1boz

From Proteopedia

(Difference between revisions)

Current revision

STRUCTURE-BASED DESIGN AND SYNTHESIS OF LIPOPHILIC 2,4-DIAMINO-6-SUBSTITUTED QUINAZOLINES AND THEIR EVALUATION AS INHIBITORS OF DIHYDROFOLATE REDUCTASE AND POTENTIAL ANTITUMOR AGENTS

Structural highlights

1boz is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.1Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

DYR_HUMAN Defects in DHFR are the cause of megaloblastic anemia due to dihydrofolate reductase deficiency (DHFRD) [MIM:613839. DHFRD is an inborn error of metabolism, characterized by megaloblastic anemia and/or pancytopenia, severe cerebral folate deficiency, and cerebral tetrahydrobiopterin deficiency. Clinical features include variable neurologic symptoms, ranging from severe developmental delay and generalized seizures in infancy, to childhood absence epilepsy with learning difficulties, to lack of symptoms.^[1] ^[2]

Function

DYR_HUMAN Key enzyme in folate metabolism. Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis. Binds its own mRNA and that of DHFRL1.^[3] ^[4]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

The synthesis and biological activities of 14 6-substituted 2,4-diaminoquinazolines are reported. These compounds were designed to improve the cell penetration of a previously reported series of 2,4-diamino-6-substituted-pyrido[2,3-d]pyrimidines which had shown significant potency and remarkable selectivity for Toxoplasma gondii dihydrofolate reductase (DHFR), but had much lower inhibitory effects on the growth of T. gondii cells in culture. The target N9-H analogues were obtained via regiospecific reductive amination of the appropriate benzaldehydes with 2,4,6-triaminoquinazoline, which, in turn, was synthesized from 2,4-diamino-6-nitroquinazoline. The N9-CH3 analogues were synthesized via a regiospecific reductive methylation of the corresponding N9-H precursors. The compounds were evaluated as inhibitors of DHFR from human, Pneumocystis carinii, T. gondii, rat liver, Lactobacillus casei, and Escherichia coli, and selected analogues were evaluated as inhibitors of the growth of tumor cells in culture. These analogues displayed potent T. gondii DHFR inhibition as well as inhibition of the growth of T. gondii cells in culture. Further, selected analogues were potent inhibitors of the growth of tumor cells in culture in the in vitro screening program of the National Cancer Institute with GI50s in the nanomolar and subnanomolar range. Crystallographic data for the ternary complex of hDHFR-NADPH and 2,4-diamino-6-[N-(2', 5'-dimethoxybenzyl)-N-methylamino]pyrido[2,3-d]pyrimidine, 1c, reveal the first structural details for a reversed N9-C10 folate bridge geometry as well as the first conformational details of a hybrid piritrexim-trimetrexate analogue.

Structure-based design and synthesis of lipophilic 2,4-diamino-6-substituted quinazolines and their evaluation as inhibitors of dihydrofolate reductases and potential antitumor agents.,Gangjee A, Vidwans AP, Vasudevan A, Queener SF, Kisliuk RL, Cody V, Li R, Galitsky N, Luft JR, Pangborn W J Med Chem. 1998 Aug 27;41(18):3426-34. PMID:9719595^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Banka S, Blom HJ, Walter J, Aziz M, Urquhart J, Clouthier CM, Rice GI, de Brouwer AP, Hilton E, Vassallo G, Will A, Smith DE, Smulders YM, Wevers RA, Steinfeld R, Heales S, Crow YJ, Pelletier JN, Jones S, Newman WG. Identification and characterization of an inborn error of metabolism caused by dihydrofolate reductase deficiency. Am J Hum Genet. 2011 Feb 11;88(2):216-25. doi: 10.1016/j.ajhg.2011.01.004. PMID:21310276 doi:10.1016/j.ajhg.2011.01.004
↑ Cario H, Smith DE, Blom H, Blau N, Bode H, Holzmann K, Pannicke U, Hopfner KP, Rump EM, Ayric Z, Kohne E, Debatin KM, Smulders Y, Schwarz K. Dihydrofolate reductase deficiency due to a homozygous DHFR mutation causes megaloblastic anemia and cerebral folate deficiency leading to severe neurologic disease. Am J Hum Genet. 2011 Feb 11;88(2):226-31. doi: 10.1016/j.ajhg.2011.01.007. PMID:21310277 doi:10.1016/j.ajhg.2011.01.007
↑ Anderson DD, Quintero CM, Stover PJ. Identification of a de novo thymidylate biosynthesis pathway in mammalian mitochondria. Proc Natl Acad Sci U S A. 2011 Sep 13;108(37):15163-8. doi:, 10.1073/pnas.1103623108. Epub 2011 Aug 26. PMID:21876188 doi:10.1073/pnas.1103623108
↑ Klon AE, Heroux A, Ross LJ, Pathak V, Johnson CA, Piper JR, Borhani DW. Atomic structures of human dihydrofolate reductase complexed with NADPH and two lipophilic antifolates at 1.09 a and 1.05 a resolution. J Mol Biol. 2002 Jul 12;320(3):677-93. PMID:12096917
↑ Gangjee A, Vidwans AP, Vasudevan A, Queener SF, Kisliuk RL, Cody V, Li R, Galitsky N, Luft JR, Pangborn W. Structure-based design and synthesis of lipophilic 2,4-diamino-6-substituted quinazolines and their evaluation as inhibitors of dihydrofolate reductases and potential antitumor agents. J Med Chem. 1998 Aug 27;41(18):3426-34. PMID:9719595 doi:10.1021/jm980081y

1 Structural highlights
2 Disease
3 Function
4 Evolutionary Conservation
5 Publication Abstract from PubMed
6 See Also
7 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/1boz"

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[1boz]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1BOZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1BOZ FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=PRD:N6-(2,5-DIMETHOXY-BENZYL)-N6-METHYL-PYRIDO[2,3-D]PYRIMIDINE-2,4,6-TRIAMINE'>PRD</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.1&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=PRD:N6-(2,5-DIMETHOXY-BENZYL)-N6-METHYL-PYRIDO[2,3-D]PYRIMIDINE-2,4,6-TRIAMINE'>PRD</scene></td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1boz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1boz OCA], [https://pdbe.org/1boz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1boz RCSB], [https://www.ebi.ac.uk/pdbsum/1boz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1boz ProSAT]</span></td></tr>
 </table>

1boz

From Proteopedia

Current revision

STRUCTURE-BASED DESIGN AND SYNTHESIS OF LIPOPHILIC 2,4-DIAMINO-6-SUBSTITUTED QUINAZOLINES AND THEIR EVALUATION AS INHIBITORS OF DIHYDROFOLATE REDUCTASE AND POTENTIAL ANTITUMOR AGENTS

Structural highlights

Disease

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox