Efficient syntheses, human and yeast farnesyl-protein transferase inhibitory activities of chaetomellic acids and analogues.
Chaetomellic acids are a class of alkyl dicarboxylic acids that were isolated from Chaetomella acutiseta. They are potent and highly specific farnesyl-pyrophosphate (FPP) mimic inhibitors of Ras farnesyl-protein transferase. We have previously described the first biogenetic type aldol condensation-based total synthesis of chaetomellic acid A. Modification of the later steps of that synthesis resulted in the efficient syntheses of chaetomellic acids A and B in three steps with 75-80% overall yield. In this report, details of the original total syntheses of chaetomellic acids A, B and C, the new syntheses of acids A and B and structure-activity relationship of these compounds against various prenyl transferases including human and yeast FPTase and bovine and yeast GGPTase I are described. Chaetomellic acids are differentially active against human and yeast FPTase. Chaetomellic acid A inhibited human and yeast FPTase activity with IC50 values of 55 nM and 225 microM, respectively. In contrast, chaetomellic acid C showed only a 10-fold differential in inhibitory activities against human versus yeast enzymes. In keeping with molecular modeling-based predictions, the compounds with shorter alkyl side chains (C-8) were completely inactive against FPTase.
Singh
S B
SB
Merck Research Laboratories, Rahway, NJ 07065, USA. sheo_singh@merck.com
Jayasuriya
H
H
Silverman
K C
KC
Bonfiglio
C A
CA
Williamson
J M
JM
Lingham
R B
RB
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D002417:Cattle; D004122:Dimethylallyltranstransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000737:chemistry / Q000302:isolation & purification; D006801:Humans; D020128:Inhibitory Concentration 50; D008298:Maleates / Q000138:chemical synthesis* / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D015003:Yeasts / Q000201:enzymology
D004791:Enzyme Inhibitors; D005231:Fatty Acids, Unsaturated; D008298:Maleates; C408473:chaetomellic acid D; C408474:chaetomellic acid E; C080569:chaetomellic acid A; C085713:chaetomellic acid B; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase; D004122:Dimethylallyltranstransferase