Synthesis and enzymic evaluation of 4-mercapto-6-oxo-1, 4-azaphosphinane-2-carboxylic acid 4-oxide as an inhibitor of mammalian dihydroorotase.
The design, synthesis, and enzymic evaluation of cis- and trans-4-mercapto-6-oxo-1,4-azaphosphinane-2-carboxylic acid 4-oxide 5 against mammalian dihydroorotase is presented. The design strategy for 5 was based on the strong affinity of phosphinothioic acids for zinc and that 5 also resembles the postulated tetrahedral transition state for the enzyme-catalyzed reaction. The synthesis of 5 utilized a novel protection/deprotection sequence upon 4-hydroxy-6-oxo-1, 4-azaphosphinane-2-carboxylic acid 4-oxide 4, followed by incorporation of alpha-phenyl benzenemethanethiol and exhaustive deprotection to afford 5 in 40% overall yield from 4. The activities of both isomers of 5 as inhibitors of mammalian dihydroorotase were marginally greater than that of the parent phosphinic acid 4, indicating a weak binding enhancement due to the phosphinothioic acid moiety.
Manthey
M K
MK
Department of Biochemistry, University of Sydney, Sydney, NSW 2006, Australia.
Huang
D T
DT
Bubb
W A
WA
Christopherson
R I
RI
D000818:Animals; D006224:Cricetinae; D003497:Cyclic N-Oxides / Q000138:chemical synthesis* / Q000494:pharmacology; D004080:Dihydroorotase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D004926:Escherichia coli / Q000378:metabolism; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D013237:Stereoisomerism
C115585:4-mercapto-6-oxo-1,4-azaphosphinane-2-carboxylic acid 4-oxide; D003497:Cyclic N-Oxides; D004791:Enzyme Inhibitors; D006571:Heterocyclic Compounds; D011994:Recombinant Proteins; D004080:Dihydroorotase