Novel biologically active nonpeptidic inhibitors of myristoylCoA:protein N-myristoyltransferase.
A new class of biologically active nonpeptidic inhibitors of Candida albicans NMT has been synthesized starting from the octapeptide ALYASKLS-NH2 (2). The synthetic strategy entailed the preparation of novel protected Ser-Lys mimics 9 and 12 from (S)- or (R)-3-iodotyrosine and then grafting key enzyme recognition elements in a stepwise manner. Like 2, compounds 16, 17, and 18 are competitive Candida NMT inhibitors that bind to the peptide recognition site of the enzyme. Moreover, 16-18 have an affinity comparable to that of 2 even though they are devoid of peptide bonds. In contrast to 2, these nonpeptidic inhibitors exhibit antifungal activity.
Devadas
B
B
Department of Medicinal and Structural Chemistry, G. D. Searle and Company, St. Louis, Missouri 63198, USA.
Freeman
S K
SK
McWherter
C A
CA
Kishore
N S
NS
Lodge
J K
JK
Jackson-Machelski
E
E
Gordon
J I
JI
Sikorski
J A
JA
D000217:Acyltransferases / Q000037:antagonists & inhibitors*; D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002176:Candida albicans / Q000187:drug effects / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D013237:Stereoisomerism
D000935:Antifungal Agents; D004791:Enzyme Inhibitors; D007093:Imidazoles; C111359:N-(1-((3-(aminobutyl)-4-(cyclohexylethoxy)phenyl)methyl)-2-hydroxyethyl)-4-((2-methyl-1H-imidazol-1-yl)butyl)benzeneethanamine; C111360:N-(1-((3-(aminopropyl)-4-(cyclohexylethoxy)phenyl)methyl)-2-hydroxyethyl)-4-((2-methyl-1H-imidazol-1-yl)butyl)benzeneethanamine; D000217:Acyltransferases; C050480:glycylpeptide N-tetradecanoyltransferase