Synthesis and Biological Evaluation of a Marine Steroidal Alkaloid Analog (3S)-Peniadenisteroid A

Peniadenisteroid A, also known as striasteroid C, is a unique marine-derived natural steroidal alkaloid with a characteristic adenine–steroid hybrid scaffold, in which an adenine moiety is bound to the C-3 position of the steroid skeleton. This natural metabolite displays evident antiviral activity through neuraminidase inhibition, with an IC50 value of 6.15 μM. In this work, the C-3 epimer, (3S)-peniadenisteroid A, was successfully synthesized in eight steps with an overall yield of 3.9%. Biological screening results revealed that the intermediate (3S)-P6 exhibited prominent inhibitory activity against cellular nitric oxide (NO) production, while both (3S)-peniadenisteroid A and peniadenisteroid A presented weak anti-inflammatory effects. Further mechanistic studies indicated that (3S)-P6 exerts significant anti-inflammatory bioactivity by negatively regulating the STAT3/NF-κB and HIF-1α signaling pathways. Moreover, network pharmacology combined with molecular docking predicted Heat Shock Protein 90α (HSP90α) as the putative binding target of (3S)-P6. Overall, this study completes the synthesis and biological evaluation of (3S)-peniadenisteroid A, highlighting that intermediate (3S)-P6 is a valuable lead compound for further anti-inflammatory drug discovery.