Transient Receptor Potential Melastatin 7 (TRPM7) Ion Channel Inhibitors: Preliminary SAR and Conformational Studies of Xenicane Diterpenoids from the Hawaiian Soft Coral Sarcothelia edmondsoni .

Waixenicin A, a xenicane diterpene from the octocoral Sarcothelia edmondsoni , is a selective, potent inhibitor of the TRPM7 ion channel. To study the structure-activity relationship (SAR) of waixenicin A, we isolated and assayed related diterpenes from S. edmondsoni . In addition to known waixenicins A ( 1 ) and B ( 2 ), we purified six xenicane diterpenes, 7 S ,8 S -epoxywaixenicins A ( 3 ) and B ( 4 ), 12-deacetylwaixenicin A ( 5 ), waixenicin E ( 6 ), waixenicin F ( 7 ), and 20-acetoxyxeniafaraunol B ( 8 ). We elucidated the structures of 3 - 8 by NMR and MS analyses. Compounds 1 , 2 , 3 , 4 , and 6 inhibited TRPM7 activity in a cell-based assay, while 5 , 7 , and 8 were inactive. A preliminary SAR emerged showing that alterations to the nine-membered ring of 1 did not reduce activity, while the 12-acetoxy group, in combination with the dihydropyran, appears to be necessary for TRPM7 inhibition. The bioactive compounds are proposed to be latent electrophiles by formation of a conjugated oxocarbenium ion intermediate. Whole-cell patch-clamp experiments demonstrated that waixenicin A inhibition is irreversible, consistent with a covalent inhibitor, and showed nanomolar potency for waixenicin B ( 2 ). Conformational analysis (DFT) of 1 , 3 , 7 , and 8 revealed insights into the conformation of waixenicin A and congeners and provided information regarding the stabilization of the proposed pharmacophore.