Conformationally constrained analogues of diacylglycerol. 21. A solid-phase method of synthesis of diacylglycerol lactones as a prelude to a combinatorial approach for the synthesis of protein kinase C isozyme-specific ligands.
A solid-phase method for the synthesis of diacylglycerol lactones as protein kinase C ligands was developed, and a small array of nine compounds were selected with the idea of testing this methodology and forecasting the reliability of the biological data as a preamble for the construction of large chemical libraries to be synthesized under the same conditions. The process started with the loading of 5-(hydroxymethyl)-5-[(4-methoxyphenoxy)methyl]-3,4,5-trihydrofuran-2-one (1) to a 3,4-dihydro-2H-pyran resin packed inside IRORI MacroKan reactors. The elements of diversity were introduced at the alpha-alkylidene (R(1)) and acyl (R(2)) positions using a set of three different aldehydes and three different acid chlorides, respectively. An LDA-mediated aldol condensation with R(1)CHO in the presence of ZnCl(2) followed by a DBU-catalyzed elimination of the triflate of the resulting aldol gave the alpha-alkylidene intermediates as mixtures of geometric isomers. Removal of the aryl-protecting group followed by acylation with R(2)COCl introduced the second element of diversity. Acid-assisted cleavage of the compounds from the resin afforded the final targets. The biological results obtained using the crude samples directly obtained from the resin compared well with those from pure materials, as the K(i) values between the two sets varied only by a factor between 1.5 and 3.7.
Duan
Dehui
D
Laboratory of Medicinal Chemistry, Center for Cancer Research, National Cancer Institute at Frederick, National Institutes of Health, Frederick, MD 21702, USA.
Lewin
Nancy E
NE
Sigano
Dina M
DM
Blumberg
Peter M
PM
Marquez
Victor E
VE
D001667:Binding, Competitive; D020650:Combinatorial Chemistry Techniques; D004075:Diglycerides / Q000138:chemical synthesis* / Q000737:chemistry; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D007783:Lactones / Q000138:chemical synthesis* / Q000737:chemistry; D008024:Ligands; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000737:chemistry; D051571:Protein Kinase C-alpha; D013329:Structure-Activity Relationship
D004075:Diglycerides; D007527:Isoenzymes; D007783:Lactones; D008024:Ligands; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha