Structure–activity relationship studies on acremomannolipin A, the potent calcium signal modulator with a novel glycolipid structure 4: Role of acyl side chains on d-mannose

Abstract

As part of an ongoing study on the structure–activity relationship of acremomannolipin A (1)—the novel glycolipid isolated from Acremonium strictum possessing potent calcium signal-modulating activity—the role of acyl substituents on the d-mannose moiety was examined. Three partially deacylated homologs (2a–2c) and 20 homologs (2d–2w) bearing different acyloxy side chains were synthesized via the stereoselective β-mannosylation of appropriately protected mannosyl sulfoxides (3) with d-mannitol derivatives (4), and their calcium signal-modulating activities were examined. The activities of 2a–2c were completely lost. Homologs bearing relatively short acyloxy groups at C-3, C-4, and C-6 positions (2t–2v) exhibited less activity than 1, whereas a heptanoyl homolog (2w: C7) maintained activity nearly equal to that of 1. When the acyl groups at these three positions were substituted by an octanoyl group (2i: C8), the activity was completely lost. On the other hand, of the 10 homologs in which the octanoyl at C-2 was substituted by other acyloxy moieties (2j–2s), three (2m: C7, 2n: C9, 2o: C10) maintained potent activity. These results suggested that peracylated mannose structure is critical for calcium signal-modulating activity, and this activity is precisely dependent on the length of four acyl side chains on d-mannose.