Siccanin

Siccanin at 3 mug/ml completely inhibited the growth of Trichophyton mentagrophytes. The primary site of action of siccanin on T. mentagrophytes is succinate dehydrogenase in the terminal electron transport system. At a concentration of siccanin giving 50% inhibition of growth (0.3 mug/ml), respiration of intact cells was inhibited more strongly than any other cellular functions tested, including the syntheses of cellular ribonucleic acid, deoxyribonucleic acid, phospholipid, protein, and cell wall fractions. In addition, at the same concentration siccanin did not cause any detectable damage in the permeability of the cells. Furthermore, the oxidation of succinate in mitochondrial preparation is more sensitive to the antibiotic than respiration in intact cells. Oxidation of other substrates tested was less sensitive to siccanin than that of succinate. The antibiotic inhibited both phosphorylation and oxidation, without causing changes in the P:O ratio. Siccanin at 0.03 mug/ml, which caused 50% inhibition of succinate oxidation in mitochondria, had effect neither on the exchange reaction between inorganic phosphate (P(i)) and adenosine triphosphate (ATP) nor on that between adenosine diphosphate and ATP. An ATP phosphohydrolase activity was also insensitive to the antibiotic. At very high concentrations, however, the antibiotic slightly inhibited the P(i)-ATP exchange reaction. From those results, it was concluded that siccanin inhibits fungal growth by inhibiting the respiratory electron transport system.

Plasmodium falciparumcontains several mitochondrial electron transport chain (ETC) dehydrogenases shuttling electrons from the respective substrates to the ubiquinone pool, from which electrons are consecutively transferred to complex III, complex IV, and finally to the molecular oxygen. The antimalarial drug atovaquone inhibits complex III and validates this parasite's ETC as an attractive target for chemotherapy. Among the ETC dehydrogenases fromP. falciparum, dihydroorotate dehydrogenase, an essential enzyme used in de novo pyrimidine biosynthesis, and complex III are the two enzymes that have been characterized and validated as drug targets in the blood-stage parasite, while complex II has been shown to be essential for parasite survival in the mosquito stage; therefore, these enzymes and complex II are considered candidate drug targets for blocking parasite transmission. In this study, we identified siccanin as the first (to our knowledge) nanomolar inhibitor of theP. falciparumcomplex II. Moreover, we demonstrated that siccanin also inhibits complex III in the low-micromolar range. Siccanin did not inhibit the corresponding complexes from mammalian mitochondria even at high concentrations. Siccanin inhibited the growth ofP. falciparumwith IC50of 8.4 μM. However, the growth inhibition of theP. falciparumblood stage did not correlate with ETC inhibition, as demonstrated by lack of resistance to siccanin in the yDHODH-3D7 (EC50= 10.26 μM) and Dd2-ELQ300 strains (EC50= 18.70 μM), suggesting a third mechanism of action that is unrelated to mitochondrial ETC inhibition. Hence, siccanin has at least a dual mechanism of action, being the first potent and selective inhibitor ofP. falciparumcomplexes II and III over mammalian enzymes and so is a potential candidate for the development of a new class of antimalarial drugs.

(-)-Siccanin (1), a natural product possessing significant antifungal properties, was synthesized enantioselectively via a biomimetic route. This synthetic route features two sequential radical cyclizations: a Ti(III)-mediated radical cyclization of epoxyolefin 48 to construct the B-ring, and a Suarez reaction to establish the tetrahyrofuran ring. Chiral chroman moiety of siccanin was prepared based on our recent development of the Pd-catalyzed asymmetric allylic alkylation (AAA) of phenol trisubstituted allyl carbonates. Several other members of the siccanin family were also synthesized including siccanochromenes A (2), B (3), E (6), F (7), and the methyl ether of siccanochromene C (55). These studies may shed light on the biosynthesis of this novel family of compounds.