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ACS Med Chem Lett. 2013 Dec 6;5(2):172-7. doi: 10.1021/ml400435h. eCollection 2014 Feb 13.

Functionally Optimized Neuritogenic Farinosone C Analogs: SAR-Study and Investigations on Their Mode of Action.

Author information

1
Department of Chemistry, University of Basel , St. Johanns-Ring 19, CH-4056 Basel, Switzerland ; Swiss Federal Institute of Technology (EPFL), Chemical Synthesis Laboratory (SB-ISIC-LSYNC) , 1015 Lausanne, Switzerland.
2
Institute of Biochemistry and Molecular Medicine, University of Bern , Bühlstrasse 28, CH-3012 Bern, Switzerland.
3
Department of Chemistry, University of Basel , St. Johanns-Ring 19, CH-4056 Basel, Switzerland.

Abstract

Several natural products derived from entomopathogenic fungi have been shown to initiate neuronal differentiation in the rat pheochromocytoma PC12 cell line. After the successful completion of the total synthesis program, the reduction of structural complexity while retaining biological activity was targeted. In this study, farinosone C served as a lead structure and inspired the preparation of small molecules with reduced complexity, of which several were able to induce neurite outgrowth. This allowed for the elaboration of a detailed structure-activity relationship. Investigations on the mode of action utilizing a computational similarity ensemble approach suggested the involvement of the endocannabinoid system as potential target for our analogs and also led to the discovery of four potent new endocannabinoid transport inhibitors.

KEYWORDS:

CB1 receptor; Neurite outgrowth; SAR; endocannabinoid membrane transport; natural products; truncated

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