Sporothioethers: deactivated alkyl citrates from the fungus Hypomontagnella monticulosa

Abstract

Submerged cultivation of Hypomontagnella monticulosa MUCL 54604 resulted in formation of a stereoisomeric mixture of new sulfur-containing sporothriolide derivatives named sporothioethers A and B. The presence of the 2-hydroxy-3-mercaptopropanoic acid moiety attenuates the antimicrobial activity in comparison to the precursor sporothriolide suggesting a detoxification mechanism. However, moderate effects on biofilms of Candida albicans and Staphylococcus aureus were observed for sporothriolide and sporothioethers A and B at concentrations below their MICs.

Scheme 1. A) Structures of alkyl citrate metabolites from fungi; (B) biosynthesis of sporothriolide 8 and sporochartines 10–13. R = C₆H₁₄.

Fig. 1. Key NMR information. (A) COSY correlations (bold lines), HMBC correlations (red arrows) and ROESY correlations (green arrows) of sporothioether 14; (B) COSY correlations (bold lines), HMBC correlations (red arrows) and ROESY correlations (green arrows) of sporothioether 15; (C) energy-minimized model structures of sporothioethers 14 and 15 used for a J-based assignment of relative stereochemistry.

Scheme 2. Synthesis and analysis of sporothioether derivates. (A) Synthetic route towards sporothioethers 14–15 and 24–25: (a) TrSH (1.3 eq.), NaH (1.3 eq.), THF, 0 °C-RT, overnight, (b) Et₃SiH (3 eq.), TFA, DCM, 30 min, (c) Sporothriolide 8 (0.8 eq.), Et₃N (5 eq.), CH₂Cl₂, RT, 2 h; Tr = triphenylmethyl; (B) comparison of ¹H NMR data of fungal sporothioethers A 14 and B 15, semisynthetic sporothioether A 14 and B 15 and semisynthetic sporothioether C 24 and D 25.

Fig. 2. Structures of metabolites containing the 2-hydroxy-3-mercaptopropanoic acid moiety and their congeners.