Piperlonguminine, an alkaloid amide isolated from the Piper species, exhibits anti-inflammatory, antitumor, neuroprotective, anti-platelet, anti-melanogenic, antifungal, and antibacterial activities. It inhibits Akt/mTOR signaling, promotes autophagy, and mediates cancer cell death.

Piperlonguminine from Piper longum was discovered to inhibit melanin production in melanoma B16 cells stimulated with alpha-melanocyte stimulating hormone (alpha-MSH), 3-isobutyl-1-methylxanthine or protoporphyrin IX, where the compound exhibited stronger depigmenting efficacy than kojic acid.?However, piperlonguminine did not affect 1-oleoyl-2-acetyl-sn-glycerol-induced melanogenesis and did not affect protein kinase C-mediated melanin production.?Surprisingly, piperlonguminine did not inhibit the catalytic activity of cell-free tyrosinase from melanoma B16 cells but rather suppressed tyrosinase mRNA expression.?This effect was attributed to the inhibitory action of piperlonguminine on alpha-MSH-induced signaling through cAMP to the cAMP responsive element binding protein that in turn regulates the expression of the microphthalmia-associated transcription factor, a key activator of the tyrosinase promoter.?This study demonstrates that piperlonguminine is an efficient depigmenting agent with a novel mechanism of action.