Lactacystin P-lactone

Craiu, A., Gaczynska, M., Akopian, X, Gramm, C.E, Fenteany, G., Goldberg, A.L., and Rock, K.L. (1997) Lactacystin and clasto-lactacystin P-lactone modify multiple proteasome P-subunits and... 

The proteasome inhibitors salinosporamide A and omuralide are both y-lactam-p-lactone bicy-clic compounds (Fig. 13.5) derived from natural sources. Salinosporamide A, also known as marizomib, is obtained from Salinospora tropica, a bacterium found in ocean sediments. The drug is an irreversible proteasome inhibitor that shows little effect on the caspase-like activity but inhibits chymotrypsin- and trypsin-like protease activities. Preclinical studies have demonstrated antitumor activity in models for multiple myeloma, hematologic malignancies, and solid tumors and, importantly, marizomib does not show cross-resistance with other proteasome inhibitors. Omuralide (clasto-lactacystin p-lactone p-clastolactacystin) is the active metabolite of... 

An example of an additive effect of trialkylalumimun on the diastereoselectivity and efficiency in the particular aldol reaction was reported [30]. During the synthesis of cfasto-lactacystin P-lactone analog (34), Adams and coworkers found that treatment of the frthium enolate of oxazoline carboxylate (35) with 2.2-2.4 equivalent MeaAlCl, prior to the reaction with the aldehyde (36), afforded the desired aldol adduct (37) exclusively (Scheme 6.24). Although detail of the role of... 

A specific inhibitor of the major proteasomal activities is lactacystin, a compound formed by Streptomyces. Lactacystin is converted reversibly, by loss of N-acetyl-cysteine, into a P-lactone known as c/asto-lactacystin. The N-terminal amino group attacks the reactive four-membered ring of the lactone (Eq. 12-22)358/359... 

Strategies used in the synthesis of lactacystin, the P-lactone, and analogues... 

An early synthesis of lactacystin, not via the P-lactone, used glucose as starting material.20 Disconnection to 115 (the vinyl group can be converted into COzH and the benzyl ether into CHO) gives a structure that can be redrawn as 116 and then, with incorporation of an extra C atom (to be removed in the synthesis by diol oxidation) derived from 117. 

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