Design and synthesis of potent nonpeptidic farnesyltransferase inhibitors based on a terphenyl scaffold

被引:38
|
作者
Ohkanda, J
Lockman, JW
Kothare, MA
Qian, YM
Blaskovich, MA
Sebti, SM
Hamilton, AD
机构
[1] Yale Univ, Dept Chem, New Haven, CT 06520 USA
[2] Univ S Florida, Drug Discovery Program, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA
[3] Univ S Florida, Dept Oncol & Biochem, Tampa, FL 33612 USA
[4] Univ S Florida, Dept Mol Biol, Tampa, FL 33612 USA
关键词
D O I
10.1021/jm0103099
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
By modification of key carboxylate, hydrophobic, and zinc-binding groups projected from a sterically restricted terphenyl scaffold, a series of simple and nonpeptide mimetics of the Cys-Val-Ile-Met tetrapeptide substrate of protein farnesyltransferase (FTase) have been designed and synthesized. A crystal structure of 4-nitro-2-phenyl-3'-methoxycarbonylbiphenyl shows that the triphenyl fragment provides a large hydrophobic surface that potentially mimics the hydrophobic side chains of the three terminal residues in the tetrapeptide. 2-Phenyl-3-(N-(1-(4-eyanobenzyl)-1H-imidazol-5-yl)methyl)amino-3'carboxylbiphenyl, in which the free thiol group was replaced with a 1-(4-cyanobenzyl)imidazole group, shows submicromolar inhibition activity against FTase in vitro and inhibits H-Ras processing in whole cells.
引用
收藏
页码:177 / 188
页数:12
相关论文
共 50 条
  • [21] Synthesis and Molecular Docking Studies of Potent Urease Inhibitors Based on Benzoxazole Scaffold
    Ozil, Musa
    Tuzcuoglu, Ozge
    Baltas, Nimet
    Emirik, Mustafa
    CHEMISTRYSELECT, 2021, 6 (21): : 5307 - 5312
  • [22] Potent inhibitors of farnesyltransferase and geranylgeranyltransferase-I
    Nguyen, DN
    Stump, CA
    Walsh, ES
    Fernandes, C
    Davide, JP
    Ellis-Hutchings, M
    Robinson, RG
    Williams, TM
    Lobell, RB
    Huber, HE
    Buser, CA
    BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2002, 12 (09) : 1269 - 1273
  • [23] Potent, non-thiol inhibitors of farnesyltransferase
    Breslin, MJ
    deSolms, SJ
    Giuliani, EA
    Stokker, GE
    Graham, SL
    Pompliano, DL
    Mosser, SD
    Hamilton, KA
    Hutchinson, JH
    BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 1998, 8 (23) : 3311 - 3316
  • [24] Molecular design and synthesis of HCV inhibitors based on thiazolone scaffold
    Al-Ansary, Ghada H.
    Ismail, Mohamed A. H.
    Abou El Ella, Dalal A.
    Eid, Sameh
    Abouzid, Khaled A. M.
    EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2013, 68 : 19 - 32
  • [25] Rapid identification of potent nonpeptidic serine protease inhibitors
    Salisbury, Cleo M.
    Ellman, Jonathan A.
    CHEMBIOCHEM, 2006, 7 (07) : 1034 - 1037
  • [26] Potent selective nonpeptidic inhibitors of human lung tryptase
    Burgess, LE
    Newhouse, BJ
    Ibrahim, P
    Rizzi, J
    Kashem, MA
    Hartman, A
    Brandhuber, BJ
    Wright, CD
    Thomson, DS
    Vigers, GPA
    Koch, K
    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (15) : 8348 - 8352
  • [27] Design, synthesis, and structure-activity relationships of tetrahydroquinoline-based farnesyltransferase inhibitors
    Lombardo, LJ
    Camuso, A
    Clark, J
    Fager, K
    Gullo-Brown, J
    Hunt, JT
    Inigo, I
    Kan, D
    Koplowitz, B
    Lee, F
    McGlinchey, K
    Qian, LG
    Ricca, C
    Rovnyak, G
    Traeger, S
    Tokarski, J
    Williams, DK
    Wu, LI
    Zhao, YF
    Manne, V
    Bhide, RS
    BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2005, 15 (07) : 1895 - 1899
  • [28] Peptide scaffold-derived peptidomimetic farnesyltransferase inhibitors
    Yang, Wei
    Wang, Kuifeng
    Wu, Hongwei
    Shao, Hui
    Chen, Huazhong
    Zhu, Jiansheng
    JOURNAL OF THE CHINESE CHEMICAL SOCIETY, 2021, 68 (09) : 1778 - 1788
  • [29] Design and synthesis of piperidine farnesyltransferase inhibitors with reduced glucuronidation potential
    Tanaka, Rieko
    Rubio, Almudena
    Harn, Nancy K.
    Gernert, Douglas
    Grese, Timothy A.
    Eishima, Jun
    Hara, Mitsunobu
    Yoda, Nobuyuki
    Ohashi, Rui
    Kuwabara, Takashi
    Soga, Shiro
    Akinaga, Shiro
    Nara, Shinji
    Kanda, Yutaka
    BIOORGANIC & MEDICINAL CHEMISTRY, 2007, 15 (03) : 1363 - 1382
  • [30] Design and synthesis of tetracyclic nonpeptidic biaryl nitrile inhibitors of cathepsin K
    Setti, Eduardo L.
    Venkatraman, Shankar
    Palmer, James T.
    Xie, Xiaoming
    Cheung, Harry
    Yu, Walter
    Wesolowski, Gregg
    Robichaud, Joel
    BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2006, 16 (16) : 4296 - 4299