Lactacystin 3-lactone

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... 

Bond insertion. A gainful application of the intramolecular Rh-carbenoid insertion into a C—H bond is described in a synthesis of ctoto-lactacystin 3-lactone. ... 

Lactacystin and derivatives Lactacystin, / -Lactone Cathepsin A, TPPII... 

There are several examples of metabolites where the tetramic acid domain is teasingly disguised. In these cases, it is difficult to be definitive about the nature of the apparent modification unless this is substantiated by biosynthetic studies. The case of lactacystin (5), Fig. (2), has already been considered. Another example is presented by the oxazolomycin group of antibiotics, e.g. (Ill), found in strains of Streptomyces [179]. Biosynthetic studies indicate that the carboxylic acid of the amino acid required to form tetramic acids contributes to the formation of the 3-lactone [180]. In this section, metabolites that probably have a tetramic acid origin are presented. 

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... 

Hydroxyalkanoic acids are easily dehydrated to either spiro or fused /3-lactones. Sulfonyl chlorides have been the traditional reagents employed for this transformation <1996S586, 2001CC753>. However, as illustrated in Equation (38) for a cyclization used as part of a synthesis of lactacystin/omuralide (see also Section 2.06.12.4), bis(oxazolidi-none) phosphinyl chloride (BOP-C1) has proven an effective agent for application in sensitive structures note also the selectivity for introduction of the fused (vs. spiro) lactone <2006JOC1220>. 

The first identified member of this latter family was omuralide, the (3-lactone product of the Streptomyces-derived secondary metabolite lactacystin.32 34 Although omuralide was never developed by the pharmaceutical industry, it continues to be used as an important biochemical tool. Moreover, it served as a model for the synthetic analogue PS-519 (Figure 12.1), which was evaluated in Phase I clinical trials based on preclinical data that indicated a protective effect in models of cerebral ischaemia.35... 

Craiu, a., Gaczynska, M., Akopian, T, Gramm, C. F., Fenteany, G., Goldberg, A.L., Rock, K. L., Lactacystm and dasto-lactacystin beta-lactone modify multiple proteasome beta-subunits and inhibit intracellular protein degradation and major histocompatibility complex class 1 antigen presentation. J. Biol. Chem. 1997,... 

Corey EJ, Li WD, Nagamitsu T, Fenteany G. The structural requirements for inhibition of proteasome function by the lactacystin-derived f -lactone and synthetic analogs. Tetrahedron 1999 55 3305-3316. 

A tetrahydropyran that inhibits leukotriene biosynthesis Asymmetric synthesis of2-methyl-tetrahydropyran-4-one by kinetic resolution Part VI - Asymmetric Desymmetrisation of a Diels-Alder Adduct Ifetroban sodium a thromboxane receptor antagonist A laboratory synthesis starting with a Diels-Alder reaction Desymmetrisation of a symmetrical anhydride with a chiral Grignard reagent Laboratory and process routes compared Part VII - Asymmetric Synthesis of A Bicyclic 3-Lactone Lactacystin a naturalproteasome inhibitor... 

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. 

Omuralide, dasto-lactacystin S-lactone, the biologically active acylating species of lactacystin. 

Salinosporamide A, NPI 0052, a microbial product of Salinispora tropica strain CNB-392 that acts as a potent protea-some inhibitor. Salinosporamide A is structurally related to omuralide, the -lactone derived from lactacystin, and is more effective as a proteasome inhibitor than omuralide. Furthermore, it exhibits cytotoxicity against many tumor cell lines, especially against Velcade resistant multiple myeloma cells [V. Caubert, N. Langlois, Tetrahedron Lett. 2007, 48, 381]. 

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... 

Soucy F, Grenier L, Behnke ML, Destree AT, McCormack TA, Adams J, Plamondon L. A novel and efficient synthesis of a highly active analogue of clasto-lactacystin beta-lactone. J. Am. Chem. Soc. 1999 121 9967 9976. 

---