title: Design and synthesis of conformationally constrained hydroxylated 4-phenyl-2-aryl chromenopyridines as novel and selective topoisomerase II-targeted antiproliferative agents.
abstract: To develop novel selective topoisomerase II inhibitors, we designed and synthesized a series of conformationally constrained hydroxylated 4-phenyl-2-aryl chromenopyridines and evaluated their topoisomerase inhibitory activity and cytotoxicity against three human cancer cell lines (DU145, HCT15, and T47D) and a normal cell line (MCF10A). All of the prepared compounds displayed stronger or similar topoisomerase II inhibitory activity as well as cytotoxicity against three human cancer cell lines compared to etoposide. Compounds 10a, 10g, 11a, 11f, 11g, 12a, 12f, and 12g especially showed stronger topoisomerase II inhibitory activity as compared to etoposide at both 100 μM and 20 μM. A structure-activity relationship study revealed that hydroxyphenyl moiety at 4-position of pyridine and ortho-hydroxyphenyl or thienyl moiety at 2-position of pyridine has an important role in displaying selective topoisomerase II inhibition. The compound 12b with para-hydroxyphenyl and meta-hydroxyphenyl at 4- and 2-position of pyridine, respectively, showed the most significant cytotoxicity against all three cancer cell lines, whereas less cytotoxicity to a normal cell line as compared to adriamycin.
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Republic of Korea.
authors.forename: Pritam
authors.initials: P
authors.lastname: Thapa
authors.affiliation: College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Global Top 5 Program Ewha Womans University, Seoul 120-750, Republic of Korea.
authors.forename: Kyu-Yeon
authors.initials: KY
authors.lastname: Jun
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Republic of Korea.
authors.forename: Tara Man
authors.initials: TM
authors.lastname: Kadayat
authors.affiliation: College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Global Top 5 Program Ewha Womans University, Seoul 120-750, Republic of Korea.
authors.forename: Chanmi
authors.initials: C
authors.lastname: Park
authors.affiliation: School of Public Health, Xinxiang Medical University, Henan 453003, China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Zheng
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Republic of Korea.
authors.forename: Til Bahadur
authors.initials: TB
authors.lastname: Thapa Magar
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Republic of Korea.
authors.forename: Ganesh
authors.initials: G
authors.lastname: Bist
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Republic of Korea.
authors.forename: Aarajana
authors.initials: A
authors.lastname: Shrestha
authors.affiliation: College of Pharmacy, Cha University, Pochon 487-010, Republic of Korea.
authors.forename: Younghwa
authors.initials: Y
authors.lastname: Na
authors.affiliation: College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Global Top 5 Program Ewha Womans University, Seoul 120-750, Republic of Korea. Electronic address: ykwon@ewha.ac.kr.
authors.forename: Youngjoo
authors.initials: Y
authors.lastname: Kwon
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Republic of Korea. Electronic address: eslee@yu.ac.kr.
authors.forename: Eung-Seok
authors.initials: ES
authors.lastname: Lee
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004264:DNA Topoisomerases, Type I / Q000737:chemistry / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000737:chemistry* / Q000378:metabolism; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D006900:Hydroxylation; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D011725:Pyridines; D059005:Topoisomerase II Inhibitors; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II
keywords: Antiproliferative agents; Cytotoxicity; Hydroxylated 4-phenyl-2-aryl chromenopyridines; Structure–activity relationships; Topoisomerase II inhibitor