Abstract
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 CysVal-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-cyanobenzyl)-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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 177-188 |
| Number of pages | 12 |
| Journal | Journal of Medicinal Chemistry |
| Volume | 45 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 3 2002 |
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ASJC Scopus subject areas
- Organic Chemistry
Cite this
Design and synthesis of potent nonpeptidic farnesyltransferase inhibitors based on a terphenyl scaffold. / Ohkanda, J.; Lockman, J. W.; Kothare, M. A.; Qian, Y.; Blaskovich, M. A.; Sebti, S. M.; Hamilton, Andrew.
In: Journal of Medicinal Chemistry, Vol. 45, No. 1, 03.01.2002, p. 177-188.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Design and synthesis of potent nonpeptidic farnesyltransferase inhibitors based on a terphenyl scaffold
AU - Ohkanda, J.
AU - Lockman, J. W.
AU - Kothare, M. A.
AU - Qian, Y.
AU - Blaskovich, M. A.
AU - Sebti, S. M.
AU - Hamilton, Andrew
PY - 2002/1/3
Y1 - 2002/1/3
N2 - 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 CysVal-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-cyanobenzyl)-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.
AB - 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 CysVal-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-cyanobenzyl)-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.
UR - http://www.scopus.com/inward/record.url?scp=0037011910&partnerID=8YFLogxK
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U2 - 10.1021/jm0103099
DO - 10.1021/jm0103099
M3 - Article
VL - 45
SP - 177
EP - 188
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 1
ER -