Coibamide A, a Potent Antiproliferative Cyclic Depsipeptide from the Panamanian Marine Cyanobacterium Leptolyngbya sp.

Abstract

Coibamide A (1) is a new, potent antiproliferative depsipeptide which was isolated from a marine Leptolyngbya cyanobacterium collected from the Coiba National Park, Panama. The planar structure of 1 was elucidated by a combination of NMR spectroscopy and mass spectrometry. Exhaustive 1D and 2D NMR spectroscopy included natural abundance 15 N and variable temperature experiments; mass spectrometry included TOF-ESI-MS n and FT-MS n experiments. Chemical degradation followed by chiral HPLC-and GC-MS analyses was used to assign the absolute configuration of 1. This highly methylated cyclized depsipeptide exhibited an unprecedented selectivity profile in the NCI 60 cancer cell line panel and appears to act via a novel mechanism.Marine organisms continue to yield a diverse array of biologically active molecules, a remarkable number of which are peptide-based cancer cell toxins of putative microbial symbiont biogenesis. 1 Development of these as anticancer drugs has met with some success: 2 ascidian-derived dihydrodidemnin B (aplidin®) has orphan drug status for the treatment of multiple myeloma and acute lymphoblastic leukemia; green algal isolate kahalalide F, and TZT-1027, a synthetic analog of the cyanobacterial metabolite dolastatin 10, reached phase II clinical trials. Other important cyanobacterial peptide leads include the cryptophycins and curacin A, 3 and these organisms continue to produce a wealth of anticancer lead compounds. 4 The high degree of N-methylation of many of these cyanobacterial peptides may improve their druggability since N-methylation has been shown to improve pharmacological parameters such as lipophilicity, proteolytic stability and duration of action, properties for which regular peptides are notoriously poor and which limits their bioavailability. 5In the context of our International Cooperative Biodiversity Groups program (ICBG) based in Panama, which focuses on drug discovery, biodiversity conservation and sustainable economic growth, we have isolated a potent cancer cell toxin with an unprecedented selectivity profile in the NCI 60 cell line panel. This cyanobacterial depsipeptide, named coibamide A in tribute

Filamentous tropical marine cyanobacteria: a rich source of natural products for anticancer drug discovery

“…9 Potent cytotoxic compounds from marine cyanobacteria the Panamanian marine cyanobacterium, Leptolyngbya sp. (Medina et al 2008 (Fig. 10), a cyclic depsipeptide, is a potent cytotoxic molecule isolated from a persistent strain of L. majuscula found at the western lagoon of Pulau Hantu, Singapore (Tripathi et al 2009).…”

Marine Peptide Secondary Metabolites

“…A threonine residue allows not only closure of the macrocycle through an ester bond with the N,O-dimethyl-tyrosine residue, but also the presence of a tail of amino acids inserted onto its amino function. This feature is commonly found in numerous socalled "lariat-type" cyclic depsipeptides of marine origin, such as the families of lyngbyastatins (Kwan et al, 2009), the kahalalide F (which will be discussed below), hassallidin A (which contains a mannose branched on a threonine; Neuhof et al, 2005), and the remarkable almost fully N-methylated coibamide A (Medina et al, 2008), to mention but a few of the most outstanding compounds (Figure 13.14).…”

Molecular Targets of Anticancer Agents from Filamentous Marine Cyanobacteria

“…27.5) is a potent antiproliferative cyclic depsipeptide purified from the Panamanian marine cyanobacterial strain, Leptolyngbya sp. [62]. The discovery of this molecule stemmed from the International Cooperative Biodiversity Groups (ICBG) program, involving scientists from the US and Panama.…”

“…, and SNB-75 at2.8 nM, 7.4 nM, 7.4 nM, and 7.6 nM, respectively. Furthermore, "COMPARE-negative" analysis indicated that coibamide A might inhibit cancer cell proliferation via a novel mechanism [62]. Mode of action studies on coibamide A were recently conducted using human U87-MG and SF-295 glioblastoma cells and mouse embryonic fibroblasts (MEFs).…”