Synthesis and Evaluation of Spumigin Analogues Library with Thrombin Inhibitory Activity

• Main Authors: Aleš Žula, Izabela Będziak, Danijel Kikelj, Janez Ilaš
• Format: Article
• Language: English
• Published: MDPI AG 2018-10-01
• Series: Marine Drugs
• Subjects: marine products; natural peptides; peptidomimetics; thrombin inhibition
• Online Access: https://www.mdpi.com/1660-3397/16/11/413

Spumigins are marine natural products derived from cyanobacteria <i>Nodularia spumigena</i>, which mimics the structure of the <span style="font-variant: small-caps;">d</span>-Phe-Pro-Arg sequence and is crucial for binding to the active site of serine proteases thrombin and factor Xa. Biological evaluation of spumigins showed that spumigins with a (2<i>S</i>,4<i>S</i>)-4-methylproline central core represent potential lead compounds for the development of a new structural type of direct thrombin inhibitors. Herein, we represent synthesis and thrombin inhibitory activity of a focused library of spumigins analogues with indoline ring or <span style="font-variant: small-caps;">l</span>-proline as a central core. Novel compounds show additional insight into the structure and biological effects of spumigins. The most active analogue was found to be a derivative containing <span style="font-variant: small-caps;">l</span>-proline central core with low micromolar thrombin inhibitory activity.