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Synthesis and biological activity of phosphonate analogues and geometric isomers of the highly potent phosphoantigen (E)-1-hydroxy-2-methylbut-2-enyl 4-diphosphate


, : Synthesis and biological activity of phosphonate analogues and geometric isomers of the highly potent phosphoantigen (E)-1-hydroxy-2-methylbut-2-enyl 4-diphosphate. Journal of Medicinal Chemistry 51(6): 1747-1754

Gammadelta-T-lymphocytes contribute to innate immunity and are selectively activated by nonpeptide phosphorylated molecules (so-called phosphoantigens) produced by organisms responsible for causing a broad range of infectious diseases. gammadelta-T-cells are also activated by synthetic phosphoantigens and are cytotoxic to tumor cells. Here we report the synthesis, NMR characterization, and comparative biological evaluation of new pyrophosphate, phosphonate, and pyrophosphonate monoesters whose structures correspond to isosteric analogues and stereoisomers of the highly potent isoprenoid metabolite ( E)-1-hydroxy-2-methylbut-2-enyl 4-diphosphate called HDMAPP (hydroxy-dimethyl-allyl pyrophosphate). Both pyrophosphate and pyrophosphonate series elicit promising gammadelta-T-cell stimulatory responses in vitro, the pyrophosphonate ester (C-HDMAPP) being by far more stable than its parent pyrophosphate ester (HDMAPP) with improved ADMET properties and a similar pharmacodynamic profile based on in vivo studies in nonhuman primate. In both series, we found that E-stereoisomers are the most active derivatives and that Z-stereoisomers show very marginal bioactivity levels. These results indicate that the use of bioisosteric analogues of HDMAPP may represent promising new leads for immunotherapy.

US$19.90

PMID: 18303828

DOI: 10.1021/jm701101g


Other references

Asanuma, N.; Iwamoto, M.; Hino, T., 1999: Structure and transcriptional regulation of the gene encoding pyruvate formate-lyase of a ruminal bacterium, Streptococcus bovis. The gene (pfl) encoding pyruvate formate-lyase (Pfl) from Streptococcus bovis was sequenced. The deduced amino acid sequence of Pfl was similar to Streptococcus mutans Pfl, and included the conserved regions necessary for free-radical formation an...

Shama, A.M., 1978: Thumb and finger sucking habit. Majallat Tibb Al-Famm Al-Suriyah 14(1-2): 17-30

Lee, J.K.; Gordon, P.R.; Stall, G.M.; Gilchrest, B.A.; Kaplan, M.M., 1989: Phenolic and tyrosyl ring iodothyronine deiodination by the Caco-2 human colon carcinoma cell line. Thyroid hormone metabolism was studied in the human Caco-2 colon carcinoma cell line, which at confluence exhibits several functions of differentiated enterocytes. Cells were harvested two to 17 days after reaching confluence. Intact cells and hom...

Rettig, A.C.; Waugh, T.R.; Evanski, P.M., 1979: Fracture of the olecranon: a problem of management. Journal of Trauma 19(1): 23-28

Anonymous, 1968: Indice general de la revista de geofisica de los anos 1953 al 1968 (general index of the revista de geofisica for the years 1953 to 1968). Revista de Geofisica (Madrid) 27: 107-108

Hauser D.; Glassgold J.; Romano D.; Klejman J.; Levandowsky M.; Hutner S.H., 1975: Chemo reception of a dinoflagellate and its inhibition by colchicine. Abstracts of the Annual Meeting of the American Society for Microbiology 75: 142

Mikuni, I.; Fujiwara, T., 1982: Early reversible changes of hydroxyurea cataract in vitro. An electron microscopic study. Nippon Ganka Gakkai Zasshi 86(9): 1308-1312

Ferdinandusse, S.; Meissner, T.; Wanders, R.J.A.; Mayatepek, E., 2002: Identification of the peroxisomal beta-oxidation enzymes involved in the degradation of leukotrienes. Leukotrienes (LTs) are metabolically inactivated via omega-oxidation and subsequent beta-oxidation from the omega-end. This beta-oxidation process takes place in peroxisomes. In this study we investigated the role of different enzymes involved in...

Dizon, D.S.; Weitzen, S.; Rojan, A.; Schwartz, J.; Miller, J.; Disilvestro, P.; Gordinier, M.E.; Moore, R.; Tejada-Berges, T.; Pires, L.; Legare, R.; Granai, C.O., 2005: Two for good measure: six versus eight cycles of carboplatin and paclitaxel as adjuvant treatment for epithelial ovarian cancer. Introduction. Although the standard of care for advanced epithelial ovarian cancer (EOC) is six cycles (6C) of platinum-taxane (PT), there have been no studies on the optimal duration of treatment in the era of adjuvant taxanes. At our center, som...

Perenyi, L., 1960: On the mechanism of action of a macromolecular enzyme model. Enzymologia 22: 208-217