title: Design, Synthesis, and Biological Activity of Sulfonamide Analogues of Antofine and Cryptopleurine as Potent and Orally Active Antitumor Agents.
abstract: Due to their profound antiproliferative activity and unique mode of action, phenanthroindolizidine and phenanthroquinolizidine alkaloids, represented by antofine and cryptopleurine, have attracted attention recently as potential therapeutic agents. We have designed, synthesized, and evaluated the methanesulfonamide analogues of these natural alkaloids with the hope of improving their druglikeness. The analogues showed enhanced growth inhibition of human cancer cells compared with the parent natural products. In particular, a methanesulfonamide analogue of cryptopleurine (5b) exhibited improved bioavailability and significant antitumor activity, which suggests that 5b is a promising new anticancer agent. Our studies suggest that the inhibition of cancer cell growth by 5b is associated with the induction of G0/G1 cell cycle arrest via nicotinamide N-methyltransferase-dependent JNK activation in Caki-1 renal cancer cells. In addition, compound 5b significantly inhibited the migration and invasion of Caki-1 cancer cells by modulating the p38 MAPK signaling pathway.
authors.affiliation: Research Institute of Pharmaceutical Science, College of Pharmacy, Seoul National University , Seoul 151-742, Korea.
authors.forename: Yongseok
authors.initials: Y
authors.lastname: Kwon
authors.affiliation: Natural Products Research Institute, College of Pharmacy, Seoul National University , Seoul 151-742, Korea.
authors.forename: Jayoung
authors.initials: J
authors.lastname: Song
authors.affiliation: Research Institute of Pharmaceutical Science, College of Pharmacy, Seoul National University , Seoul 151-742, Korea.
authors.forename: Honggu
authors.initials: H
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Korea University , Sejong 339-700, Korea.
authors.forename: Eun-Yeong
authors.initials: EY
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Korea University , Sejong 339-700, Korea.
authors.forename: Kiho
authors.initials: K
authors.lastname: Lee
authors.affiliation: Natural Products Research Institute, College of Pharmacy, Seoul National University , Seoul 151-742, Korea.
authors.forename: Sang Kook
authors.initials: SK
authors.lastname: Lee
authors.affiliation: Research Institute of Pharmaceutical Science, College of Pharmacy, Seoul National University , Seoul 151-742, Korea.
authors.forename: Sanghee
authors.initials: S
authors.lastname: Kim
mesh_terms: D000284:Administration, Oral; D000470:Alkaloids / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D001682:Biological Availability; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008813:Mice, Inbred ICR; D008819:Mice, Nude; D015394:Molecular Structure; D050903:Nicotinamide N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D010618:Phenanthrolines / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000470:Alkaloids; D000970:Antineoplastic Agents; D007211:Indoles; D010618:Phenanthrolines; D013449:Sulfonamides; C473343:antofine; C036871:methanesulfonamide; C007160:cryptopleurine; C494406:NNMT protein, human; D050903:Nicotinamide N-Methyltransferase