title: Synthesis, resolution, and biological evaluation of atropisomeric (aR)- and (aS)-16-methyllamellarins N: unique effects of the axial chirality on the selectivity of protein kinases inhibition.
abstract: The total synthesis of the optically active (aR)- and (aS)-16-methyllamellarins N (3a and 3b) was achieved via resolution on HPLC chiral stationary phase. The kinase inhibitory activities of both enantiomers were evaluated on eight protein kinases relevant to cancer and neurodegenerative diseases (CDK1/cyclin B, CDK2/cyclin A, CDK5/p25, GSK-3α/β, PIM1, DYRK1A, CLK3, and CK1). Isomer (aR)-3b exhibited potent but nonselective inhibition on all protein kinases except CK1, while (aS)-3a selectively inhibited only GSK-3α/β, PIM1, and DYRK1A. The different inhibition profiles of (aS)-3a and (aR)-3b were elucidated by docking simulation studies. Although parental lamellarin N (2) inhibited the action of topoisomerase I, both (aS)-3a and (aR)-3b showed no inhibition of this enzyme. The phenotypic cytotoxic activities of 2, (aS)-3a, and (aR)-3b on three cancer cell lines (HeLa, SH-SY5Y, and IMR32) changed according to their topoisomerase I and protein kinase inhibitory activities.
authors: Division of Chemistry and Materials Sciences, Graduate School of Engineering, Nagasaki University , 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan.
authors: Kenyu
authors: K
authors: Yoshida
authors: Ryosuke
authors: R
authors: Itoyama
authors: Masashi
authors: M
authors: Yamahira
authors: Junji
authors: J
authors: Tanaka
authors: Nadège
authors: N
authors: Loaëc
authors: Olivier
authors: O
authors: Lozach
authors: Emilie
authors: E
authors: Durieu
authors: Tsutomu
authors: T
authors: Fukuda
authors: Fumito
authors: F
authors: Ishibashi
authors: Laurent
authors: L
authors: Meijer
authors: Masatomo
authors: M
authors: Iwao
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic; D004264:DNA Topoisomerases, Type I / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D062105:Molecular Docking Simulation; D011083:Polycyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011494:Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D059004:Topoisomerase I Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D011083:Polycyclic Compounds; D047428:Protein Kinase Inhibitors; D059004:Topoisomerase I Inhibitors; D011494:Protein Kinases; D004264:DNA Topoisomerases, Type I