Waixenicin A, a marine-derived TRPM7 inhibitor: a promising CNS drug lead

Abstract

Ion channels are the third largest class of targets for therapeutic drugs. The pharmacology of ion channels is an important research area for identifying new treatment options for human diseases. The past decade or so has seen increasing interest in an ion channel protein belonging to the transient receptor potential (TRP) family, namely the melastatin subfamily member 7 (TRPM7), as an emerging drug target. TRPM7 is a bifunctional protein with a magnesium and calcium-conducting divalent ion channel fused with an active kinase domain. TRPM7 is ubiquitously expressed in human tissues, including the brain, and regulates various cell biology processes such as magnesium and calcium homeostasis, cell growth and proliferation, and embryonic development. TRPM7 provides a link between cellular metabolic status and intracellular calcium homeostasis in neurons due to TRPM7's unique sensitivity to fluctuating intracellular Mg•ATP levels. Thus, the protein plays a key role in ischemic and hypoxic neuronal cell death and brain injury, and is one of the key nonglutamate mechanisms in cerebral ischemia and stroke. Currently, the most potent and specific TRPM7 inhibitor is waixenicin A, a xenicane diterpenoid from the Hawaiian soft coral Sarcothelia edmondsoni. Using waixenicin A as a pharmacological tool, we demonstrated that TRPM7 is involved in promoting neurite outgrowth in vitro. Most recently, we found that waixenicin A reduced hypoxic-ischemic brain injury and preserved long-term behavioral outcomes in mouse neonates. We here suggest that TRPM7 is an emerging drug target for CNS diseases and disorders, and waixenicin A is a viable drug lead for these disorders.

Marine natural products

“…581 Waixenicin A, a xenicane diterpenoid originally isolated from Sarcothelia edmondsoni, demonstrates several pharmacological activities including neurite outgrowth and reduction of hypoxic-ischemic brain injury, all of which have been recently reviewed. 582 The structures and biological activities observed for over 200 sterols isolated from cnidarians has also been reviewed. 583 Twenty-seven new sterols were reported from so corals, including secosterols 1330 and 1331 (Clavularia ava), 546 two anti-inammatory secosterols 1332 and 1333 (Sinularia leptoclados), 584 1334 (Iciligorgia sp.…”

“…581 Waixenicin A, a xenicane diterpenoid originally isolated from Sarcothelia edmondsoni , demonstrates several pharmacological activities including neurite outgrowth and reduction of hypoxic-ischemic brain injury, all of which have been recently reviewed. 582…”

Total Syntheses of (+)-Waixenicin A, (+)-9-Deacetoxy-14,15-deepoxyxeniculin, and (−)-Xeniafaraunol A

“…In 1984, Scheuer and Clardy reported the isolation of waixenicin A ( 1 ) from an extract of the marine soft coral Sarcothelia edmondsoni harvested along the Hawaiian coast (Figure ). 1 stands out due to its unique biological profile and has been intensively investigated for its potential to act as a specific inhibitor of transient receptor potential melastatin 7 (TRPM7) channels, blocking cell proliferation with an Mg 2+ -dependent IC 50 value of 16 nM. Interestingly, 1 displayed no inhibitory activity for TRPM6, which represents the closest homologue of TRPM7 .…”

Drugs/agents for the treatment of ischemic stroke: Advances and perspectives

“…Sun and colleagues found that 19 could promote the growth of neural synapses in vitro, and reduced neonatal hypoxic-ischemic brain damage and improved long-term behavioral outcomes in mice, suggesting that 19 could be used as a tool molecule for selective inhibition of TRPM7 and an active lead compound for the treatment of TRPM7-related diseases. 91 Na + -Ca 2+ exchangers (NCX) agonists…”