(S,R)-3-PHENYL-4,5 DIHYDRO-5-ISOXAZOLE ACETIC ACID

专利名称：(S,R)-3-PHENYL-4,5 DIHYDRO-5-ISOXAZOLE

ACETIC ACID-NITRIC OXIDE AND USETHEREOF AS ANTI-CANCER AND ANTIVIRALAGENT

发明人：NICOLETTI, Ferninando,AL-ABED,

Yousef,GAROTTA, Gianni

申请号：EP08749348.2申请日：20080506公开号：EP2144904B1公开日：20110309

摘要：The present invention relates to an isoxazole derivative, the compound offormula (I) herein after referred to as GIT27-NO, which is the NO-donating structurallymodified form of (S,R)-3-phenyl-4,5-dihydro-5-isoxasole acetic acid, herein after referredto as VGX-1027. Treatment of three tumor cell lines, rat astrocytoma C6, mousefibrosarcoma L929, and mouse melanoma B16 cells with GIT27-NO resulted in a

significant reduction of cell respiration and of number of viable cells, while VGX-1027 wascompletely ineffective. Hemoglobin, which act as NO-scavenger, restored cell viability,thus indicating the NO-mediated tumoricidal effect of compound (I). GIT27-NO triggeredapoptotic cell death in L929 cell cultures, while autophagic cell death is mainly

responsible for the diminished viability of C6 and B16 cells. Moreover, GIT27-NO inducedthe production of reactive oxygen species which can be neutralized by antioxidant N-acetyl cysteine (NAC), indicating that reactive oxygen species (ROS) are at least partlyinvolved in the reduction of cell viability. The anti-tumor activity of GIT27-NO is mediated

through activation of MAP kinases (ERK1/2, p38 and JNK) in cell-specific manner. The roleof MAP kinases was further confirmed by specific inhibitors of these molecules, PD98059,SB202190, and SP600125. Finally, in vivo treatment with GIT27-NO significantly reducedtumor growth in syngeneic C57BL/6 mice implanted with B16 melanoma.

申请人：GANIAL IMMUNOTHERAPEUTICS INC

地址：US

国籍：US

代理机构：Minoja, Fabrizio

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