Palstimolide A: A Complex Polyhydroxy Macrolide with Antiparasitic Activity

Abstract

Marine Cyanobacteria (blue-green algae) have been shown to possess an enormous potential to produce structurally diverse natural products that exhibit a broad spectrum of potent biological activities, including cytotoxic, antifungal, antiparasitic, antiviral, and antibacterial activities. Here, we report the isolation and structure determination of palstimolide A, a complex polyhydroxy macrolide with a 40-membered ring that was isolated from a tropical marine cyanobacterium collected at Palmyra Atoll. NMR-guided fractionation in combination with MS2-based molecular networking and isolation via HPLC yielded 0.7 mg of the pure compound. The small quantity isolated along with the presence of significant signal degeneracy in both the 1H and 13C-NMR spectra complicated the structure elucidation of palstimolide A. Various NMR experiments and solvent systems were employed, including the LR-HSQMBC experiment that allows the detection of long-range 1H–13C correlation data across 4-, 5-, and even 6-bonds. This expanded NMR data set enabled the elucidation of the palstimolide’s planar structure, which is characterized by several 1,5-disposed hydroxy groups as well as a tert-butyl group. The compound showed potent antimalarial activity with an IC50 of 223 nM as well as interesting anti-leishmanial activity with an IC50 of 4.67 µM.

Exploring the Chemical Space of Macro- and Micro-Algae Using Comparative Metabolomics

“…This approach, coupled with approaches such as molecular networking, has been utilised in drug discovery, including the discovery of tutuilamides A–C, from a marine cyanobacterium, with potent elastase inhibition (IC 50 1–5 nM) and anticancer activity against lung H-460 cells [ 17 ]. Comparative metabolomics using the Global Natural Products Social (GNPS) molecular networking [ 18 ] platform led to the discovery of several new metabolites from cyanobacteria and microalgae, including yuvalamide A [ 19 ], pagoamide A [ 20 ], and palstimolide A, which exhibited strong anti-parasitic activity (IC 50 of 223 nM against malaria and 4.67 μM against leishmaniasis) [ 21 ].…”

Genomic and Targeted Approaches Unveil the Cell Membrane as a Major Target of the Antifungal Cytotoxin Amantelide A

“…Characterization of the amantelide A binding mode to actin and mechanism of polymerization is warranted. Furthermore, our study might prompt mechanistic investigations of other polyol polyketides that share a similar scaffold to amantelide A such as palstimolide A and bastimolide A (Figure S7), which may share related mechanisms [48,49] …”

“…Furthermore, our study might prompt mechanistic investigations of other polyol polyketides that share a similar scaffold to amantelide A such as palstimolide A and bastimolide A (Figure S7), which may share related mechanisms. [48,49] Natural products, including those from the marine environment, like polytheonamide B and theonellamides, show different recognition modes to the membrane lipids. [50] This furnishes them as a useful tool to uncover different aspects of the cell membrane by developing them into lipid-detecting probes.…”

Potentials of marine natural products against malaria, leishmaniasis, and trypanosomiasis parasites: a review of recent articles

“…5 b) Macrolide Central Pacific Ocean cyanobacterium Leptolyngbya sp. USA [ 45 ] P. falciparum strain HB3 (NA and 5.7 ± 0.7 μmol/L) NT Bastimolide A (1) and B (2) (Fig. 5 c) Macrolide Tropical marine cyanobacterium Okeania hirsute USA [ 46 ] Active against stages/forms of P. falciparum; L. infantum amastigote (7.64 and 3.19 µmol/L) and promastigotes (28.1 and 7.42 µmol/L), and L. tropica promastigotes (20.28 and 7.08 µmol/L) HMEC‐1 (62.19 ± 1.98 and 36.85 ± 5.79 µmol/L); THP‐1 (> 100 and 31.75 µmol/L) Sesquiterpene avarone (1) and avarol (3) (Fig.…”

“…A macrolide with a 40-membered ring, palstimolide A (Fig. 5 b), isolated from Central Pacific Ocean Cyanobacterium exhibited interesting anti-parasitic activities against blood-stage of the P. falciparum Dd2 (IC 50 = 223 nmol/L) and intracellular L. donovani (IC 50 = 4.67 μmol/L), as well as low toxicity [ 45 ]. Likewise, another new 24-membered polyhydroxy macrolide bastimolide B (2) was isolated along with a known bastimolide A (1) (Fig.…”