| The synthesis of a series of nucleoside dicarboxylates (maleates and succinates) and their biological evaluation against nucleoside diphosphate (NDP) kinase, the enzyme responsible for the phosphorylation of nucleoside diphosphates to their corresponding triphosphates, is first described. Efforts towards preparing analogues with an ether or a thioether linkage to the dicarboxylate moiety focused on the 1,4-addition to various esters of acetylenedicarboxylic acid. In all cases, the final step involving several different deprotection strategies failed to afford any of the desired products.;The final approach involved olefin cross metathesis to attach the dicarboxylate portion to the nucleoside. Although access to dimethyl 2-(3-((3aR, 4R,6R,6aR)-6-(2,4-dioxo-3,4-dihydropyrimidin-1(2 H)-yl)-2,2-dimethyltetrahydrofuro[3,4-d] [1,3]dioxol-4-yl)allyl)maleate (148) was possible using this methodology, selective reduction of its 5',6'-double bond could not be achieved.;In a revised strategy, the 5',6'-double bond was reduced prior to formation of the maleate, which was later accessed via a Horner-Emmons-Wadsworth (HEW) reaction between methyl diethylphosphonoacetate (163) and an alpha-keto ester. Using this approach, the uridine maleates lithium 1-((2 R,3R,4S,5R)-5-((Z)-3,4-dicarboxylatobut-3-enyl)-3,4-dihydroxytetrahydrofuran-2-yl)-2,4-dioxo-2,4-dihydro-1 H-pyrimidin-3-ide (182), lithium 1-((2R,3 R,4S,5R)-5-((Z)-4,5-dicarboxylatopent-4-enyl)-3,4-dihydroxytetrahydrofuran-2-yl)-2,4-dioxo-2,4-dihydro-1 H-pyrimidin-3-ide (188), and lithium 1-((2R, 3R,4S,5R)-5-((Z)-5,6-dicarboxylatohex-5-enyl)-3,4-dihydroxytetrahydrofuran-2-yl)-2,4-dioxo-2,4-dihydro-1 H-pyrimidin-3-ide (193) were obtained. Reduction of the maleates after the HEW reaction followed by deprotection gave the corresponding uridine succinates lithium 1-((2R,3R,4 S,5R)-5-(3,4-dicarboxylatobutyl)-3,4-dihydroxytetrahydrofuran-2-yl)-2,4-dioxo-2,4-dihydro-1 H-pyrimidin-3-ide (200), lithium 1-((2R,3 R,4S,5R)-5- (4,5-dicarboxylatopentyl)-3,4-dihydroxytetrahydrofuran-2-yl)-2,4-dioxo-2,4-dihydro-1 H-pyrimidin-3-ide (201), and lithium 1-((2R, 3R,4S,5R)-5-(5,6-dicarboxylatohexyl)-3,4-dihydroxytetrahydrofuran-2-yl)-2,4-dioxo-2,4-dihydro-1 H-pyrimidin-3-ide (202). None of the analogues inhibited NDP kinase at a concentration of 1 mM. The six dicarboxylate salts and their corresponding dimethyl diesters 180, 186, 191, 196, 197, and 198 also exhibited no antimicrobial activity against several pathogenic bacteria at 20 mug/mL.;Several analogues of the type IIa bacteriocin pediocin PA-1 in which one of the disulfide bonds was replaced with amino acids capable of hydrophobic interactions were synthesized on solid phase and tested for their antimicrobial activity against Listeria monocytogenes ATCC 43256 and Carnobacterium divergens LV13. The analogues, 9,14-diallyl 31-butyl pediocin PA-1 (211), 9,14-dibenzyl 31-butyl pediocin PA-1 ( 212), 9,14-dipropyl 31-butyl pediocin PA-1 (213), and 24,44-diallyl 31-butyl pediocin PA-1 (214), were inactive against these strains.;Various strategies were explored for the synthesis of the analogues containing methylene spacers. Approaches involving the treatment of dimethyl acetylenedicarboxylate (46) with nucleoside-derived organocuprates were unsuccessful. Other strategies employing modified Stille conditions for alkyl bromides containing beta-hydrogens, or the photolysis of diacyl peroxides, also failed to provide any of the desired products. |
