Serine-threonine phosphatase inhibitors

The serine/threonine phosphatase inhibitor okadaic acid (incubation time and concentration vary from 10 nM, 30 minutes to 1 pM, 1 hour at 37°C) leads to selective stimulation of caveolae uptake (18,64). 

The utility of the phenacyl group is exemplified in the C-terminal deprotection [Scheme 6.70] taken from Schmidt s synthesis of the immunosuppressive and antiviral cyclodepsipeptide Didemnin.113 Here, the phenacyl ester was reduc-tively cleaved with zinc in acetic acid. A similar transformation was used in a synthesis of the potent protein serine/threonine phosphatase inhibitor Motupor-in.lM Zinc-copper couple is an attractive alternative that can be used on a large scale [Scheme 6.71 ]J70... 

Introduction of a phosphate monoester and removal of its protecting groups was a serious impediment in a synthesis of the serine-threonine phosphatase inhibitor Calyculin A by Evans and co-workers [Scheme 7,22].38 The four phosphate protecting groups evaluated were 2-cyanoethyl and 2-(trimethylsi]y])ethyl (see below), benzyl and p-methoxybenzyl. Of these, the p-methoxybenzyl phosphate ester offered the best compromise between base stability (it survived a Wittig reaction in the presence of a metal amide base) and acid lability required for the final deprotection step in which three secondary terf-butyldimethylsiiyl... 

Recently, Lazo and co-workers reported a combinatorial library of PTPIB inhibitors based on a pharmacophore derived from the structure-activity relationships for several natural product inhibitors of PSTPases such as oka-daic acid, microcystins and calyculin A [425, 426], The pharmacophore model involved a carboxylate, a non polar aromatic group and hydrogen-bond acceptors and donors and was used as a platform for functional group variation. Among the 18 library compounds generated by parallel solid-phase chemistry, a non-competitive inhibitor for PTPIB was identified (library 41, Kj=0.85 jiM) [425] and as well a serine/threonine phosphatase inhibitor (library 42, IC50 < 100 /iM) [426],... 

Motuporin and other members of serine/threonine phosphatase inhibitors such as calyculins, microcystins, nodularins have attracted considerable synthetic interest in the last years. Schreiber s group reported the first total synthesis of motuporin in 1995 [154], whereas very recently three alternative approaches appeared in the literature [155]. 

The calyculins make up a family of potent, selective serine-threonine phosphatase inhibitors, which have been isolated from the Japanese sponge Discodermia calyx.There are at least 13 different members of this family, and the most abundant are calyculin A 1189a and calyculin C 1189c." As nanomolar inhibitors of protein phosphatases 1 and 2A (PPl and PP2A), 1189a and analogs have... 

Honkakoski P, Negishi M (1998) Protein serine/ threonine phosphatase inhibitors suppress phenobar-bital-induced Cyp2bl0 gene transeription in mouse primary hepatoeytes. Bioehem J 330 889-895... 

Lera and coworkers successfully employed this thallium(i) hydroxide-aecelerated Suzuki reaction in the stereocontrolled polyene syntheses of retinol (vitamin A) and derivatives and polyenic alarm pheromones of cephalaspidean molluscs navenone A and haminol Despite some initial examples where thallium(i) ethoxide failed as an alternative for thallium(i) hydroxide there are an appreciable number of cases where thallium(i) ethoxide furnished great results. The first successful use of thallium(i) ethoxide was reported by Chamberlin and coworkers in the total synthesis of microcystin LA, a serine-threonine phosphatase inhibitor (Scheme 20.17). A few years after the synthesis of mieroeystin L, Roush and coworkers extended the use of thallium(i) ethoxide in Suzuki couplings for a range of boronic acids and halides. Simultaneously, Danishefslq and Chemler ... 

Humphrey, J.M., Aggen, J.B., and Chamberlin. A.R. (1996) Total synthesis of the serine-threonine phosphatase inhibitor microcystin-LA./. Am. Chem. Soc., 118,11759-11770. 

Fostriecin (20, CI-920) is a novel metabolite of Streptomyces pulveraceus that was first isolated in 1983 by a research group at Warner Lambert-Parke Davis.22 It displays antitumor activity against a broad range of cancerous cell lines in vitro. This activity is suggested to be intimately related to the potent and highly selective inhibitory activity against serine/threonine phosphatase PP2A.23 In fact, fostriecin is the most selective protein phosphatase inhibitor reported to date, and it... 

In the case of a substrate bearing a second hydroxyl group, the aHenylidene can undergo nucleophilic attack at the y-carbon to re-form a vinylidene [15]. In such an event, the newly formed vinylidene can then undergo the reconstitutive condensation shown in Equation 1.14 [16]. This reaction provides access to the spiroketal of calyculin A, a nanomolar inhibitor of serine/threonine phosphatases. 

Inhibitors of serine/threonine phosphatases, such as okadaic acid or microcystin, can be used to investigate the effects of serine/threonine phosphorylation on kinase targeting. Tyrosine phosphatase inhibitors can be used to investigate the effect of tyrosine phosphorylation on kinase targeting in a specific cell type. For example, orthovanadate has been shown to induce translocation of the immunoreactivity of phospholipase C gamma from the cytosolic to the membrane fraction of mast cells (Atkinson et al, 1993). Conversely, in permeabilized preparations, the phosphatases themselves, if known, can be added to inhibit the putative pathway. 

Studies on the nonmembrane-spanning type 1 tyrosine phosphatase revealed no significant inhibition of the enzyme by OA class compounds at concentrations up to 0.01 mM. In previous reports, OA was also shown to be inactive as inhibitor of any protein tyrosine phosphatase, confirming its selectivity for serine/threonine phosphatases. ... 

In one of the very few examples using natural products as a template for enzyme inhibitor discovery, Wipf and co-workers described a library of putative protein serine/threonine phosphatase (PSTPase) inhibitors [44]. There are a number of natural prod-... 

Figure 2. Structural basis for a natural product derived library of protein serine/threonine phosphatase (PSTPase) inhibitors [44].

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