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Mar. Drugs 2013, 11(9), 3209-3223; doi:10.3390/md11093209
Article

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

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Received: 7 June 2013; in revised form: 1 August 2013 / Accepted: 8 August 2013 / Published: 26 August 2013
(This article belongs to the Special Issue Marine Compounds as Protein Kinase Inhibitors)
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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.
Keywords: marine sponge derived hamacanthins; pyrazin-2(1H)-ones; receptor tyrosine kinases; PDGFR inhibitors; anti-cancer activity marine sponge derived hamacanthins; pyrazin-2(1H)-ones; receptor tyrosine kinases; PDGFR inhibitors; anti-cancer activity
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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MDPI and ACS Style

Pinchuk, B.; Johannes, E.; Gul, S.; Schlosser, J.; Schaechtele, C.; Totzke, F.; Peifer, C. Marine Derived Hamacanthins as Lead for the Development of Novel PDGFRβ Protein Kinase Inhibitors. Mar. Drugs 2013, 11, 3209-3223.

AMA Style

Pinchuk B, Johannes E, Gul S, Schlosser J, Schaechtele C, Totzke F, Peifer C. Marine Derived Hamacanthins as Lead for the Development of Novel PDGFRβ Protein Kinase Inhibitors. Marine Drugs. 2013; 11(9):3209-3223.

Chicago/Turabian Style

Pinchuk, Boris; Johannes, Eugen; Gul, Sheraz; Schlosser, Joachim; Schaechtele, Christoph; Totzke, Frank; Peifer, Christian. 2013. "Marine Derived Hamacanthins as Lead for the Development of Novel PDGFRβ Protein Kinase Inhibitors." Mar. Drugs 11, no. 9: 3209-3223.



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