2,4-Diaryl-5,6-dihydro-1,10-phenanthroline and 2,4-diaryl-5,6-dihydrothieno[2,3-h] quinoline derivatives for topoisomerase I and II inhibitory activity, cytotoxicity, and structure–activity relationship study

• Published in: Bioorganic chemistry 2012-02, Vol.40 (1), p.67-78
• Main Authors: Thapa, Pritam, Karki, Radha, Yoo, Han Young, Park, Pil-Hoon, Lee, Eunyoung, Jeon, Kyung-Hwa, Na, Younghwa, Cho, Won-Jea, Kwon, Youngjoo, Lee, Eung-Seok
• Format: Article
• Language: English
• Subjects: 2,4-Diaryl-5,6-dihydro-1,10-phenanthroline; 2,4-Diaryl-5,6-dihydrothieno[2,3-h] quinoline; Cell Line, Tumor; Cell Survival - drug effects; Cytotoxicity; DNA Topoisomerases, Type I - chemistry; DNA Topoisomerases, Type I - metabolism; DNA Topoisomerases, Type II - chemistry; DNA Topoisomerases, Type II - metabolism; Drug Screening Assays, Antitumor; Enzyme Activation - drug effects; Humans; Phenanthrolines - chemical synthesis; Phenanthrolines - chemistry; Phenanthrolines - pharmacology; Quinolines - chemical synthesis; Quinolines - chemistry; Quinolines - pharmacology; Structure-Activity Relationship; Terpyridine; Topoisomerase I and II; Topoisomerase I Inhibitors - chemical synthesis; Topoisomerase I Inhibitors - chemistry; Topoisomerase I Inhibitors - pharmacology; Topoisomerase II Inhibitors - chemical synthesis; Topoisomerase II Inhibitors - chemistry; Topoisomerase II Inhibitors - pharmacology
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2011.09.001

2,4-Diaryl-5,6-dihydro-1,10-phenanthroline and 2,4-diaryl-5,6-dihydrothieno[2,3-h] quinoline derivatives as rigid analogs of 2,4,6-trisubstituted pyridines were prepared, and evaluated for topoisomerase I and II inhibitory activities as well as cytotoxicities against several human cancer cell lines. Structure–activity relationship study showed that [2,2′;6′,2″]-terpyridine skeleton is important for the cytotoxicity against several human cancer cell lines. [Display omitted] ▸ Thirty-two conformationally constrained phenanthrolines and dihydrothienoquinolines were synthesized. ▸ Prepared compounds were evaluated for topo I and II inhibitors, and cytotoxicity. ▸ Compounds 33 and 35 displayed significant topo I inhibitory activity. ▸ Compounds 10, 14, and 18 exhibited strong cytotoxicity. ▸ SAR exhibited that [2,2′;6′,2″]-terpyridine skeleton is important for cytotoxicity. Designed and synthesized thirty-two 2,4-diaryl-5,6-dihydro-1,10-phenanthroline and 2,4-diaryl-5,6-dihydrothieno[2,3-h] quinoline derivatives as rigid analogs of 2,4,6-trisubstituted pyridines were evaluated for topoisomerase I and II inhibitory activities as well as cytotoxicities against several human cancer cell lines. Structure–activity relationship study showed that [2,2′;6′,2″]-terpyridine skeleton is important for the cytotoxicity against several human cancer cell lines.