Potent dual thymidylate synthase and dihydrofolate reductase inhibitors: classical and nonclassical 2-amino-4-oxo-5-arylthio-substituted-6-methylthieno[2,3-d]pyrimidine antifolates.
N-{4-[(2-Amino-6-methyl-4-oxo-3,4-dihydrothieno[2,3- d]pyrimidin-5-yl)sulfanyl]benzoyl}-L-glutamic acid (4) and nine nonclassical analogues 5-13 were synthesized as potential dual thymidylate synthase (TS) and dihydrofolate reductase (DHFR) inhibitors. The key intermediate in the synthesis was 2-amino-6-methylthieno[2,3-d]pyrimidin-4(3 H)-one (16), which was converted to the 5-bromo-substituted compound 17 followed by an Ullmann reaction to afford 5-13. The classical analogue 4 was synthesized by coupling the benzoic acid derivative 19 with diethyl L-glutamate and saponification. Compound 4 is the most potent dual inhibitor of human TS (IC 50 = 40 nM) and human DHFR (IC 50 = 20 nM) known to date. The nonclassical analogues 5- 13 were moderately potent against human TS with IC 50 values ranging from 0.11 to 4.6 microM. The 4-nitrophenyl analogue 7 was the most potent compound in the nonclassical series, demonstrating potent dual inhibitory activities against human TS and DHFR. This study indicated that the 5-substituted 2-amino-4-oxo-6-methylthieno[2,3-d]pyrimidine scaffold is highly conducive to dual human TS-DHFR inhibitory activity.
Gangjee
Aleem
A
Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, Pennsylvania 15282, USA. gangjee@duq.edu
Qiu
Yibin
Y
Li
Wei
W
Kisliuk
Roy L
RL
D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005493:Folic Acid Antagonists / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D013762:Tetrahydrofolate Dehydrogenase / Q000187:drug effects*; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D005493:Folic Acid Antagonists; D011743:Pyrimidines; D013762:Tetrahydrofolate Dehydrogenase; D013940:Thymidylate Synthase
J Med Chem. 1992 Nov 13;35(23):4450-4
1447744
Acta Crystallogr D Biol Crystallogr. 1997 Nov 1;53(Pt 6):638-49
15299851
J Med Chem. 1977 Nov;20(11):1531-3
410932
Cancer Res. 1991 Oct 15;51(20):5579-86
1913676
J Biol Chem. 1999 Apr 9;274(15):10388-94
10187828
Biochem Pharmacol. 1991 Oct 24;42(10):1885-95
1741766
Biochemistry. 1990 Oct 9;29(40):9467-79
2248959
Anticancer Agents Med Chem. 2008 Feb;8(2):205-31
18288923
J Med Chem. 1993 Oct 15;36(21):3103-12
8230096
J Med Chem. 1993 Mar 19;36(6):733-46
8459400
Ann Intern Med. 1984 May;100(5):663-71
6231873
Biochem Pharmacol. 1993 Feb 24;45(4):863-9
7680860
J Infect Dis. 1990 May;161(5):858-64
2182728
J Med Chem. 1996 Nov 8;39(23):4563-8
8917644
Drugs. 1997 Jan;53(1):40-73
9010648
J Biol Chem. 1962 Dec;237:3794-801
13998281
Anticancer Agents Med Chem. 2007 Sep;7(5):524-42
17896913
J Med Chem. 1995 Oct 27;38(22):4495-502
7473577
J Med Chem. 2004 Dec 30;47(27):6730-9
15615522
J Med Chem. 1973 Mar;16(3):185-8
4632693
J Med Chem. 1991 Feb;34(2):479-85
1995868
Biochemistry. 1997 Jan 21;36(3):586-603
9012674
Biochem Pharmacol. 2006 Mar 30;71(7):941-8
16359642
Semin Oncol. 1999 Apr;26(2 Suppl 6):42-7
10598554
J Biol Chem. 1980 Jun 25;255(12):5776-88
6892914
Biochem Pharmacol. 1988 Nov 1;37(21):4047-54
2461200
Curr Med Chem. 2006;13(4):377-98
16475929
Prog Med Chem. 1989;26:1-252
2690183
Cancer Res. 1997 Mar 15;57(6):1116-23
9067281
Curr Pharm Des. 2007;13(6):609-39
17346178
J Biol Chem. 1991 Apr 5;266(10):6181-7
2007575
J Med Chem. 1973 Mar;16(3):191-4
4632695
J Med Chem. 2008 Jan 10;51(1):68-76
18072727
J Med Chem. 2000 Oct 19;43(21):3837-51
11052789
Cancer Surv. 1986;5(1):47-79
3297313