ABSTRACT
A novel series of potent blockers of the monocarboxylate transporter, MCT1, is disclosed. From very potent but lipophilic lead compounds, systematic changes to all parts of the molecule, targeting reduction in log D, afforded compounds with significantly improved overall properties. These compounds show potent immunomodulatory activity.
Subject(s)
Aryl Hydrocarbon Hydroxylases/metabolism , Cytochrome P-450 Enzyme System/metabolism , Herpesviridae/drug effects , Immunologic Factors/pharmacology , Monocarboxylic Acid Transporters/antagonists & inhibitors , Symporters/antagonists & inhibitors , T-Lymphocytes/drug effects , Animals , Aryl Hydrocarbon Hydroxylases/immunology , Cytochrome P-450 CYP2C9 , Cytochrome P-450 CYP3A , Cytochrome P-450 Enzyme System/immunology , Graft vs Host Disease/immunology , Herpesviridae/immunology , Herpesviridae/metabolism , Humans , Immunologic Factors/chemistry , Monocarboxylic Acid Transporters/immunology , Monocarboxylic Acid Transporters/metabolism , Symporters/immunology , Symporters/metabolism , T-Lymphocytes/immunology , T-Lymphocytes/metabolismABSTRACT
A concise approach to the cephalotaxine CDE ring skeleton based on the intramolecular formal [5 + 2] photocycloaddition of cyclopentenyl-substituted maleimides is described. An investigation of the diastereoselectivity afforded by various protected alkoxy groups demonstrated that the best selectivity (3.5:1) was afforded by the free hydroxyl group, strongly suggesting a hydrogen-bonded excited state. Reaction: see text.
