Potent Cytotoxic Analogs of Amphidinolides from the Atlantic Octocoral Stragulum bicolor.

Genoveffa Nuzzo,Otília Pessoa,Evelyne Santos,Adrianna Ianora,Pietro Amodeo,Rosa Vitale,Clementina Sansone,Bruno Gomes,Carmela Gallo,Emiliano Manzo,Angelo Fontana,Leticia Costa-Lotufo

doi:10.3390/md17010058

Abstract

Amphidinolides are cytotoxic macrolides produced by symbiotic unicellular microalgae of the genus Amphidinium. Here we describe the identification of four related molecules belonging to this macrolide family isolated from the invertebrate Stragulum bicolor. The new molecules, named amphidinolide PX1-PX3 and stragulin A (1–4), show an unprecedented carbon skeleton whose complete stereochemistry has been determined by spectroscopic and computational methods. Differences in the structures of these molecules modulate their biological activity in a panel of tumor cell lines, but the opened derivative stragulin (4) shows a very potent and specific cytotoxic activity (IC50 0.18 µM) against the aggressive human melanoma cell A2058.

Highlights

Amphidinolides (AMPs) and related compounds are a diverse class of more than 40 macrolides with extremely high cytotoxicity against several carcinoma cell lines [1,2,3,4]
Since preliminary calculations showed the occurrence of conformational equilibria in solution, an iterative computational protocol based on repeated cycles of Simulated Annealing (SA)/Molecular Dynamics (MD)/Energy Minimization (EM) was applied to both possible epimers at C-4 of 2
We have not correlated by chemical methods the stereochemistry of 4 to 1–3, we suggest that the 4S configuration is shared by the other products of S. bicolor because of a common biogenesis of the polyketide chain

Summary

Introduction

Amphidinolides (AMPs) and related compounds are a diverse class of more than 40 macrolides with extremely high cytotoxicity against several carcinoma cell lines [1,2,3,4]. Together with similar macrolides reported with other names (amphidinolactones, iriomoteolides and caribenolide I) [9,10,11,12,13]. We have reported the extraction of a number of amphidinolides from the softcoral Stragulum bicolor [18,19], including the known amphidinolide P and T1 and three new analogues named amphidinolide C4, B8 and B9 according to the structural relationship with other known members of the family. We describe the full characterization of three new cytotoxic members of the AMP family (1–3), together with the linear polyketide stragulin A (4) that showed

Methods

Results

Conclusion