General solid-phase method for the preparation of mechanism-based cysteine protease inhibitors

被引:68
作者
Lee, A [1 ]
Huang, L [1 ]
Ellman, JA [1 ]
机构
[1] Univ Calif Berkeley, Dept Chem, Berkeley, CA 94720 USA
关键词
D O I
10.1021/ja992009a
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
The first general method has been developed for the expedient solid-phase synthesis of ketone-based cysteine protease inhibitors. The synthesis approach was designed to allow the introduction of diverse functionality at all variable sites about the ketone carbonyl using readily available precursors. The chloromethyl ketone scaffold 7 is attached to the solid support through the newly developed hydrazine linker 6. Successful nucleophilic displacement of the support-bound a-chloro hydrazones 8 with carboxylates, thiolates, and amines provides entry to the acyloxymethyl, mercaptomethyl, and amidomethyl ketone classes of cysteine protease inhibitors. Further transformations followed by cleavage from support provides the fully substituted ketone products in 40-100% overall yields after release from support. Significantly, racemization of the alpha-stereocenter does not occur during loading onto support, nucleophilic displacement, or cleavage from support.
引用
收藏
页码:9907 / 9914
页数:8
相关论文
共 28 条
  • [1] Cyclopropenone-containing cysteine proteinase inhibitors. Synthesis and enzyme inhibitory activities
    Ando, R
    Sakaki, T
    Morinaka, Y
    Takahashi, C
    Tamao, Y
    Yoshii, N
    Katayama, S
    Saito, K
    Tokuyama, H
    Isaka, M
    Nakamura, E
    [J]. BIOORGANIC & MEDICINAL CHEMISTRY, 1999, 7 (04) : 571 - 579
  • [2] [Anonymous], 1972, Inorg. Synth, DOI DOI 10.1002/9780470132449.CH23
  • [3] Attanasi OA, 1997, SYNLETT, P1128
  • [4] SYNTHESIS OF A CYCLIC ANALOG OF OXIDIZED GLUTATHIONE BY AN INTERSITE REACTION IN A SWOLLEN POLYMER NETWORK
    BHARGAVA, KK
    SARIN, VK
    TRANG, NL
    CERAMI, A
    MERRIFIELD, RB
    [J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1983, 105 (10) : 3247 - 3251
  • [5] Proteolytic activity of human osteoclast cathepsin K - Expression, purification, activation, and substrate identification
    Bossard, MJ
    Tomaszek, TA
    Thompson, SK
    Amegadzie, BY
    Hanning, CR
    Jones, C
    Kurdyla, JT
    McNulty, DE
    Drake, FH
    Gowen, M
    Levy, MA
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (21) : 12517 - 12524
  • [6] P-1 ASPARTATE-BASED PEPTIDE ALPHA-((2,6-DICHLOROBENZOYL)OXY)METHYL KETONES AS POTENT TIME-DEPENDENT INHIBITORS OF INTERLEUKIN-1-BETA-CONVERTING ENZYME
    DOLLE, RE
    HOYER, D
    PRASAD, CVC
    SCHMIDT, SJ
    HELASZEK, CT
    MILLER, RE
    ATOR, MA
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 1994, 37 (05) : 563 - 564
  • [7] alpha-((tetronoyl)oxy)- and alpha-((tetramoyl)oxy)methyl ketone inhibitors of the interleukin-1 beta converting enzyme (ICE)
    Graybill, TL
    Prouty, CP
    Speier, GJ
    Hoyer, D
    Dolle, RE
    Helaszek, CT
    Ator, MA
    Uhl, J
    Strasters, J
    [J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 1997, 7 (01) : 41 - 46
  • [8] Allylic protecting groups and their use in a complex environment -: Part II:: Allylic protecting groups and their removal through catalytic palladium π-allyl methodology
    Guibé, F
    [J]. TETRAHEDRON, 1998, 54 (13) : 2967 - 3042
  • [9] Structure-based design and combinatorial chemistry yield low nanomolar inhibitors of cathepsin D
    Kick, EK
    Roe, DC
    Skillman, AG
    Liu, GC
    Ewing, TJA
    Sun, YX
    Kuntz, ID
    Ellman, JA
    [J]. CHEMISTRY & BIOLOGY, 1997, 4 (04): : 297 - 307
  • [10] PEPTIDYL (ACYLOXY)METHYL KETONES AND THE QUIESCENT AFFINITY LABEL CONCEPT - THE DEPARTING GROUP AS A VARIABLE STRUCTURAL ELEMENT IN THE DESIGN OF INACTIVATORS OF CYSTEINE PROTEINASES
    KRANTZ, A
    COPP, LJ
    COLES, PJ
    SMITH, RA
    HEARD, SB
    [J]. BIOCHEMISTRY, 1991, 30 (19) : 4678 - 4687