein Structure, Tertiary; Protein tyrosine kinase; Stereoisomerism; Structure-Activity Relationship; Time Factors
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2006.09.063

The prepared 2-deoxo-2-phenyl-5-deazaflavins ( 1) and 2-deoxo-2-phenylflavin-5-oxides ( 2) exhibited significant antitumor activities against CCRF-HSB-2, KB, NCI-H460, A 431, and HCT 116 cells. A good correlation between IC 50 and binding free energy for 1 and 2 was obtained by docking into PTK pp60 c-src. Novel 2-deoxo-2-phenyl-5-deazaflavins and 2-deoxo-2-phenylflavin-5-oxides were prepared as a new class of antitumor agents and showed significant antitumor activities against NCI-H 460, HCT 116, A 431, CCRF-HSB-2, andKB cell lines. In vivo investigation, 2-deoxo-10-methyl-2-phenyl-5-deazaflavin exhibited the effective antitumor activity against A 431 human adenocarcinoma cells transplanted subcutaneously into nude mouse. Furthermore, AutoDock study has been done by binding of the flavin analogs into PTK pp60 c-src, where a good correlation between their IC 50 and AutoDock binding free energy was exhibited. In particular, 2-deoxo-2-phenylflavin-5-oxides exhibited the highest potential binding affinity within the binding pocket of PTK.