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

Kenyu Yoshida; Ryosuke Itoyama; Masashi Yamahira; Junji Tanaka; Nadège Loaëc; Olivier Lozach; Emilie Durieu; Tsutomu Fukuda; Fumito Ishibashi; Laurent Meijer; Masatomo Iwao

doi:10.1021/jm400719y

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

J Med Chem. 2013 Sep 26;56(18):7289-301. doi: 10.1021/jm400719y. Epub 2013 Sep 13.

Authors

Kenyu Yoshida¹, Ryosuke Itoyama, Masashi Yamahira, Junji Tanaka, Nadège Loaëc, Olivier Lozach, Emilie Durieu, Tsutomu Fukuda, Fumito Ishibashi, Laurent Meijer, Masatomo Iwao

Affiliation

¹ Division of Chemistry and Materials Sciences, Graduate School of Engineering, Nagasaki University , 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan.

PMID: 23981088
DOI: 10.1021/jm400719y

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / metabolism
Antineoplastic Agents / pharmacology
Cell Line, Tumor
Chemistry Techniques, Synthetic
DNA Topoisomerases, Type I / chemistry
DNA Topoisomerases, Type I / metabolism
Humans
Molecular Docking Simulation
Polycyclic Compounds / chemical synthesis*
Polycyclic Compounds / chemistry
Polycyclic Compounds / metabolism
Polycyclic Compounds / pharmacology*
Protein Conformation
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / metabolism
Protein Kinase Inhibitors / pharmacology
Protein Kinases / chemistry
Protein Kinases / metabolism*
Stereoisomerism
Structure-Activity Relationship
Substrate Specificity
Topoisomerase I Inhibitors / chemical synthesis
Topoisomerase I Inhibitors / chemistry
Topoisomerase I Inhibitors / metabolism
Topoisomerase I Inhibitors / pharmacology

Substances

Antineoplastic Agents
Polycyclic Compounds
Protein Kinase Inhibitors
Topoisomerase I Inhibitors
Protein Kinases
DNA Topoisomerases, Type I