Lactacystin 3-lactam

The structurally-related 7-lactams salinosporamide A 1, omuralide 2 and lactacystin 3, of bacterial origin, inhibit proteasome activity, and so are of interest as lead compounds for the development of anticancer agents. Barbara . M. Potts of Nereus Pharmaceuticals in San Diego has reported (J. Med. Chem. 2005,48,3684) a detailed structure-activity studies in this series, and E.J. Corey of Harvard University has prepared (J. Am. Chem. Soc. 2005,127, 8974, 15386) several interesting structural analogues. Susumi Hatakeyama of Nagasaki University, building on previous work in this area, has reported (J. Org. Chem. 2004, 69,7765) a synthesis of 2 and 3 from Tris. 

The potently cytotoxic proteasome inhibitor salinosporamide A (26, NPI-0052) was isolated from a new genus of marine bacteria called Salinispora The bicyclic (/3-lactam-7-lactam) core structure of salinosporamide A is also found in the activated form of lactacystin known as r/iMto-lactacystin /3-lactone (24, omuralide). While structurally similar to omuralide, salinosporamide A (26) is pharmacologically and mechanistically distinct/ Unlike omuralide, chloride displacement from the chlorinated side chain in salinosporamide A... 

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... 

The enantioselective Miehael addition of a,p-unsaturated p-silyl imides to aminocyanoacetate derivatives was also deseribed by the Jaeobsen group. ° With (S,S)-[(salen)Al]20 ent-4 as the eatalyst, the reaetion of (AT-p-methox-ybenzylamino) eyanoaeetate to allyldimethylsilyl imide proceeded well, affording the y-lactam in 87% yield, 9 1 dr, and 98% enantiomeric excess. Notably, with lactam in hand, the total synthesis of (+)-lactacystin could be accomplished in 12 additional steps (Seheme 19.24). 

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