Synthesis and evaluation of nitro 5-deazaflavin-pyrrolecarboxamide(s) hybrid molecules as novel DNA targeted bioreductive antitumor agents

• Published in: Bioorganic & medicinal chemistry 1998-03, Vol.6 (3), p.301-314
• Main Authors: Kanaoka, Yoshitomo, Ikeuchi, Yoshihiro, Kawamoto, Tetsuji, Bessho, Kiyoshi, Akimoto, Naoshige, Mikata, Yuji, Nishida, Mamiko, Yano, Shigenobu, Sasaki, Takuma, Yoneda, Fumio
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; DNA - drug effects; DNA - metabolism; DNA Damage; Drug Screening Assays, Antitumor; Flavins - chemical synthesis; Flavins - pharmacology; Humans; KB Cells; Leukemia L1210 - drug therapy; Mice; Oxidation-Reduction; Pyrroles - chemical synthesis; Pyrroles - pharmacology; Structure-Activity Relationship
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/S0968-0896(97)10036-0

A series of 6-nitro-5-deazaflavins bearing at N(3) or N(10) position the pyrrolecarboxamide(s) group as DNA minor groove binder has been synthesized. These hybrid molecules show similar redox properties to those of 6-nitro-5-deazaflavins with no pyrrolecarboxamide(s) group, suggesting that they generate stable one- and two-electron reduction product(s). Electrolytic reductions of the hybrid molecules were carried out at a controlled potential under anaerobic conditions in the presence of plasmid pBR322 DNA. Significant conversions of the supercoiled circular pBR322 DNA (form I) to the open circular DNA (form II) have been found by treatment with the reductively activated 6-nitro-5-deazaflavin derivatives. Their DNA damaging effects have been found to be enhanced as the number of pyrrolecarboxamide group as the DNA binder increases. Antitumor activities of the hybrid molecules towards KB and L1210 cells were evaluated in vitro. It has been found that the antitumor effects of the compounds on KB cells slightly change and those on L1210 cells decrease as the number of the pyrrolecarboxamide group increases. These results reveal that the combination of 6-nitro-5-deazaflavin molecule with the pyrrolecarboxamide(s) group increase the DNA binding properties of the compounds, giving rise to promoted DNA damaging effects, and also suggest that the combination would affect the capacity of the compounds to act as the substrate for intracellular reductases and/or the cellular uptake of the compounds.