Structure-activity relationship for calanthoside, a potential hair-growth stimulant with an indole 2-S-,3-O-bis-glucoside structure. Part 1: role of two glucoside moieties in promoting HFDPC proliferation.

The development of new and effective drugs for treating androgenetic alopecia (AGA) remains challenging. Minoxidil and finasteride, two drugs currently used to treat AGA, were originally developed for treating hypertension and prostate disease, respectively. Therefore, the pharmacological effects of these drugs may be double-edged in patients with AGA. Calanthoside (1) is an indole 2-S-,3-O-bis-glucoside isolated from the Calanthe genus. Compared to minoxidil, 1 induces significantly higher proliferation of human hair follicle dermal papilla cells (HFDPCs). This study aimed to identify the key structures responsible for the activity of 1. To this end, calanthoside derivatives were synthesised and evaluated. Analogues (9b, 9d-9f), in which the 3-O-glucoside moiety of 1 was replaced with different glycosides, exhibited minimal activity. In contrast, analogues (8c-8f), in which the 2-S-thioglucoside unit of 1 was substituted with various thioglycosides, demonstrated potent activity comparable to that of 1. These results suggest that 3-O-glucoside is an essential structural feature for activity. The 2-S-ethylated derivative (8g) exhibited a complete loss of activity. Similarly, compounds 10a and 10b, in which all the hydroxyl groups of the sugar residue of 1 were ester-protected, also exhibited a complete loss of activity. Therefore, highly polar sugar structures are required at the 2- and 3-positions. Collectively, the findings of this initial evaluation of the structure-activity relationship (SAR) provide valuable insights for expanding the chemical space for the future development of AGA treatments.