47771-56-2Relevant academic research and scientific papers
Synthesis and structure-activity relationship studies of CD4 down-modulating cyclotriazadisulfonamide (CADA) analogues
Bell, Thomas W.,Anugu, Sreenivasa,Bailey, Patrick,Catalano, Vincent J.,Dey, Kaka,Drew, Michael G. B.,Duffy, Noah H.,Jin, Qi,Samala, Meinrado F.,Sodoma, Andrej,Welch, William H.,Schols, Dominique,Vermeire, Kurt
, p. 1291 - 1312 (2007/10/03)
HIV attachment via the CD4 receptor is an important target for developing novel approaches to HIV chemotherapy. Cyclotriazadisulfonamide (CADA) inhibits HIV at submicromolar levels by specifically down-modulating cell-surface and intracellular CD4. An effective five-step synthesis of CADA in 30% overall yield is reported. This synthesis has also been modified to produce more than 50 analogues. Many tail-group analogues have been made by removing the benzyl tail of CADA and replacing it with various alkyl, acyl, alkoxycarbonyl and aminocarbonyl substituents. A series of sidearm analogues, including two unsymmetrical compounds, have also been prepared by modifying the CADA synthesis, replacing the toluenesulfonyl sidearms with other sulfonyl groups. Testing 30 of these compounds in MT-4 cells shows a wide range of CD4 down-modulation potency, which correlates with ability to inhibit HIV-1. Three-dimensional quantitative structure-activity relationship (3D-QSAR) models were constructed using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) approaches. The X-ray crystal structures of four compounds, including CADA, show the same major conformation of the central 12-membered ring. The solid-state structure of CADA was energy minimized and used to generate the remaining 29 structures, which were similarly minimized and aligned to produce the 3D-QSAR models. Both models indicate that steric bulk of the tail group, and, to a lesser extent, the sidearms mainly determine CD4 down-modulation potency in this series of compounds.
Syntheses, conformations, and basicities of bicyclic triamines
Bell, Thomas W.,Choi, Heung-Jin,Harte, William,Drew, Michael G. B.
, p. 12196 - 12210 (2007/10/03)
The multistep syntheses of several bicyclic triamines are described, all of which have an imbedded 1,5,9-triazacyclododecane ring. In 1,5,9-triazabicyclo[7.3.3]pentadecanes 12, 13, 15, and 16, two nitrogens are bridged by three carbons. The monoprotonated forms of these triamines are highly stabilized by a hydrogen-bonded network involving the bridge and both bridgehead nitrogens, producing a difference of more than 8 pKa units in acidities of their monoprotonated and diprotonated forms. The one- and zero-carbon bridges in 1,5,9-triazabicyclo[9.1.1]tridecane (23) and 7-methyl-1,5,9-triazabicyclo[5.5.0]dodecane (39) do not enhance the stabilities of their monoprotonated forms. X-ray crystal structures and computational studies of 12·HI and 16·HI reveal similar, but somewhat weaker, hydrogen-bonded networks, relative to 15·HI. The activation free energies for conformational inversion of 13·HI (14.4 ± 0.2 kcal/mol), 16·HI (15.0 ± 0.1 kcal/mol) and 16 (8.8 ± 0.3 kcal/mol) were measured by variable-temperature 1H and 13C NMR spectroscopy. These experimental barriers give an estimate of 6.2 kcal/mol for the strength of the bifurcated hydrogen bond between the bridge nitrogen and cavity proton in 16·HI. Computational studies support the hypothesis that N-inversion occurs in an open conformation, leading to an estimate of 10.32 kcal/mol for the enthalpy of the bifurcated hydrogen bond in 16·HI in the gas phase.
Anti-viral triaza compounds and compositions
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Page column 7, (2010/01/30)
The invention relates to a family of new synthetic triamine compounds which can be used in antiviral pharmaceutical compositions.
Multi-layer macromonocyclic polyamines. I. Molecular design and synthesis of component monocyclic precursors
Iwata, Masaaki
, p. 693 - 704 (2007/10/03)
We designed 'multi-layer macromonocyclic polyamines' which might be appropriate polymorphismic molecular scaffolds as host-molecules in ionic or molecular interaction with small or large guest ions or molecules. In polymorphismic molecules, several macromonocyclic polyamines with the same and/or different ring sizes and nitrogen contents are connected to each other by alkylene spacers with various length of the chain. Actual target molecules are characterized by possessing methylene chain arrays of natural polyamines, and we have synthesized from simple starting materials fourteen component macromonocycles with various sizes, 12- to 34-membered rings containing three to eight nitrogen atoms, as essential building blocks required for construction of multi-layer molecules. Our method of synthesis was shown to be very efficient. In a final step, the N-protecting benzyl group was successfully removed by hydrogenation on 10%-Pd/C under 4 kg cm-2 H2 to give the cyclic amine precursors, which could be internal and terminal components in the architecture of the multi-layer molecules. The structures of synthesized compounds were characterized and confirmed by EA, 1H NMR, SIMS, and FAB(+) mass spectrometry.
Unequivocal synthesis of 1,9-dibenzyl-1,5,9,13-tetracydohexadecane
Fasseur, Dominique,Lacour, Sylvie,Guilard, Roger
, p. 285 - 294 (2007/10/03)
Condensation of two N-benzylated derivatives 3 and 4 according to the Richman and Atkins's method allows the unequivocal synthesis of 1,9-dibenzyl-1,5,9,13-tetracyclohexadecane (2). Preparation of the two precursors 3 and 4 is also described.
