SYNTHESIS AND BIOLOGICAL-ACTIVITY OF A SQUALENOID MALEIMIDE AND OTHER CLASSES OF SQUALENE DERIVATIVES AS IRREVERSIBLE INHIBITORS OF 2,3-OXIDOSQUALENE CYCLASE

被引:11
作者
GROSA, G [1 ]
VIOLA, F [1 ]
CERUTI, M [1 ]
BRUSA, P [1 ]
DELPRINO, L [1 ]
DOSIO, F [1 ]
CATTEL, L [1 ]
机构
[1] UNIV TORINO,IST CHIM FARMACEUT APPLICATA,I-10125 TURIN,ITALY
关键词
2,3-OXIDOSQUALENE CYCLASE; SQUALENE MALEIMIDE; IRREVERSIBLE INHIBITOR;
D O I
10.1016/0223-5234(94)90121-X
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
New classes of squalene derivatives were rationally designed and synthesized as irreversible inhibitors of 2,3-oxido-squalene cyclase (OSC), a key enzyme in sterol biosynthesis. The derivatives synthesized were maleimide 5, disulfides 8-9, alpha,beta-unsaturated nitriles 10-11 and oxirane 12. The inhibitor activities of these derivatives were determined in vitro on OSC associated with pig liver microsomes. Squalene and dodecyl maleimide were the best inhibitors of OSC, showing a time-dependent enzyme from squalene maleimide inactivation whereas the dodecyl derivative did not. This fact and the complex kinetics shown by squalene maleimide suggest the presence of different classes of thiolic groups essential to the activity of OSC.
引用
收藏
页码:17 / 23
页数:7
相关论文
共 39 条
[11]   THE SQUALENE-2,3-EPOXIDE CYCLASE AS A MODEL FOR THE DEVELOPMENT OF NEW DRUGS [J].
CATTEL, L ;
CERUTI, M ;
VIOLA, F ;
DELPRINO, L ;
BALLIANO, G ;
DURIATTI, A ;
BOUVIERNAVE, P .
LIPIDS, 1986, 21 (01) :31-38
[12]  
CATTEL L, 1992, REGULATION ISOPENTEN, P174
[13]  
CATTEL L, 1992, PHYSL BIOCH STEROLS, P50
[14]   STEREOSPECIFIC SYNTHESIS OF SQUALENOID EPOXIDE VINYL ETHERS AS INHIBITORS OF 2,3-OXIDOSQUALENE CYCLASE [J].
CERUTI, M ;
VIOLA, F ;
DOSIO, F ;
CATTEL, L ;
BOUVIERNAVE, P ;
UGLIENGO, P .
JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 1, 1988, (03) :461-469
[15]   2,3-EPOXY-10-AZA-10,11-DIHYDROSQUALENE, A HIGH-ENERGY INTERMEDIATE ANALOG INHIBITOR OF 2,3-OXIDOSQUALENE CYCLASE [J].
CERUTI, M ;
BALLIANO, G ;
VIOLA, F ;
GROSA, G ;
ROCCO, F ;
CATTEL, L .
JOURNAL OF MEDICINAL CHEMISTRY, 1992, 35 (16) :3050-3058
[16]   SYNTHESIS AND BIOLOGICAL-ACTIVITY OF AZASQUALENES, BIS-AZASQUALENES AND DERIVATIVES [J].
CERUTI, M ;
BALLIANO, G ;
VIOLA, F ;
CATTEL, L ;
GERST, N ;
SCHUBER, F .
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 1987, 22 (03) :199-208
[17]   PURIFICATION OF THE 2,3-OXIDOSQUALENE-LANOSTEROL CYCLASE FROM SACCHAROMYCES-CEREVISIAE [J].
COREY, EJ ;
MATSUDA, SPT .
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1991, 113 (21) :8172-8174
[18]   THE METHYL-GROUP AT C(10) OF 2,3-OXIDOSQUALENE IS CRUCIAL TO THE CORRECT FOLDING OF THIS SUBSTRATE IN THE CYCLIZATION REARRANGEMENT STEP OF STEROL BIOSYNTHESIS [J].
COREY, EJ ;
VIRGIL, SC ;
LIU, DR ;
SARSHAR, S .
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1992, 114 (04) :1524-1525
[19]  
DEAN PDG, 1967, J BIOL CHEM, V242, P3014
[20]   PARTIAL-PURIFICATION OF 2,3-OXIDOSQUALENE-LANOSTEROL CYCLASE FROM HOG-LIVER - EVIDENCE FOR A FUNCTIONAL THIOL RESIDUE [J].
DURIATTI, A ;
SCHUBER, F .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1988, 151 (03) :1378-1385