Synthesis and in vitro evaluation of new wortmannin esters: Potent inhibitors of phosphatidylinositol 3-kinase

被引：29

作者：

Creemer, LC ^{[1
]}

Kirst, HA ^{[1
]}

Vlahos, CJ ^{[1
]}

Schultz, RM ^{[1
]}

机构：

[1] LILLY CORP CTR, LILLY RES LABS, INDIANAPOLIS, IN 46285 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 1996年 / 39卷 / 25期

关键词：

D O I：

10.1021/jm960283z

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

New C-11 esters of the fermentation product wortmannin have been synthesized, with some of them further derivatized at C-17. The new esters show greater inhibition of isolated phosphatidylinositol 3-kinase and increased cell cytotoxicity in a rapidly proliferating leukemia cell line, when compared to wortmannin. Reduction of the C-17 ketone caused a slight increase in activity, while acylation of this new alcohol caused severe loss of activity. With their increased activity, the new C-11 esters may be good candidates to explore the in vivo antitumor effects of phosphatidylinositol 3-kinase inhibitors.

引用

页码：5021 / 5024

页数：4

共 18 条

[11]

SCHULTZ RM, 1995, ANTICANCER RES, V15, P1135

[12]

SERUNIAN LA, 1989, J BIOL CHEM, V264, P17809

[13] AGONIST-STIMULATED SYNTHESIS OF PHOSPHATIDYLINOSITOL(3,4,5)-TRISPHOSPHATE - A NEW INTRACELLULAR SIGNALING SYSTEM [J].

STEPHENS, LR ;

JACKSON, TR ;

HAWKINS, PT .

BIOCHIMICA ET BIOPHYSICA ACTA, 1993, 1179 (01) :27-75

[14] THE COLONY STIMULATING FACTOR-I RECEPTOR ASSOCIATES WITH AND ACTIVATES PHOSPHATIDYLINOSITOL-3 KINASE [J].

VARTICOVSKI, L ;

DRUKER, B ;

MORRISON, D ;

CANTLEY, L ;

ROBERTS, T .

NATURE, 1989, 342 (6250) :699-702

[15]

VLAHOS CJ, 1994, J BIOL CHEM, V269, P5241

[16] SIGNAL TRANSDUCTION IN NEUTROPHIL ACTIVATION - PHOSPHATIDYLINOSITOL 3-KINASE IS STIMULATED WITHOUT TYROSINE PHOSPHORYLATION [J].

VLAHOS, CJ ;

MATTER, WF .

FEBS LETTERS, 1992, 309 (03) :242-248

[17] ASSOCIATION OF PHOSPHATIDYLINOSITOL KINASE-ACTIVITY WITH POLYOMA MIDDLE-T COMPETENT FOR TRANSFORMATION [J].

WHITMAN, M ;

KAPLAN, DR ;

SCHAFFHAUSEN, B ;

CANTLEY, L ;

ROBERTS, TM .

NATURE, 1985, 315 (6016) :239-242

[18]

YANO H, 1993, J BIOL CHEM, V268, P25846

← 1 2 →