Synthesis and biological evaluation of 1,1-difluoro-2-(tetrahydro-3-furanyl)ethylphosphonic acids possessing a N9-purinylmethyl functional group at the ring.: A new class of inhibitors for purine nucleoside phosphorylases

被引：35
作者：
Yokomatsu, T
Hayakawa, Y
Suemune, K
Kihara, T
Soeda, S
Shimeno, H
Shibuya, S
机构：
[1] Tokyo Univ Pharm & Life Sci, Sch Pharm, Tokyo 1920392, Japan
[2] Fukuoka Univ, Fac Pharmaceut Sci, Jonan Ku, Fukuoka 8140180, Japan
来源：
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 1999年 / 9卷 / 19期
关键词：
enzyme inhibitors; phosphonic acids and derivatives; isosteres; mimetics; nucleotides;
D O I：
10.1016/S0960-894X(99)00495-3
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
1,1-Difluaro-2-(tetrahydro-3-furanyl)ethylphosphonic acids cis-3 and trans-3 possessing a N9-purinylmethyl functionality at the ring were synthesized and tested as "multi-substrate analogue" inhibitors for purine nucleoside phosphorylases. Radical cyclization of allyic alpha,alpha-difluorophosphonate (E)-7 was applied to construct the alpha,alpha-difluorophosphonate-functionalized tetrahydrofuranyl moiety. The IC50 values of cis-3 and trans-3 for human erythrocyte PNP-catalyzed phosphorylation of inosine were determined to be 88 and 320 nM, respectively. The stereochemistry of the inhibitors was found to affect significantly the inhibitory potency. (C) 1999 Elsevier Science Ltd. All rights reserved.
引用
收藏
页码：2833 / 2836
页数：4
相关论文
共 18 条
  • [1] Crystallization and preliminary X-ray studies of purine nucleoside phosphorylase from Cellulomonas sp.
    Bzowska, A
    Tebbe, J
    Luic, M
    Wielgus-Kutrowska, B
    Schroder, W
    Shugar, D
    Saenger, W
    Koellner, G
    [J]. ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY, 1998, 54 : 1061 - 1063
  • [2] APPLICATION OF CRYSTALLOGRAPHIC AND MODELING METHODS IN THE DESIGN OF PURINE NUCLEOSIDE PHOSPHORYLASE INHIBITORS
    EALICK, SE
    BABU, YS
    BUGG, CE
    ERION, MD
    GUIDA, WC
    MONTGOMERY, JA
    SECRIST, JA
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1991, 88 (24) : 11540 - 11544
  • [3] 9-(DIFLUOROPHOSPHONOALKYL)GUANINES AS A NEW CLASS OF MULTISUBSTRATE ANALOG INHIBITORS OF PURINE NUCLEOSIDE PHOSPHORYLASE
    HALAZY, S
    EHRHARD, A
    DANZIN, C
    [J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1991, 113 (01) : 315 - 317
  • [4] Fluorophosphonate derivatives of N-9-benzylguanine as potent, slow-binding multisubstrate analogue inhibitors of purine nucleoside phosphorylase
    Halazy, S
    Ehrhard, A
    Eggenspiller, A
    BergesGross, V
    Danzin, C
    [J]. TETRAHEDRON, 1996, 52 (01) : 177 - 184
  • [5] 9-[(PHOSPHONOALKYL)BENZYL]GUANINES - MULTISUBSTRATE ANALOG INHIBITORS OF HUMAN ERYTHROCYTE PURINE NUCLEOSIDE PHOSPHORYLASE
    KELLEY, JL
    LINN, JA
    MCLEAN, EW
    TUTTLE, JV
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 1993, 36 (22) : 3455 - 3463
  • [6] Montgomery J. A., 1994, EXPERT OPIN INV DRUG, V3, P1303
  • [7] PARKS RE, 1972, ENZYMES, V7, P483
  • [8] STOECKLER JD, 1986, FASEB J, V45, P2773
  • [9] STOECKLER JD, 1984, DEV CANC CHEMOTHERAP, P35
  • [10] Tebbe J, 1997, PROTEIN ENG, V10, P90
12