Synthesis and preliminary biological evaluation of new derivatives of the marine alkaloid leucettamine B as kinase inhibitors.

Mansour Debdab (1) , Stéven Renault (1) , Olivier Lozach , Laurent Meijer , Ludovic Paquin (1) , François Carreaux (1) , Jean-Pierre Bazureau (1)

1 ISCR - Institut des Sciences Chimiques de Rennes

New derivatives of the marine alkaloid leucettamine B were prepared in five steps with overall yields ranging from 23 to 30%. The key step of our strategy has been the sulfur/nitrogen displacement under solvent-free microwave irradiation of (5Z) 5-benzo[1,3]-dioxo-5-ylmethylene-2-ethylsulfanyl-3,5-dihydroimidazol-4-one 3 with a mono-protected ethylenediamine 2. After deprotection of the N-Boc group, the amino derivative of leucettamine B 5 was subjected to reductive amination in two steps with retention of configuration of the double bond, to lead to eight new analogs of leucettamine B. The effect of these compounds on CK1alpha/beta, CDK5/p25, and GSK-3alpha/beta were investigated.

Keywords: Marine alkaloid; Leucettamine B; Sulfur/nitrogen displacement; Reductive amination; Microwave irradiation; Solvent-free; Kinase inhibitors

Domains: Medicinal Chemistry

Mansour Debdab, Stéven Renault, Olivier Lozach, Laurent Meijer, Ludovic Paquin, et al.. Synthesis and preliminary biological evaluation of new derivatives of the marine alkaloid leucettamine B as kinase inhibitors.. European Journal of Medicinal Chemistry, 2010, 45 (2), pp.805-10. ⟨10.1016/j.ejmech.2009.10.009⟩. ⟨hal-00869769⟩