Synthesis and protein kinase C inhibitory activities of balanol analogs with replacement of the perhydroazepine moiety

被引：42

作者：

Lai, YS

Mendoza, JS

Jagdmann, GE

Menaldino, DS

Biggers, CK

Heerding, JM

Wilson, JW

Hall, SE

Jiang, JB

Janzen, WP

Ballas, LM

机构：

[1] Sphinx Pharmaceuticals, A Division of Eli Lilly and Company, Durham, NC 27707

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 1997年 / 40卷 / 02期

关键词：

D O I：

10.1021/jm960497g

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Balanol is a potent protein kinase C (PKC) inhibitor that is structurally composed of a benzophenone diacid, a 4-hydroxybenzamide, and a perhydroazepine ring. A number of balanol analogs in which the perhydroazepine moiety is replaced have been synthesized and their biological activities evaluated against both PKC and cAMP-dependent kinase (PKA). The results suggested that the activity and the isozyme/kinase selectivity of these compounds are largely related to the conformation about this nonaromatic structural element of the molecules.

引用

页码：226 / 235

页数：10

共 29 条

[1] TOTAL SYNTHESIS OF BALANOL - A POTENT PROTEIN-KINASE-C INHIBITOR OF FUNGAL ORIGIN [J].

ADAMS, CP ;

FAIRWAY, SM ;

HARDY, CJ ;

HIBBS, DE ;

HURSTHOUSE, MB ;

MORLEY, AD ;

SHARP, BW ;

VICKER, N ;

WARNER, I .

JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 1, 1995, (18) :2355-2362

[2] SEQUENCE AND EXPRESSION OF HUMAN PROTEIN KINASE-C-EPSILON [J].

BASTA, P ;

STRICKLAND, MB ;

HOLMES, W ;

LOOMIS, CR ;

BALLAS, LM ;

BURNS, DJ .

BIOCHIMICA ET BIOPHYSICA ACTA, 1992, 1132 (02) :154-160

[3] THERAPEUTIC POTENTIAL OF PROTEIN-KINASE-C INHIBITORS [J].

BRADSHAW, D ;

HILL, CH ;

NIXON, JS ;

WILKINSON, SE .

AGENTS AND ACTIONS, 1993, 38 (1-2) :135-147

[4] VIRTUAL KINETICS - USING STATISTICAL EXPERIMENTAL-DESIGN FOR RAPID ANALYSIS OF ENZYME-INHIBITOR MECHANISMS [J].

BRONSON, DD ;

DANIELS, DM ;

DIXON, JT ;

REDICK, CC ;

HAALAND, PD .

BIOCHEMICAL PHARMACOLOGY, 1995, 50 (06) :823-831

[5]

CASTAGNA M, 1982, J BIOL CHEM, V257, P7847

[6] Synthesis and protein kinase C inhibitory activities of acyclic balanol analogs that are highly selective for protein kinase C over protein kinase A [J].

Defauw, JM ;

Murphy, MM ;

Jagdmann, GE ;

Hu, H ;

Lampe, JW ;

Hollinshead, SP ;

Mitchell, TJ ;

Crane, HM ;

Heerding, JM ;

Mendoza, JS ;

Davis, JE ;

Darges, JW ;

Hubbard, FR ;

Hall, SE .

JOURNAL OF MEDICINAL CHEMISTRY, 1996, 39 (26) :5215-5227

[7]

DOW RL, 1994, CURR MED CHEM, V1, P192

[8]

HANNUN YA, 1986, J BIOL CHEM, V261, P2604

[9] 2 PRACTICAL SYNTHESES OF STERICALLY CONGESTED BENZOPHENONES [J].

HOLLINSHEAD, SP ;

NICHOLS, JB ;

WILSON, JW .

JOURNAL OF ORGANIC CHEMISTRY, 1994, 59 (22) :6703-6709

[10] 2 EFFICIENT SYNTHESES OF (+/-)-ANTI-N-BENZYL-3-AMINO-4-HYDROXYHEXAHYDROAZEPINE [J].

HU, H ;

JAGDMANN, GE ;

HUGHES, PF ;

NICHOLS, JB .

TETRAHEDRON LETTERS, 1995, 36 (21) :3659-3662

← 1 2 3 →