Tetsuo Murano

Facile synthesis of aryl(difluoromethyl)phosphonates through CuBr-mediated cross coupling reactions of [(diethoxyphosphinyl)difluoromethyl]zinc bromide with aryl iodides

Abstract The CuBr-promoted coupling reaction of [(diethoxyphosphinyl)difluoromethyl]zinc bromide 6 with aryl iodides in either DMF or DMA was examined to give a series of aryl(difluoromethyl)phosphonates. The coupling reaction was applicable to the selective synthesis of α,α-difluoro-4- iodobenzylphosphonale 11e, a useful intermediate for the preparation of F2Pmp. 1-[(Diethylphosphono)difluoromethyl] naphthalene 15 and the regioisomer 16 were obtained in high yields from 1- and 2-iodonaphthalene, respectively. The phosphonate 16 was transformed to the free acid 4a, a low molecular-mass inhibitor of protein phosphatases.

Synthesis of non-competitive inhibitors of sphingomyelinases with significant activity.

A series of short-chain analogues of N-palmitoylsphingosine-1-phosphate, modified by replacement of the phosphate and the long alkenyl side chain with hydrolytically stable difluoromethylene phosphonate and phenyl, respectively, were prepared to study the structure-activity relationship for inhibition of sphingomyelinase. The study revealed that inhibition is highly dependent upon the stereochemistry of the asymmetric centers of the acylamino moiety, and resulted in identification of a non-competitive inhibitor with the same level of inhibitory activity of schyphostatin, the most potent of the few known small molecular inhibitors of sphingomyelinase.

Inhibition of sphingomyelinase activity helps to prevent neuron death caused by ischemic stress

Magnesium-dependent neutral sphingomyelinase (N-SMase) present in plasma membranes is an enzyme that can be activated by stress in the form of inflammatory cytokines, serum deprivation, and hypoxia. The design of small molecule N-SMase inhibitors may offer new therapies for the treatment of inflammation, ischemic injury, and cerebral infarction. Recently, we synthesized a series of difluoromethylene analogues (SMAs) of sphingomyelin. We report here the effects of SMAs on the serum/glucose deprivation-induced death of neuronally differentiated pheochromocytoma (PC-12) cells and on cerebral infarction in mice. SMAs inhibited the enhanced N-SMase activity in the serum/glucose-deprived PC-12 cells, and thereby suppressed the apoptotic sequence: ceramide formation, c-Jun N-terminal kinase phosphorylation, caspase-3 activation, and DNA fragmentation in the nuclei. Administration of SMA-7 (10 mg/kg i.v.) with IC50= 3.3 microM to mice whose middle cerebral arteries were occluded reduced significantly the size of the cerebral infarcts, compared to the control mice. These results suggest that N-SMase is a key component of the signaling pathways in cytokine- and other stress-induced cellular responses, and that inhibiting or stopping N-SMase activity is an important strategy to prevent neuron death from ischemia.

Enzymatic desymmetrization of prochiral 2-benzyl-1,3-propanediol derivatives: A practical chemoenzymatic synthesis of novel phosphorylated tyrosine analogues

Abstract (Phosphonomethyl)phenylalanine (Pmp) and (phosphonodifluoromethyl)phenylalanine (F2Pmp) as well as their β-amino acid congeners were prepared as a protecting variant amenable to the peptide synthesis from readily available 2-benzyl-1,3-propandiols possessing either a diethylphosphonomethyl- or diethylphosphonodifluoromethyl functionality at the para-position via the lipase-catalyzed desymmetrization.

Synthesis and biological evaluation of α,α-difluorobenzylphosphonic acid derivatives as small molecular inhibitors of protein-tyrosine phosphatase 1B

A series of α,α-difluorobenzylphosphonic acids having a hydrophobic functional group were prepared via the Stille coupling reaction from halogenated α,α-difluorobenzylphosphonates. Evaluation of inhibitory activity toward protein tyrosine phosphatase (PTP 1B) revealed that the ethynyl, phenylethynyl and (E)-styryl groups on the benzene nuclei increased the inhibitory activity of α,α-difluorobenzylphosphonic acid. Inhibitory activities significantly increased upon introducing both (E)-styryl and bis-methylsulfonamide functional groups onto the benzene nuclei of α,α-difluorobenzylphosphonic acid.