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The syntheses of configurationally restricted mono- and bis-macrocyclic copper(II) perchlorate complexes (copper(II) 5-benzyl-1,5,8,12-tetraazabicyclo[10.2.2]hexadecane and dicopper(II) 5,5'-[1,4-phenylenebis(methylene)]-bis(1,5,8,12-tetraazabicyclo[10.2.2]hexadecane)) are reported and the X-ray structure of the copper(II) mono-macrocyclic complex has been determined. EXAFS studies on the bis-macrocyclic species in aqueous solution show that the copper coordination spheres are essentially identical to the solid state structure, and do not vary in the presence of 20 equivalents of sodium acetate per metal centre. DFT calculations were carried out at the BP86/TZP level to determine the nature of potential binding interactions with CXCR4 aspartate residues. The alkylated single macrocyclic compound was modelled with an acetate included to represent the aspartate residue, demonstrating that the predicted macrocycle configuration has the lowest energy and the acetate interaction is effectively monodentate giving a distorted trigonal bipyramidal geometry at the copper centre. In vitro anti-HIV infection assays show that the configurationally restricted dicopper(II) complex is more active (average EC(50) = 0.026 microM against HIV-1) than the non-constrained dicopper(II) 1,1'-[1,4-phenylenebis(methylene)]-bis(1,4,8,11-tetraazacyclotetradecane) (average EC(50) = 0.047 microM against HIV-1) although it is an order of magnitude less active than the configurationally restricted dizinc(II) complex.
From our investigations the following compounds have emerged as particularly potent and selective inhibitors of HIV replication: sulphated polysaccharides (i.e. heparin, dextran sulphate, pentosan polysulphate), dideoxynucleoside analogues such as the 3'-azido-and 3'-fluoro-substituted 2',3'-dideoxyribosides of both purines (i.e. guanine, 2,6-diaminopurine) and pyrimidines (i.e. uracil, thymine), and the 9-(2-phosphonylmethoxyethyl) derivatives of adenine, 2-monoaminopurine and 2,6-diaminopurine. All these compounds yield great promise for the treatment of retrovirus infections in humans. Whereas the sulphated polysaccharides interfere with the virus adsorption process, the nucleoside analogues (following intracellular phosphorylation to their 5'-triphosphate) appear to be targeted at the reverse transcriptase.
Evans Blue, an anionic dye which has been found to inhibit the replication of human immunodeficiency virus, proved also inhibitory to the DNA polymerases alpha and beta. The mode of inhibition was competitive with respect to the template X primer, and noncompetitive with respect to the deoxynucleoside triphosphate substrates. The inhibitory effect of Evans Blue on DNA polymerases is discussed in relation to that of suramin.
Abstract Direct introduction of a N‐atom in one step at C (5) of 5‐hydroxyuridine (4a) or 5‐hydroxy‐2′‐deoxyuridine (4b) by certain primary amines led to the synthesis of two novel C(5)‐N‐spin‐labeled nucleoside analogs and to several C(5)‐N‐aryl adducts. Substitution by 4‐amino‐2,2,6,6‐tetramethylpiperidinooxyl (3) at C(5) of 4a or 4b led to the spin‐labeled nucleosides 5‐[(1‐oxyl‐2,2,6,6‐tetramethyl‐4‐piperidinyl)amino]uridine and ‐2′‐deoxyuridine ( 2a and 2b , respectively). The analogous C(5)‐substituted aniline adducts 5‐anilino uridine (5a) and 5‐anilino‐2′‐deoxyuridine (5b) and the p ‐toluidine adducts 5‐( p ‐toluidino)uridine (6a) and 5‐( p ‐toluidino)‐2‐deoxyuridine (6b) were also prepared. In addition, results of the antiviral and antimetabolic activity of some of these analogs are reported.
An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
