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

[1] ISOLATION AND PURIFICATION OF A HEMORRHAGIC FACTOR (WORTMANNIN) FROM FUSARIUM-OXYSPORUM (N17B) [J].

ABBAS, HK ;

MIROCHA, CJ .

APPLIED AND ENVIRONMENTAL MICROBIOLOGY, 1988, 54 (05) :1268-1274

[2]

ABRAHAM RJ, COMMUNICATION

[3] WORTMANNIN IS A POTENT PHOSPHATIDYLINOSITOL 3-KINASE INHIBITOR - THE ROLE OF PHOSPHATIDYLINOSITOL 3,4,5-TRISPHOSPHATE IN NEUTROPHIL RESPONSES [J].

ARCARO, A ;

WYMANN, MP .

BIOCHEMICAL JOURNAL, 1993, 296 :297-301

[4] PHOSPHATIDYLINOSITOL 3'-KINASE IS ACTIVATED BY ASSOCIATION WITH IRS-1 DURING INSULIN STIMULATION [J].

BACKER, JM ;

MYERS, MG ;

SHOELSON, SE ;

CHIN, DJ ;

SUN, XJ ;

MIRALPEIX, M ;

HU, P ;

MARGOLIS, B ;

SKOLNIK, EY ;

SCHLESSINGER, J ;

WHITE, MF .

EMBO JOURNAL, 1992, 11 (09) :3469-3479

[5]

BOYD MR, 1992, DEV ONCOL, V68, P11

[6] A PHOSPHATIDYLINOSITOL-3 KINASE BINDS TO PLATELET-DERIVED GROWTH-FACTOR RECEPTORS THROUGH A SPECIFIC RECEPTOR SEQUENCE CONTAINING PHOSPHOTYROSINE [J].

ESCOBEDO, JA ;

KAPLAN, DR ;

KAVANAUGH, WM ;

TURCK, CW ;

WILLIAMS, LT .

MOLECULAR AND CELLULAR BIOLOGY, 1991, 11 (02) :1125-1132

[7]

FUKUI Y, 1991, ONCOGENE, V6, P407

[8] SELECTIVE FUNCTIONALIZATION OF WORTMANNIN USING FURAN RING MASKING [J].

HAEFLIGER, W ;

KIS, Z ;

HAUSER, D .

HELVETICA CHIMICA ACTA, 1975, 58 (06) :1620-1628

[9]

NAKANISHI S, 1992, J BIOL CHEM, V267, P2157

[10]

POWIS G, 1994, CANCER RES, V54, P2419

← 1 2 →