Conformationally constrained analogues of diacylglycerol. 10. Ultrapotent protein kinase C ligands based on a racemic 5-disubstituted tetrahydro-2-furanone template.
5,5-Bis(hydroxymethyl)tetrahydro-2-furanone and its isomer 4,4-bis(hydroxymethyl)tetrahydro-2-furanone were investigated as possible templates for the construction of conformationally constrained analogues of the biologically important second messenger, diacylglycerol (DAG). The former lactone contains embedded within its structure an exact glycerol moiety, while in the latter the ring oxygen has been transposed to the other side of the carbonyl group. All target compounds were synthesized as racemates from 1,3-dihydroxy-2-propanone. The 5,5-bis(hydroxymethyl)tetrahydro-2-furanone proved to be the better template for the construction of DAG surrogates that were demonstrated to have high binding affinities for the biological target, protein kinase C (PK-C). The simplest target compounds derived from this template (3e and 3f) have one of the hydroxyl moieties functionalized either as a myristate or as an oleate ester. The simplest target compound (9c) derived from the ineffective 4,4-bis-(hydroxymethyl)tetrahydro-2-furanone template was investigated only with a myristoyl acyl chain. Reducing the long acyl chain to an acetyl moiety and attaching a compensating lipophilic chain to the lactone ring as an alpha-alkylidene moiety produced compounds 10e and 10f (Z-isomers) and 11e and 11f (E-isomers), which were constructed on the more effective 5,5-bis(hydroxymethyl)tetrahydro-2-furanone template. Targets 14c (Z-isomer) and 15c (E-isomer) were derived, in turn, from 4,4-bis(hydroxymethyl)tetrahydro-2-furanone. The affinities of these ligands for PK-C were assessed in terms of their ability to displace bound [3H-20]phorbol 12,13-dibutyrate (PDBU) from the single isozyme PK-C alpha. The biological data support the hypothesis that the increase in binding affinity for PK-C shown by some of these constrained DAG mimetics appears to be entropic in nature. Two of the designed ligands (10e and 10f) showed the highest affinities (34 and 24 nM, respectively) reported so far for a DAG analogue. Assuming that the interaction between these racemic compounds and PK-C is stereospecific, the potency of the active enantiomer is anticipated to double.
Sharma
R
R
Laboratory of Medicinal Chemistry, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Lee
J
J
Wang
S
S
Milne
G W
GW
Lewin
N E
NE
Blumberg
P M
PM
Marquez
V E
VE
D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D001667:Binding, Competitive; D004075:Diglycerides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D004098:Dihydroxyacetone / Q000378:metabolism; D007783:Lactones / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D019814:Myristic Acid; D009227:Myristic Acids / Q000737:chemistry / Q000378:metabolism; D019301:Oleic Acid; D009829:Oleic Acids / Q000737:chemistry / Q000378:metabolism; D015240:Phorbol 12,13-Dibutyrate / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D013237:Stereoisomerism
C097762:5-((acetyloxy)methyl)-5-(hydroxymethyl)-3-tetradecanylidenetetrahydro-2-furanone; C097763:5--((acetyloxy)methyl)-5-(hydroxymethyl)-3-(9-octadecenylidene)tetrahydro-2-furanone; D004075:Diglycerides; D007783:Lactones; D008024:Ligands; D009227:Myristic Acids; D009829:Oleic Acids; D019814:Myristic Acid; D019301:Oleic Acid; D015240:Phorbol 12,13-Dibutyrate; D011493:Protein Kinase C; D004098:Dihydroxyacetone; D015107:4-Butyrolactone