From Proteopedia
(Difference between revisions)
proteopedia linkproteopedia link
|
|
| Line 1: |
Line 1: |
| - | [[Image:1e26.gif|left|200px]] | + | {{Seed}} |
| | + | [[Image:1e26.png|left|200px]] |
| | | | |
| | <!-- | | <!-- |
| Line 9: |
Line 10: |
| | {{STRUCTURE_1e26| PDB=1e26 | SCENE= }} | | {{STRUCTURE_1e26| PDB=1e26 | SCENE= }} |
| | | | |
| - | '''DESIGN, SYNTHESIS AND X-RAY CRYSTAL STRUCTURE OF A POTENT DUAL INHIBITOR OF THYMIDYLATE SYNTHASE AND DIHYDROFOLATE REDUCTASE AS AN ANTITUMOR AGENT.'''
| + | ===DESIGN, SYNTHESIS AND X-RAY CRYSTAL STRUCTURE OF A POTENT DUAL INHIBITOR OF THYMIDYLATE SYNTHASE AND DIHYDROFOLATE REDUCTASE AS AN ANTITUMOR AGENT.=== |
| | | | |
| | | | |
| - | ==Overview==
| + | <!-- |
| - | A novel N- inverted question mark2-amino-4-methyl[(pyrrolo[2, 3-d]pyrimidin-5-yl)ethyl]benzoyl inverted question mark-L-glutamic acid (3a) was designed and synthesized as a potent dual inhibitor of thymidylate synthase (TS) and dihydrofolate reductase (DHFR) and as an antitumor agent. Compound 3b, the N7-benzylated analogue of 3a, was also synthesized as an antitumor agent. The synthesis of 3a was accomplished via a 12-step sequence which involved the synthesis of 2-amino-4-methylpyrrolo[2,3-d]pyrimidine (10) in 5 steps from 2-acetylbutyrolactone. Protection of the 2-amino group of 10 and regioselective iodination at the 5-position followed by palladium-catalyzed coupling afforded intermediate 14 which was converted to 3a by reduction and saponification. Similar synthetic methodology was used for 3b. X-ray crystal structure of the ternary complex of 3a, DHFR, and NADPH showed that the pyrrolo[2, 3-d]pyrimidine ring binds in a "2,4-diamino mode" in which the pyrrole nitrogen mimics the 4-amino moiety of 2,4-diaminopyrimidines. This is the first example of a classical pyrrolo[2,3-d]pyrimidine antifolate shown to have this alternate mode of binding to DHFR. Compounds 3a and 3b were more inhibitory than LY231514 against TS from Lactobacillus casei and Escherichia coli. Analogue 3a was also more inhibitory against DHFR from human, Toxoplasma gondii, and Pneumocystis carinii. Evaluation of 3a against methotrexate (MTX)-resistant cell lines with defined mechanisms indicated that cross-resistance of 3a was much lower than that of MTX. Metabolite protection studies and folylpoly-gamma-glutamate synthetase studies suggest that the antitumor activity of 3a against the growth of tumor cells in culture is a result of dual inhibition of TS and DHFR. Compound 3a inhibited the growth of CCRF-CEM and FaDu cells in culture at ED(50) values of 12.5 and 7.0 nM, respectively, and was more active against FaDu cells than MTX. In contrast, compound 3b was inactive against both cell lines. Compound 3a was evaluated in the National Cancer Institute in vitro preclinical antitumor screening program and afforded IG(50) values in the nanomolar range against a number of tumor cell lines.
| + | The line below this paragraph, {{ABSTRACT_PUBMED_11052789}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 11052789 is the PubMed ID number. |
| | + | --> |
| | + | {{ABSTRACT_PUBMED_11052789}} |
| | | | |
| | ==About this Structure== | | ==About this Structure== |
| Line 32: |
Line 36: |
| | [[Category: Dihydrofolate reductase]] | | [[Category: Dihydrofolate reductase]] |
| | [[Category: Thymidylate synthase]] | | [[Category: Thymidylate synthase]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 14:33:56 2008'' | + | |
| | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 1 00:01:29 2008'' |
Revision as of 21:01, 30 June 2008
Template:STRUCTURE 1e26
DESIGN, SYNTHESIS AND X-RAY CRYSTAL STRUCTURE OF A POTENT DUAL INHIBITOR OF THYMIDYLATE SYNTHASE AND DIHYDROFOLATE REDUCTASE AS AN ANTITUMOR AGENT.
Template:ABSTRACT PUBMED 11052789
About this Structure
1E26 is a Single protein structure of sequence from Pneumocystis carinii. Full crystallographic information is available from OCA.
Reference
Design, synthesis, and X-ray crystal structure of a potent dual inhibitor of thymidylate synthase and dihydrofolate reductase as an antitumor agent., Gangjee A, Yu J, McGuire JJ, Cody V, Galitsky N, Kisliuk RL, Queener SF, J Med Chem. 2000 Oct 19;43(21):3837-51. PMID:11052789
Page seeded by OCA on Tue Jul 1 00:01:29 2008
