Synthesis of chiral amino cyclic phosphoric acids
Chiral amino cyclic phosphoric acids, 5-amino-2-hydroxy-4-(4-nitrophenyl)-1,3,2-dioxaphosphorinane 2-oxide and 2-hydroxy-4-(4-methylsulfonylphenyl)-5-phthalimido-1,3,2-dioxaphos phorinane 2-oxide are synthesized in good over yields (64.2% and 72.8% respectively) from 2-amino-1-aryl-1,3-propanediols. The different reaction conditions are necessary in hydrolysis reactions of amino cyclic phosphonyl chlorides.
Phenyl phosphorodichloridate in the synthesis of cyclic phosphate diesters of biological interest
The general usefulness of phenyl phosphorodichloridate (PPDC) in the synthesis of non-nucleoside cyclic phosphates is described. The method is illustrated with several examples including cyclic phosphates incorporating six to nine members. However, the reagent could not be used for the preparation of five-membered cyclic phosphates or 3′,5′-cycloadenylic acid (cAMP) from adenosine. Based on a number of observations, the conclusion was reached that PPDC cannot be used for the synthesis of strained or reactive cyclic phosphates. A convenient synthesis of cis- and trans-2-hydroxycyclopentanemethanol and a simple, quantitative method of separation of the two isomers is described. A number of cyclic phosphates were tested as substrates and inhibitors for cyclic purine phosphodiesterase and protein kinase.
Sphingolipid metabolism and cell growth regulation
Sphingolipide have been implicated in the regulation of cell growth, differentiation, and programmed cell death. The current paradigm for their action is that complex sphingolipids such as gangliosides interact with growth factor receptors, the extracellular matrix, and neighboring cells, whereas the backbones—sphingosine and other long‐chain or “sphingoid” bases, ceramides, and sphingosine l‐phosphate—activate or inhibit protein kinases and phosphatases, ion transporters, and other regulatory machinery. Tumor necrosis factor‐α, inter‐leukin lβ, and nerve growth factor, for example, induce sphingomyelin hydrolysis to ceramide. Other agonists, such as platelet‐derived growth factor, trigger further hydrolysis of ceramide to sphingosine and activate sphingosine kinase to form sphingosine l‐phosphate. These metabolites either stimulate or inhibit growth and may be cytotoxic (in some cases via induction of apoptosis), depending on which products are formed (or added exogenously), the cellular levels (and possibly intracellular localization), and the cell type. In Swiss 3T3 cells, for example, sphingosine and sphingosine l‐phosphate are growth stimulatory at low concentrations via calcium mobilization from intracellular stores and activation of the mitogen‐activated protein kinase (MAP kinase) pathway and transcription factors (AP‐1), but are toxic at high concentrations. High levels of endogenous sphingoid bases are also produced by inhibition of ceramide synthase by fumonisins, my‐cotoxins produced by Fusarium moniliforme, resulting in growth stimulation or toxicity. Thus, sphingolipid metabolites appear to serve as second messengers for growth factors, cytokines, and other “physiological” agonists and, when elevated abnormally, to lead to disease.—Spiegel, S., Merrill, A. H., Jr. Sphingolipid metabolism and cell growth regulation. FASEB J. 10, 1388‐1397 (1996)