Cytotoxic halogenated macrolides and modified peptides from the apratoxin-producing marine cyanobacterium Lyngbya bouillonii from Guam

Abstract

Collections of the marine cyanobacterium Lyngbya bouillonii from shallow patch reefs in Apra Harbor, Guam, afforded three hitherto undescribed analogues of the glycosidic macrolide lyngbyaloside, namely, 2-epi-lyngbyaloside (1) and the regioisomeric 18E- and 18Z-lyngbyalosides C (2 and 3). Concurrently we discovered two new analogues of the cytoskeletal actin-disrupting lyngbyabellins, 27-deoxylyngbyabellin A (4) and lyngbyabellin J (5), a novel macrolide of the laingolide family, laingolide B (6), and a linear modified peptide, lyngbyapeptin D (7), along with known lyngbyabellins A and B, lyngbyapeptin A, and lyngbyaloside. The structures of 1-7 were elucidated by a combination of NMR spectroscopic and mass spectrometric analysis. Compounds 1-6 were either brominated (1-3) or chlorinated (4-6), consistent with halogenation being a hallmark of many marine natural products. All extracts derived from these L. bouillonii collections were highly cytotoxic due to the presence of apratoxin A or apratoxin C. Compounds 1-5 showed weak to moderate cytotoxicity to HT29 colorectal adenocarcinoma and HeLa cervical carcinoma cells.

Figure 1

Natural products isolated from shallow-water L. bouillonii found in Apra Harbor (Guam) and closely related analogues found in Palau (lyngbyaloside B) or Papua New Guinea (laingolide and laingolide A).

Figure 2

Proposed stereostructure and selected key NOESY correlations for 2-epi-lyngbyaloside (1). Configurational difference to lyngbyaloside is indicated in red. Other groups and protons with critical stereoelectronical effects discussed in the text are shown in blue. Δδ values for H-4a/b and H-6a/b relative to the corresponding resonances in lyngbyaloside are shown in blue and Δδ values between diastereotopic protons in 1 are depicted in green.

Figure 3

ESI-MS/MS of the lyngbyapeptin D degradation product 7a.