Marine-Derived 2-Aminoimidazolone Alkaloids. Leucettamine B-Related Polyandrocarpamines Inhibit Mammalian and Protozoan DYRK & CLK Kinases

Abstract

A large diversity of 2-aminoimidazolone alkaloids is produced by various marine invertebrates, especially by the marine Calcareous sponges Leucetta and Clathrina. The phylogeny of these sponges and the wide scope of 2-aminoimidazolone alkaloids they produce are reviewed in this article. The origin (invertebrate cells, associated microorganisms, or filtered plankton), physiological functions, and natural molecular targets of these alkaloids are largely unknown. Following the identification of leucettamine B as an inhibitor of selected protein kinases, we synthesized a family of analogues, collectively named leucettines, as potent inhibitors of DYRKs (dual-specificity, tyrosine phosphorylation regulated kinases) and CLKs (cdc2-like kinases) and potential pharmacological leads for the treatment of several diseases, including Alzheimer’s disease and Down syndrome. We assembled a small library of marine sponge- and ascidian-derived 2-aminoimidazolone alkaloids, along with several synthetic analogues, and tested them on a panel of mammalian and protozoan kinases. Polyandrocarpamines A and B were found to be potent and selective inhibitors of DYRKs and CLKs. They inhibited cyclin D1 phosphorylation on a DYRK1A phosphosite in cultured cells. 2-Aminoimidazolones thus represent a promising chemical scaffold for the design of potential therapeutic drug candidates acting as specific inhibitors of disease-relevant kinases, and possibly other disease-relevant targets.

Natural Compounds and Derivatives as Ser/Thr Protein Kinase Modulators and Inhibitors

“…CDKs also have been targeted with natural compounds from other sources than plants, e.g., from marine organisms. This is a potential new source for finding further potent kinase inhibitors [105,106,107].…”

“…There are increasing reports of the isolation of protein kinase inhibitors from other sources, beside plants. Recently protein kinase inhibitors have been isolated from marine sources [106,107]. This is a new and promising approach in the search for new types of kinase inhibitors.…”

Ascidian Toxins with Potential for Drug Development

“…are 2-aminoimidazolone alkaloids. Several synthetic analogs of leucettamine B (a sponge natural product) with the 2-aminoimidazolone scaffold have been synthesized [ 164 ]. The researchers also tested a small library of sponge- and ascidian-derived 2-aminoimidazolone alkaloids for their kinase inhibitory activity against a panel of kinases (14 mammalian and 2 parasitic).…”

[b]-Annulated Halogen-Substituted Indoles as Potential DYRK1A Inhibitors

“…Harmine ( 1 ), a β-carboline alkaloid, is a strong DYRK1A inhibitor but, due to inhibition of monoamine-oxidase A (MAO-A), is not suitable as drug candidate [19]. Leucettine L41 ( 2 ), derived from the marine natural product leucettamine B, is a dual DYRK1A/CLK1 inhibitor and one of the pharmacologically best profiled DYRK1A inhibitors [20,21,22,23,24,25,26]. The halogenated indole derivative KH-CB19 ( 3 ) also inhibits CLK1 and DYRK1A [27].…”