Spiralisones A–D: acylphloroglucinol hemiketals from an Australian marine brown alga, Zonaria spiralis

Abstract

An intertidal sample of the Australian marine brown alga, Zonaria spiralis, exhibited promising kinase inhibitory and antibacterial activity. Chemical analysis returned six phloroglucinol-derived lipids, the new hemiketal spiralisones A-D (1-4) and the known chromones 5-6, and the known norsesquiterpenoid apo-9'-fucoxanthinone (7). Structures 1-7 were assigned on the basis of detailed spectroscopic analysis, biosynthetic considerations and total synthesis. Spiralisones undergo facile acid-mediated dehydration to yield the corresponding chromones, revealing for the first time that brown algal chromones may be handling artifacts rather than natural products. Hemiketals 1 and 2, and chromone 6, displayed inhibitory activity against the neurodegenerative disease kinase targets CDK5/p25, CK1δ and GSK3β, while hemiketals 1, 3 and 4, and chromone 6, displayed growth inhibitory activity against the Gram-positive bacteria Bacillus subtilis (ATCC 6051 and 6633). The promising kinase inhibitory and antibacterial properties of the Z. spiralis extract were attributed to the cumulative effect of many moderately potent phloroglucinol-derived lipid co-metabolites.

Omega-3 polyunsaturated lipophenols, how and why?

“…2) have been isolated from vegetables or animals from marine origin. Hemiketal spiralisone 25 was isolated from Zonaria spiralis (5.3%) [40], a marine brown algae, together with the chromone 26 (1.6%), which was also found in several other brown algae of the Zonaria genus, like Zonaria tournefortii [41]. Chromone 26 is presented to be a possible artifact of 25, by dehydration, favored by mildly acidic conditions.…”

“…In addition to inhibition of kinase, hemiketal spiralisone 25 and chromone 26 exhibited moderate growth inhibitory activity (IC 50 ¼ 2.5e10 mM) against gram positive bacteria Bacillus subtilis (ATCC 6051 and 6633) [40]. The antibacterial properties of the crude Z. spiralis extract was more expended than isolated lipophenols.…”

“…Zhang et al [40] proposed a biosynthetic pathway, starting from the monomeric phloroglucinol to access the racemic spiralisone 25 and chromone derivative 26, found in various sources of algae: after formation of an acylphloroglucinol intermediate in the presence of acetyl-CoA, elongation via a Claisen condensation on an activated fatty acid would lead to the incorporation of the polyunsaturated part. The resulting acylphloroglucinol b-diketone would undergo intramolecular cyclization to afford the spiralisone derivative, then the chromone upon dehydration.…”

“…In vitro cell free assays of hemiketal spiralisone 25 and chromone 26 (both EPA analogues) highlighted inhibitory activities (with IC 50 < 10 mM) against kinase targets, casein kinase 1d (CK1d), cyclin-dependent kinase 5 (CDK5/p25) and glycogen synthase kinase 3b (GSK3b), which are involved in Alzheimer's disease [40]. Interestingly the crude alga Z. spiralis extract presented kinase inhibitory potency, most probably linked to the cumulative effect of multiple moderately potent spiralisone inhibitors.…”

Anticancer Drugs and Potential Anticancer Leads Inspired by Natural Products

“…Hymenialdisine (190) exhibited potent CDKs inhibitory activity with the IC 50 values of 22 and 28 nM for CDK1 and CDK5, respectively [287]. 5.24) are acylphloroglucinol hemiketals isolated from a marine brown alga, Zonaria spiralis [288]. Several analogs of 190 were synthesized and tested for the inhibition of CDKs; the analogs 191 and 192 with a hydrazone functionality (Fig.…”