SYNTHESIS AND CHARACTERIZATION OF AZA ANALOG INHIBITORS OF SQUALENE AND GERANYLGERANYL DIPHOSPHATE SYNTHASES

被引:54
作者
STEIGER, A [1 ]
PYUN, HJ [1 ]
COATES, RM [1 ]
机构
[1] UNIV ILLINOIS, DEPT CHEM, 1209 W CALIF ST, URBANA, IL 61801 USA
关键词
D O I
10.1021/jo00038a038
中图分类号
O62 [有机化学];
学科分类号
070303 ; 081704 ;
摘要
One-carbon homologation of geranyl and farnesyl chlorides to secondary N-methylamines (12 and 17) via alpha-lithioformamidine alkylations followed by N-alkylation with bromoacetate esters afforded alpha-(homogeranylamino)-and alpha-(homofarnesylamino)acetates 13 and 18. After alpha-farnesylation of 13, hydride reductions gave branched and straight-chain tertiary beta-amino alcohols 15 and 19. The diphosphate derivatives (7 and 8) of 15 and 19 prepared by SN2 displacements may be regarded as "aza analogs" of plausible carbocation intermediates (5 and 6) in the biosynthesis of squalene and geranylgeranyl diphosphate since, in preliminary collaborative evaluations, they inhibit the respective synthase enzymes at micromolar concentrations.
引用
收藏
页码:3444 / 3449
页数:6
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共 52 条
  • [1] INDUCED BIOSYNTHESIS OF 7-DEHYDROCHOLESTEROLS IN YEAST - POTENTIAL SOURCES OF NEW PROVITAMIN D-3 ANALOGS
    AVRUCH, L
    FISCHER, S
    PIERCE, H
    OEHLSCHLAGER, AC
    [J]. CANADIAN JOURNAL OF BIOCHEMISTRY, 1976, 54 (07): : 657 - 665
  • [2] BENEDICT CR, 1983, BIOSYNTHESIS ISOPREN, V2, pCH6
  • [3] THE 1ST POTENT INHIBITOR OF SQUALENE SYNTHASE - A PROFOUND CONTRIBUTION OF AN ETHER OXYGEN TO INHIBITOR ENZYME INTERACTION
    BILLER, SA
    SOFIA, MJ
    DELANGE, B
    FORSTER, C
    GORDON, EM
    HARRITY, T
    RICH, LC
    CIOSEK, CP
    [J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1991, 113 (22) : 8522 - 8524
  • [4] SYNTHESIS OF AMMONIUM ANALOGS OF CARBOCATIONIC INTERMEDIATES IN THE CONVERSION OF PRESQUALENE DIPHOSPHATE TO SQUALENE
    CAPSON, TL
    THOMPSON, MD
    DIXIT, VM
    GAUGHAN, RG
    POULTER, CD
    [J]. JOURNAL OF ORGANIC CHEMISTRY, 1988, 53 (25) : 5903 - 5908
  • [5] COREY EJ, 1972, TETRAHEDRON LETT, P4339
  • [6] CRAMER F, 1962, LIEBIGS ANN CHEM, V654, P180
  • [7] DIE HYDROLYSE VON PHOSPHATEN UND PYROPHOSPHATEN EINIGER MONOTERPENALKOHOLE - MODELLREAKTIONEN ZUR BIOSYNTHESE DER MONOTERPENE
    CRAMER, F
    RITTERSDORF, W
    [J]. TETRAHEDRON, 1967, 23 (07) : 3015 - +
  • [8] A FACILE SYNTHESIS OF METHANESULFONATE ESTERS
    CROSSLAN.RK
    SERVIS, KL
    [J]. JOURNAL OF ORGANIC CHEMISTRY, 1970, 35 (09) : 3195 - &
  • [9] NEGATIVE-ION FAST ATOM BOMBARDMENT MASS-SPECTROMETRY OF ISOPRENOID DIPHOSPHATES AND RELATED ANALOGS
    DAVISSON, VJ
    SHARP, TR
    POULTER, CD
    [J]. BIOORGANIC CHEMISTRY, 1988, 16 (02) : 111 - 123
  • [10] DAVISSON VJ, 1985, METHOD ENZYMOL, V110, P130