Synthesis and evaluation of novel phosphate ester analogs as neutral sphingomyelinase inhibitors

Novel inhibitor of bacterial sphingomyelinase, SMY-540, developed based on three-dimensional structure analysis

“…Of these, one compound, SMY-540 was an especially effective inhibitor. In fact, SMY-540 was a more effective than RY221B-a and is comparable to the most potent SMase inhibitors that have been described 34 . The in silico docking analysis supports the observation that SMY-540 is a more effective inhibitor than RY221B-a.…”

“…The in silico docking analysis supports the observation that SMY-540 is a more effective inhibitor than RY221B-a. We previously reported that the docking energy of RY221B-a was À117 kCal/mol 34 . Here, we measured the docking energy of SMY-540 at À240 kCal/mol, suggesting a more stable bond between this SMY-540 and Bc-SMase.…”

“…Garner P, Park J, Malecki E. A stereodivergent synthesis of D-erythro-sphingosine and D-threo-sphingosine from L-serine. We slightly improved our previously reported method 34 for the synthesis of RY-221-Ba [1, below]. The synthesis began with the known sphingosine derivative 13 39,40 which was prepared from Garner's aldehyde 41 in two steps.…”

“…Several synthetic inhibitors, such as a carbamate analog, carbon-analog or fluorinated carbon-analog, that mimic the phosphate ester moiety of phosphocholine by substituting it with stable functional groups have also been developed [29][30][31][32][33][34] . We previously developed an inhibitor (RY221B-a) that is based on the crystal structure of Bc-SMase 6,34 . In this study, we investigated the inhibitory effect of various synthetic RY221B-a analogues on Bc-SMase-induced hydrolysis of SM.…”

Estudo dos mecanismos moleculares envolvidos na ação tóxica das esfingomielinases D do veneno de aranhas <i>Loxosceles</i> e de sua modulação pelo uso de inibidores.

“…Em todos os ensaios, a SMase D se mostrou mais eficiente que o veneno de L. laeta. Inibidores de SMases ácidas, alcalinas ou neutras foram analisados em diversos estudos e uma grande variação nos valores de IC 50 tem sido descrita (ARENZ, 2010;IMAGAWA et al, 2010;LEE et al, 2011;OKUIDARA et al, 2000;PITSINOS et al, 2003;UCHIDA et al, 1999;WELZENBACH;HOMMEL;WEITZ-SCHMIDT, 2002). Okuidara et al 2000, em um estudo de screening de produtos naturais em busca de inibidores da SMase ácida, identificaram três compostos provenientes da casca de Garcinia speciosa, com valores de IC 50 de 14,1, 19,2 e 10,9 µM.…”