Protein kinase C ligands based on tetrahydrofuran templates containing a new set of phorbol ester pharmacophores.
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 (C(3)-C=O, C(20)-OH and C(13)-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 [(3)H-20]phorbol 12, 13-dibutyrate (PDBU) from a recombinant alpha 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 microM. 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 approximately II > III > IV. These compounds represent the first generation of rigid glycerol templates seeking to mimic the binding of the C(13)-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 C(9)-OH pharmacophore surrogate. This finding confirms that mimicking the binding of the C(13)-C=O pharmacophore of phorbol is a useful strategy. However, since the C(9)-OH and C(13)-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.
Lee
J
J
Laboratory of Medicinal Chemistry, College of Pharmacy, Seoul National University, Shinlim-Dong, Kwanak-Ku, Seoul 151-742, Korea. jeewoo@snu.ac.kr
Kang
J H
JH
Lee
S Y
SY
Han
K C
KC
Torres
C M
CM
Bhattacharyya
D K
DK
Blumberg
P M
PM
Marquez
V E
VE
D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry*; D007527:Isoenzymes / Q000737:chemistry*; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D015240:Phorbol 12,13-Dibutyrate / Q000737:chemistry; D010703:Phorbol Esters / Q000138:chemical synthesis* / Q000737:chemistry; D011493:Protein Kinase C / Q000737:chemistry*; D051571:Protein Kinase C-alpha; D011994:Recombinant Proteins / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D005663:Furans; D007527:Isoenzymes; D008024:Ligands; D010703:Phorbol Esters; D011994:Recombinant Proteins; D015240:Phorbol 12,13-Dibutyrate; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha