Marine Derived Hamacanthins as Lead for the Development of Novel PDGFRβ Protein Kinase Inhibitors

Abstract

In this study, we report on pyrazin-2(1H)-ones as lead for the development of potent adenosine triphosphate (ATP) competitive protein kinase inhibitors with implications as anti-cancer drugs. Initially, we identified the pyrazin-2(1H)-one scaffold from hamacanthins (deep sea marine sponge alkaloids) by Molecular Modeling studies as core binding motif in the ATP pocket of receptor tyrosine kinases (RTK), which are validated drug targets for the treatment of various neoplastic diseases. Structure-based design studies on a human RTK member PDGFR (platelet-derived growth factor receptor) suggested a straight forward lead optimization strategy. Accordingly, we focused on a Medicinal Chemistry project to develop pyrazin-2(1H)-ones as optimized PDGFR binders. In order to reveal Structure-Activity-Relationships (SAR), we established a flexible synthetic route via microwave mediated ring closure to asymmetric 3,5-substituted pyrazin-2(1H)-ones and produced a set of novel compounds. Herein, we identified highly potent PDGFR binders with IC50 values in an enzymatic assay below µM range, and possessing significant activity against PDGFR dependent cancer cells. Thus, marine hamacanthin-derived pyrazin-2(1H)-ones showing interesting properties as lead for their further development towards potent PDGFR-inhibitors.

The use of marine-derived bioactive compounds as potential hepatoprotective agents

“…www.nature.com/aps Nair DG et al Acta Pharmacologica Sinica npg leagues showed the inhibitory effects of the pyrazin-2(1H)-one scaffold from hamacanthins, which were also isolated from a marine sponge and are highly potent in binding and inhibiting PDGFR-β [51] . Based on the outstanding role of the PDGF system in liver fibrosis, it will be extremely worthwhile to study the effects of these molecules on the setting of experimental liver disease models.…”

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Preparation of symmetrical C2-C2-linked bis- and tris-6-bromoindoles by Sonogashira couplings and 5-endo-dig cyclization induced by nBu4NF

“…It is noteworthy that structural modifications of these natural products had led to synthetic analogs with DNAquadruplex recognition, 4 antibacterial, 5,6 antilesihmanial, 7 antitumoral, [8][9][10][11] and angiogenesis inhibition 12 activity. Most of these compounds are linked through the indole C3 position, with only a few exceptions such as Gelliusines F which is a C2-C3 linked bis-indole.…”

Marine Sponge Derived Antiangiogenic Compounds

“…Recently, a number of hamacanthin-derived pyrazin-2(1H)-ones have shown interesting properties as lead for the further development of highly potent and selective PDGFRβ-inhibitors. Modeling studies showed the core moiety of hamacanthins to bind in the ATP binding pocket of the receptor tyrosine kinase, and suggested a straightforward strategy towards potent PDGFRβ binders [93].…”