Potent Cytotoxic Analogs of Amphidinolides from the Atlantic Octocoral Stragulum bicolor

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.

Keywords: Stragulum bicolor; amphidinolides; cytotoxic macrolides; stereochemistry.

Scheme 1

Amphidinolide PX1-PX3 (1–3), stragulin A (4) with related Mosher’s derivatives 4a and 4b and amphidinolide P (5).

Figure 1

Stereochemical assignment of compounds 1–4. (A) Key correlations to support the relative stereochemistry of 1 and 2. Double arrow = Nuclear Overhauser Effect (NOE); simple arrow = Heteronuclear Multiple Bond Coherence (HMBC); (B) Newman projection of the C-12/C-20 fragment of amphidinolide PX1 (1) and PX2 (2) with the anti configuration of the substituents at C-14 and C-15. Double arrow = NOE; (C) Chemical shift differences Δδ_{(δSester−δRester)} between (S)- and (R)-α-Methoxy-α-(trifluoromethyl)phenylacetic acid (MTPA) derivatives of stragulin A (4).

Figure 2

Restrained Energy Minimization (rEM) structures of amphidinolide PX2 (2) representative conformers. Panel (A): conformers I (beige) and V (salmon); panel (B): conformer II (violet); panel (C): conformers III (pink) and IV (light green); panel (D): conformer VI (gray). Structures are best-fit of the macrocycle atoms. Oxygen and hydrogen atoms are colored red and white, respectively. Methyl groups are shown as spheres colored as the carbon atoms of the corresponding conformer (colors in parenthesis).