26537-71-3Relevant articles and documents
Functionally optimized neuritogenic farinosone C analogs: SAR-study and investigations on their mode of action
Burch, Patrick,Chicca, Andrea,Gertsch, Juerg,Gademann, Karl
supporting information, p. 172 - 177 (2014/03/21)
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.
Identification of Darmstoff analogs as selective agonists and antagonists of lysophosphatidic acid receptors
Gududuru, Veeresa,Zeng, Kui,Tsukahara, Ryoko,Makarova, Natalia,Fujiwara, Yuko,Pigg, Kathryn R.,Baker, Daniel L.,Tigyi, Gabor,Miller, Duane D.
, p. 451 - 456 (2007/10/03)
Darmstoff describes a family of gut smooth muscle-stimulating acetal phosphatidic acids initially isolated and characterized from the bath fluid of stimulated gut over 50 years ago. Despite similar structural and biological profiles, Darmstoff analogs have not previously been examined as potential LPA mimetics. Here, we report a facile method for the synthesis of potassium salts of Darmstoff analogs. To understand the effect of stereochemistry on lysophosphatidic acid mimetic activity, synthesis of optically pure stereoisomers of selected Darmstoff analogs was achieved starting with chiral methyl glycerates. Each Darmstoff analog was evaluated for subtype-specific LPA receptor agonist/antagonist activity, PPARγ activation, and autotaxin inhibition. From this study we identified compound 12 as a pan-antagonist and several pan-agonists for the LPA1-3 receptors. Introduction of an aromatic ring in the lipid chain such as analog 22 produced a subtype-specific LPA3 agonist with an EC50 of 692 nM. Interestingly, regardless of their LPA1/2/3 ligand properties all of the Darmstoff analogs tested activated PPARγ. However, these compounds are weak inhibitors of autotaxin. The results indicate that Darmstoff analogs constitute a novel class of lysophosphatidic acid mimetics.
