1,2-Bis(1-aryl-3-alkyltriazen-3-yl)ethanes and related compounds

Hooper, D. L.; Pottie, Ian R.; Vacheresse, Marc; Vaughan, Keith

doi:10.1139/cjc-76-1-125

Cited by 3 publications

(4 citation statements)

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“…We envisaged that the generous proportions of the active site of the pcDHFR enzyme could allow suitable ligands to bind in multiple conformations. The lead compound TAB displays several interesting structural features: the N(1)N(2) double bond in triazenes, like that in azo-compounds, is fixed in the trans geometrical configuration; there is restricted rotation about the N(2)−N(3) triazenyl bond because the terminal N(3) atom in triazenes displays considerable sp 2 character ( , ); and finally, like the comparable phenomenon in biphenyls ( , ), the pivotal pyrimidine-phenyl bond in TAB is restricted from free rotation (atropisomerism) because of the flanking substituents in the diaminopyrimidine moiety and the buttressing effect which the triazenyl group exerts on the 2‘-H atom in the 5-phenyl residue. We reasoned that TAB might exhibit multiple-binding conformations when interacting with the pcDHFR enzyme.…”

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confidence: 99%

Structural Studies on Bioactive Compounds. 30. Crystal Structure and Molecular Modeling Studies on the Pneumocystis carinii Dihydrofolate Reductase Cofactor Complex with TAB, a Highly Selective Antifolate^,^,

et al. 2000

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The crystal structure of the ternary complex of NADPH, the potent antifolate [2, 4-diamino-5-¿3-[3-(2-acetyloxyethyl)-3-benzyltriazen-1-yl]-4 -chloroph enyl¿-6-ethylpyrimidine] (TAB, 1) and Pneumocystis carinii dihydrofolate reductase (pcDHFR), refined to 2.1 A resolution, reveals that TAB binds similar to the antifolates trimethoprim and methotrexate. These data also reveal multiple conformations for the binding geometry of TAB with two preferred orientations of the acetyloxy and benzyl groups that results from a 180 degrees rotation about the N2-N3 triazenyl bond. The methyl of the acetyloxy and benzyl ring of TAB probes large hydrophobic regions of the p-aminobenzoyl folate binding pocket of the active site, in particular the region near Phe69, which is unique to the pcDHFR sequence. These results confirm prior molecular modeling investigations of the binding of TAB to pcDHFR that identified four low-energy binding geometries, two involving rotations about the terminal N(2)-N(3) triazenyl linkage and two involving atropisomerism about the pivotal pyrimethamine-phenyl bond. The primary differences in the molecular dynamics (MD) models and those observed in this crystal complex result from small conformational changes in active-site residues on energy minimization. However, two MD models place the acetyloxy and benzyl ring groups in a region of the active site between the cofactor-binding region and the p-aminobenzoyl folate pocket; an orientation never observed in any DHFR crystal structure to date. These conformers interact with solvent near the enzyme surface and are probably not observed due to the loss of specific hydrogen bonds with the enzyme. The high species pcDHFR selectivity of TAB could be the result of ligand flexibility that enables multiple binding orientations at the enzyme active site. Further modification of the acetyloxy region of TAB could increase its potency and selectivity for pcDHFR.

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confidence: 99%

Structural Studies on Bioactive Compounds. 30. Crystal Structure and Molecular Modeling Studies on the Pneumocystis carinii Dihydrofolate Reductase Cofactor Complex with TAB, a Highly Selective Antifolate^,^,

et al. 2000

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“…When the N2−N3 rotation is slow enough, the cis and trans C* can be differentiated. Variable-temperature NMR studies of triazenes confirmed that distinct cis and trans C* signals can be resolved at about 250 K, and fine coupling structures of 1 H NMR signals appear at lower temperatures. , The electronic and steric effects of substituents on the aromatic rings also influence the N2−N3 rotational isomerism. The presence of a strong electron-withdrawing group on the aromatic ring promotes the formation of 1,3-dipolar compounds (Scheme , bottom left and right).…”

Section: Nmr Spectra Of 1-aryl-33-dialkyltriazenesmentioning

confidence: 91%

“…The presence of a strong electron-withdrawing group on the aromatic ring promotes the formation of 1,3-dipolar compounds (Scheme , bottom left and right). Under these circumstances, N2−N3 rotation is restricted to the point where CH 2 * is either cis or trans to N1, and the signals due to CH 2 * (both 1 H and 13 C NMR) in the cis and trans rotamers are distinct at room temperature . Figures and compare the N -ethyl resonance of the two 1-aryl-3,3-diethyltriazene compounds 35b and 35d .…”

Section: Nmr Spectra Of 1-aryl-33-dialkyltriazenesmentioning

confidence: 97%

Preparative Fluorous Mixture Synthesis of Diazonium-Functionalized Oligo(phenylene vinylene)s

Jian

Tour

2005

J. Org. Chem.

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[structure: see text] A series of building blocks for the synthesis of oligo(phenylene vinylene)s (OPVs) and hybrid oligomers were prepared, and alternating Heck coupling and Horner-Wadswoth-Emmons (HWE) reactions were used to couple the building blocks. Model studies were carried out to optimize the reaction strategies. The products were made to bear aryl diazonium functionalities that allow them to be used as surface grafting moieties in hybrid silicon/molecule assemblies. A library of OPV and hybrid oligomer tetramers was synthesized using fluorous mixture synthesis (FMS). The fluorous tags, which are secondary amines bearing different numbers of fluorine atoms, were synthesized and used as phase tags in mixture synthesis. The tags and substrates were anchored together by triazene linkages. The mixture synthesis was monitored by analytical HPLC on a fluorous column, and isolation of final OPV and hybrid oligomer tetramers was achieved by preparative HPLC. At the end of the FMS, after demixing, the tagged products were detagged by cleaving the triazene linkage and generating a series of aryl diazonium compounds. The fluorous tags could be recovered and reused. The NMR spectra of the 1-aryl-3,3-dialkyltriazenes are discussed.

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“…Although the terminal nitrogen atom in 1-aryl-3,3-dialkyltriazenes is (formally) tetrahedral, X-ray crystal studies have shown it has sp 2 character and the terminal N−N linkage is intermediate in length between a single and a double bond . This leads to restricted rotation about the N(2)−N(3) triazenyl bond and significant temperature-dependent line broadening of the alkyl protons in 3,3-dialkyltriazenes is often observed. , Thus the 1 H NMR spectrum of 13a in DMSO- d 6 at 289 K shows two broadened singlets for the methyl protons at δ 3.13 and 3.52 whereas the methylene absorption of the benzyl group is a slightly broadened singlet at δ 5.01. However, in the 1 H NMR spectrum of the simple model triazene 13c , only one sharp methyl resonance is observed, indicating that N−N rotation is too fast to be observed by this technique at ambient temperature.…”

Section: Chemistrymentioning

confidence: 99%

Structural Studies on Bioactive Compounds. 34. Design, Synthesis, and Biological Evaluation of Triazenyl-Substituted Pyrimethamine Inhibitors of Pneumocystis carinii Dihydrofolate Reductase

et al. 2001

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The triazenyl-pyrimethamine derivative 3a (TAB), a potent and selective inhibitor of Pneumocystis carinii DHFR, was selected as the starting point for a lead optimization study. Molecular modeling studies, corroborated by a recent crystal structure determination of the ternary complex of P. carinii DHFR--NADPH bound to TAB, predicted that modifications to the acetoxy residue of the lead inhibitor could exploit binding opportunities in the vicinity of an active site pocket bounded by residues Ile33, Lys37, and Leu72. Substitutions in the benzyl moiety with electron-donating and electron-withdrawing groups were predicted to probe face-edge interactions with amino acid Phe69 unique to the P. carinii enzyme. New triazenes 10a--v and 12a--f were prepared by coupling the diazonium tetrafluoroborate salt 6b of aminopyrimethamine with substituted benzylamines or phenethylamines. The most potent of the new inhibitors against P. carinii DHFR was the naphthylmethyl-substituted triazene 10t (IC(50): 0.053 microM), but a more substantial increase in potency against the rat liver DHFR led to a reduction in selectivity (ratio rat liver DHFR IC(50)/P. carinii DHFR IC(50): 5.36) compared to the original lead structure 3a (ratio rat liver DHFR IC(50)/P. carinii DHFR IC(50): 114).

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1,2-Bis(1-aryl-3-alkyltriazen-3-yl)ethanes and related compounds

Cited by 3 publications

References 0 publications

Structural Studies on Bioactive Compounds. 30. Crystal Structure and Molecular Modeling Studies on the Pneumocystis carinii Dihydrofolate Reductase Cofactor Complex with TAB, a Highly Selective Antifolate^,^,

Structural Studies on Bioactive Compounds. 30. Crystal Structure and Molecular Modeling Studies on the Pneumocystis carinii Dihydrofolate Reductase Cofactor Complex with TAB, a Highly Selective Antifolate^,^,

Preparative Fluorous Mixture Synthesis of Diazonium-Functionalized Oligo(phenylene vinylene)s

Structural Studies on Bioactive Compounds. 34. Design, Synthesis, and Biological Evaluation of Triazenyl-Substituted Pyrimethamine Inhibitors of Pneumocystis carinii Dihydrofolate Reductase

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1,2-Bis(1-aryl-3-alkyltriazen-3-yl)ethanes and related compounds

Cited by 3 publications

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Structural Studies on Bioactive Compounds. 30. Crystal Structure and Molecular Modeling Studies on the Pneumocystis carinii Dihydrofolate Reductase Cofactor Complex with TAB, a Highly Selective Antifolate,,

Structural Studies on Bioactive Compounds. 30. Crystal Structure and Molecular Modeling Studies on the Pneumocystis carinii Dihydrofolate Reductase Cofactor Complex with TAB, a Highly Selective Antifolate,,

Preparative Fluorous Mixture Synthesis of Diazonium-Functionalized Oligo(phenylene vinylene)s

Structural Studies on Bioactive Compounds. 34. Design, Synthesis, and Biological Evaluation of Triazenyl-Substituted Pyrimethamine Inhibitors of Pneumocystis carinii Dihydrofolate Reductase

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Structural Studies on Bioactive Compounds. 30. Crystal Structure and Molecular Modeling Studies on the Pneumocystis carinii Dihydrofolate Reductase Cofactor Complex with TAB, a Highly Selective Antifolate^,^,

Structural Studies on Bioactive Compounds. 30. Crystal Structure and Molecular Modeling Studies on the Pneumocystis carinii Dihydrofolate Reductase Cofactor Complex with TAB, a Highly Selective Antifolate^,^,