A REVERSED THIOESTER ANALOG OF ACETYL-COENZYME-A - AN INHIBITOR OF THIOLASE AND A SYNTHON FOR OTHER ACYL-COA ANALOGS

We have previously reported a general synthetic approach to analogues of coenzyme A (CoA) and CoA esters using a combination of enzymatic an d nonenzymatic reactions (Martin et al. J. Am. Chem. Sec. 1994, 116, 4 660). We report here the extension of this method to a CoA ester analo gue 1c in which the orientation of the thioester is reversed. A key to this synthesis is the use of a trithioortho ester as a protected thio ester. The reversed thioester analogue Ic is a time-dependent inhibito r of thiolase, apparently forming an acyl enzyme in which the CoA moie ty rather than an acetyl moiety is covalently attached to an active si te nucleophile. This analogue also serves as a general synthon for ana logues having other functionality at the site of the thioester group. This has been applied to the synthesis of a reversed thioester analogu e of succinyl-CoA 6 and hydroxamate 7 and hydrazide 8 analogues of ace tyl-CoA, analogues which are not available by the previously described methodology. The hydroxamate and hydrazide analogues are potent inhib itors of the enzyme citrate synthase. The reversed thioester analogue of acetyl-CoA may have useful applications in enzymology and permits t he ready access to a range of additional CoA analogues modified in the thioester moiety.