Synthesis and SAR of Lehualide B: A Marine-Derived Natural Product with Potent Anti-Multiple Myeloma Activity

Abstract

We report a concise and convergent laboratory synthesis of the rare marine natural product lehualide B that has led to the discovery that: (1) this compound has low nanomolar activity against human multiple myeloma cells, and (2) the anti-cancer effects of lehualide B and its analogs are selective (i.e., they are ~ two to three orders of magnitude less toxic to human breast cancer cells). Synthetic lehualide B is shown to be an effective inhibitor of complex I of the mitochondrial electron transport chain, with potency similar to that observed for the terrestrial natural products piericidin A1 and rotenone – an observation that led to the discovery that piericidin A1 is also selectively cytotoxic toward human multiple myeloma cells. Interestingly, synthetic derivatives of lehualide B that resemble verticipyrone (an established complex I inhibitor composed of a γ-pyrone and a simple mono-unsaturated hydrophobic chain) lack the potent anti-myeloma activity of the natural product. Finally, the synthesis and evaluation of a collection of lehualide-inspired analogs led to the elucidation of structure-activity relationships for this rare natural product that established important roles for the substituted γ-pyrone head group and the skipped polyene side chain.

Antimicrobial potential of culturable actinobacteria isolated from the Pacific oyster Crassostrea gigas (Bivalvia, Ostreidae)

“…These metabolites have been found to be produced exclusively by actinobacteria and particularly by Streptomyces (Zhou & Fenical, 2016). Various bioactivities have been identified for this compound, including insecticidal activity through the inhibition of the NADH‐ubiquinone oxidoreductase (complex I) in the mitochondrial electron transport chain (Hall et al, 1966), cytotoxic activity against cancer cell lines (Jeso et al, 2013), and antimicrobial activity against Gram‐positive bacteria (e.g. B. subtilis ) and fungi (Kroiss et al, 2010).…”

Kalkitoxin Inhibits Angiogenesis, Disrupts Cellular Hypoxic Signaling, and Blocks Mitochondrial Electron Transport in Tumor Cells

“…Mechanistically, kalkitoxin and other recently reported marine natural product HIF-1 inhibitors ( Figure 8 ) suppress the multi-enzyme mitochondrial NADH-ubiquinone oxidoreductase system (electron transport chain complex I), thus disrupting mitochondria-mediated hypoxic signaling. Examples of mitochondria-targeted HIF-1 inhibitors include an assortment of sponge metabolites (e.g., mycothiazole [ 28 ], lehualide B [ 36 ], furospongolide [ 37 ], and the mycalinitriles [ 38 ]), and structurally dissimilar algal natural products [ 39 , 40 ]. Kalkitoxin production by the marine cyanobacterium, Moorea producens , is physiologically and ecologically intriguing.…”

Multiple Myeloma: Possible Cure from the Sea

“…The cytotoxic activity of lehualide B has been deeply investigated in several myeloma cell lines using an MTT assay. In particular, antimyeloma activity is exerted through the selective inhibition of mitochondrial complex I, which results in the specific inhibition of myeloma progression [ 61 ], as MM cells are susceptible to mitochondrial inhibitors [ 70 ].…”