Structural Basis for the Binding of the Anticancer Compound 6-(7-Nitro-2,1,3-Benzoxadiazol-4-Ylthio)Hexanol to Human Glutathione S-Transferases

Abstract

Glutathione S-transferases

Synthesis and structure–activity relationship of new cytotoxic agents targeting human glutathione-S-transferases

“…Based on the crystal structures of either GSTP1-1 or GSTM2-2 bound to 1 [20], first we designed and synthesized 23 new NBD analogs (2e24) in which the 6-hydroxyhexyl chain of 1 was replaced by a variously substituted phenyl ring, to confer conformational rigidity to the new molecules and to potentially establish p-stacking interactions within the active site of GSTP1-1. The presence of the phenyl ring at the C4-sulfur atom resulted in good affinity of the new molecules towards GSTP1-1.…”

“…All bonds in the ligands were treated as free to rotate. The GSTP1-1 structure was built starting from the PDB file 3GUS, removing water and the co-crystallized 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX, 1) inhibitor [20]. A large grid volume (18.5 Â 18.5 Â 26.25 Å), centered in the GSTP1-1 active site, has been chosen to allow the ligands to freely rotate, even when they are in their most fully extended conformations.…”

“…Chemical reliability of the best docking results have been obtained examining the interactions between the active site and the best docked conformations. When compared with the 1 location in the crystal [20] far residing poses were excluded and, between the remaining, the lowest energy pose has been considered as representative. This protocol was then similarly applied to all synthesized compounds.…”

“…Based on the crystal structure of 1 bound to either GSTP1-1 or GSTM2-2 [20], a number of 1 analogs (2e40) have been designed and synthesized, bearing at the C4-sulfur atom variously substituted aryl moieties (compounds 2e24), or branched or linear alkyl chains, further substituted with hydroxy, amine, ester, amide, carbamate, and/or ketone functions (25e36) (Fig. 2).…”

Ways for Overcoming Drug Resistance in Cancer: Designing New Drugs: Invited Commentary

“…29,30 Di ğer yan dan bu bi le şi ğin iki farklı me la no ma hüc re di zi sin de (Me501 ve A375) apop ito zu in dük le di ği, in vi vo ola rak da efek tif ol du ğu ve me lano ma mo del le rin de tü mör bü yü me sin de %70 azal ma ya yol aç tı ğı da ra por edil miş tir. 29,31 GSH kon ju gat la rı içe ri sin de en iyi bi li nen ve kanser te da vi sin de en çok kul la nı lan bi le şik ler den biri olan dok so ru bi sin (GSH-DXR), GSTP1-1'in non kom pe ti tif in hi bi tö rü dür. Ard ar da ya pı lan ça-lış ma lar GSH-DXR'nin GSTP1-1'e bağ lan ma sı nın sa de ce en zi ma tik ak ti vi te yi bas kı la ma dı ğı, ay nı zaman da JNK ak ti vas yo nun da da ar tı şa ne den ol du ğu gös te ril miş tir.…”