249930-15-2Relevant academic research and scientific papers
Protein kinase C ligands based on tetrahydrofuran templates containing a new set of phorbol ester pharmacophores
Lee, Jeewoo,Kang, Ji-Hye,Lee, Sang-Yoon,Han, Kee-Chung,Torres, Christina M.,Bhattacharyya, Dipak K.,Blumberg, Peter M.,Marquez, Victor E.
, p. 4129 - 4139 (2007/10/03)
A series of substituted tetrahydrofurans with an embedded glycerol backbone carrying additional tetrahydrofuranylideneacetate or tetrahydrofuranylacetate motifs were grouped into four distinct templates (I- IV) according to stereochemistry. The compounds were designed to mimic three essential pharmacophores (C3-C=O, C20-OH and C13-C=O) of the phorbol esters according to a new, revised model. The tetrahydrofuran ring was constructed from glycidyl 4-methoxyphenyl ether, and the structures of the isomeric templates were assigned by NMR spectroscopy, including NOE. The binding affinity for protein kinase C (PKC) was assessed in terms of the ability of the ligands to displace bound [3H-20]phorbol 12,13-dibutyrate (PDBU) from a recombinant α isozyme of PKC. Geometric Z- and E-isomers (1 and 3, respectively) containing a tetrahydrofuranylideneacetate motif were the most potent ligands with identical K(i) values of 0.35 μM. Molecular modeling studies of the four templates showed that the rms values when fitted to a prototypical phorbol 12,13-diacetate ester correlated inversely with affinities in the following order: I ? II > III > IV. These compounds represent the first generation of rigid glycerol templates seeking to mimic the binding of the C13-C=O of the phorbol esters. The binding affinities of the most potent compounds are in the same range of the diacylglycerols (DAGs) despite the lack of a phorbol ester C9-OH pharmacophore surrogate. This finding confirms that mimicking the binding of the C13-C=O pharmacophore of phorbol is a useful strategy. However, since the C9-OH and C13-C=O in the phorbol esters appear to form an intramolecular hydrogen bond that functions as a combined pharmacophore, it is possible the lack of this combined motif in the target templates restricts the compounds from reaching higher binding affinities.
