Inhibitors of inositol monophosphatase

Dihydroxytropolone derivatives have emerged as the foremost representatives of a new class of potent, competitive inhibitors of inositol monophosphatase. The first successful preparations of mono- and disubstituted 3,7-dihydroxytropolones were accomplished by single or double Suzuki coupling reactions between these permethylated monobromo- and... 

Piettre SR, Ganzhorn A, Hoflack J, Islam K, Hornsperger J-M. a-Hydroxytropoloes a new class of potent inhibitors of inositol monophosphatase and other bimetallic enxymes. J. Am. Chem. Soc. 1997 119 3201-3204. 

The 3,5,6-trideoxy derivative of myo-inositol-1-monophosphate, viz. (IS)-phosphonyloxy-(2fi/4S)- dihydroxycyclohexane (32), has been synthesized from 4-hydroxycyclohexene and shown to be the most potent inhibitor of inositol monophosphatase yet identified. 

A racemic synthesis of the cyclopentane phosphate derivatives 66 and 67 as potential inhibitors and substrates of inositol monophosphatase has been described. The products were compared with the furanose ring equivalent. ... 

In recent years, research on the molecular mechanisms underlying lithium s therapeutic effects has focused on intracellular second messenger generating systems and, in particular, receptor-coupled hydrolysis of phosphoinositide 4,5-biphosphate (PIP2) (Baraban et al. 1989). Lithium, at therapeutically relevant concentrations in the brain, is a potent inhibitor of the intracellular enzyme, inositol monophosphatase [Kj = 0.8 mM), which plays a major role in... 

Mood disorders characterized by elevations of mood above normal as well as depressions below normal are classically treated with lithium, an ion whose mechanism of action is not certain. Candidates for its mechanism of action are sites beyond the receptor in the second messenger system, perhaps either as an inhibitor of an enzyme, called inositol monophosphatase, involved in the phosphatidyl inositol system as a modulator of G proteins, or even as a regulator of gene expression by modulating protein kinase C (Fig. 7—22). 

The phosphate derivatives (301)-(303) of 6-0-(2-hydroxyethyl)cyclohexane-l,2,4,6-tetraol have been synthesized as inositol monophosphatase inhibitors, the putative target for lithium therapy.270 Compounds (303) and (302) are the most potent examples of a primary alkyl phosphate and phosphate monanion inhibitor so far reported. 

Ins(l,4,5)P3. A number of phosphates, e.g. (37), which act as inositol monophosphatase inhibitors have been synthesised from the l,6-epoxy-4-benzyloxycyc-lohexan-2-ol (36)7" Conduritol derivatives (39) are useful synthetic building blocks. However, the enantioselective palladium-catalysed allyl alkylation and similar reactions of (38) are complex due to C2 symmetry. It has now been reported that dynamic kinetic asymmetric transformation (DYKAT) of racemic... 

Inositol monophosphatase catalyses the hydrolysis of a range of phosphate esters of inositol, and in so doing, participates in brain cell chemistry and is believed to be the target for lithium therapy. In the search for inhibitors of the enzyme, phosphate derivatives from 6-0-(2 -hydroxyethyl)cyclohexane-l,2,4,6-tetraol have been prepared, the racemic epoxide (26) acting as a key intermediate. The conversion of (26) into the racemic 1-phosphate (29) via (27) and (28) employed the steps indicated in Scheme 1. Further, the racemic alcohol (27) was... 

The steroidal a-(isocyanomethyl)phosphonates (130) and (133) have been synthesized by methylation of the carbanions (129) and (132), respectively.66 Compounds (130) and (133) behave as N,P-ketals in that they can be hydrolysed to the corresponding ketones (131) and (134) (Scheme 10). A range of a-substituted a-aminophosphonic acids (136) have been prepared in moderate to excellent yield by the alkylation of the protected a-aminophosphonate (135) with alkyl and aryl halides and Michael acceptors under phase transfer catalysis (Scheme 11).67 The reactions of the lithium carbanion of diethyl prop-2-enyIphosphonate (137) with a,P-unsaturated ketones and esters have been investigated.6S Attack can be at the a- or y-positions in the phosphonate although in all cases Michael addition to the a, p-unsaturated carbonyl is preferred to attack at carbonyl carbon. In some examples simple adducts (138) are formed, but in more complex cases addition is followed by cyclisation to give (139) (Scheme 12). The bisphosphonate (141), which is a potent inhibitor of myo-inositol monophosphatase, has been prepared with the phosphonylation of the carbanion of (140) as a key step.6 9... 

Screening for inhibitors of human brain mvo-inositol monophosphatase... 

The methylene bisphosphonic acid derivatives (101) were also prepared and found to be potent inhibitors of /nyo-inositol monophosphatase. ... 

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