Synthetic DNA minor groove-binding drugs.

Na3Co(NO2)6 has been investigated as a new reagent for the nitrosation of various substrates containing an amino functionality. Reactions took place in an aqueous solution of the reagent. The pH of the reaction mixture remained in the range 4.3−5. Thus, hydrazides were transformed to the corresponding acyl azides, and the reactions with arenesulfonyl hydrazines afforded arenesulfonyl azides. Treatment of aromatic amines with Na3Co(NO2)6 gave 1,3-diaryltriazenes in excellent yields; coupling of the initially formed diazo compound to the electron rich aromatic ring was also observed. Nitrosation of aliphatic amines was not possible due to complex formation with the reagent.

Nitrosation with Sodium Hexanitrocobaltate(III).

The aromatic diamidines berenil and propamidine bind reversibly to A+T-rich sites in the minor groove of B-form DNA duplexes. Based on extensive solution and crystallographic information we have designed a non-self-complementary double-stranded DNA sequence, d(GCAATGAGCG) d(CGCTCATTGC), that should contain a near-ideal binding site for berenil and a poorer site for the larger propamidine molecule, viz. d(AAT) d(ATT). 1H-NMR studies show that both ligands bind with 1:1 stoichiometry to the embedded 5′-AAT site, and induce numerous shifts of NMR resonances of DNA protons located in the minor groove. In addition, interactions with each strand can be distinguished by NOE spectroscopy due to the inherent asymmetry of the DNA. Detailed modelling based on experimental data show that no significant distortion of the B-DNA duplex is induced by either ligand. Sufficient NOE data were obtained to determine the position of the bound ligands in each complex. These conclusions are in agreement with predictions from molecular modelling calculations that provide a microscopic energy profile for interaction with the minor groove tract. Such calculations reveal an unexpected heterogeneous 5′-ATGA binding site that includes a spanned guanosine. This secondary binding site accounts for the extensive chemical shift perturbation induced by these ligands. The structures of the free DNA and the reversible complexes formed with each ligand molecule have been refined using an NOE-restrained isothermal annealing procedure. These structures confirm that the introduced ligands effect minimal perturbation of the helix, with binding to the 5′-AAT base sequence largely determined by specific non-bonded interactions.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1432-1033.1995.0433k.x

Interaction of Minor-Groove-Binding Diamidine Ligands with an Asymmetric DNA Duplex

Stable Triazenes Derived from 2-Alkylaminonaphthalenes and 5-Nitrobenzo[c]-1,2-thiazole-3-diazonium Hydrogensulfate

1,3-Diaryltriazenes, prepared from a 2-methoxy-4-nitrobenzenediazonium salt and primary arylamines, exist as “azo-transfer” tautomers in which the 2-methoxy-4-nitrophenyl group is present on the sa...

2-Methoxy-4-nitrobenzenediazonium Salt as a Practical Diazonium-Transfer Agent for Primary Arylamines via Tautomerism of 1,3-Diaryltriazenes: Deaminative Iodination and Arylation of Arylamines without Direct Diazotization

1,3-Bis(4-acetylphenyl)triazene (II): C16H15N3O2, Mr = 281.32, monoclinic, P2(1)/c, a = 14.002 (5), b = 12.359 (3), c = 8.457 (3) A, beta = 96.35 (2) degrees, V = 1454.5 A3, Z = 4, Dx = 1.287 Mg m-3, Cu K alpha, lambda = 1.54178 A, mu = 0.672 mm-1, F(000) = 592, T = 294 K, final R = 0.089 for 1890 unique observed reflections. 1,3-Bis(4-[2-dimethylamino)ethoxycarbonyl]phenyl)triazene monohydrate (III): C22H29N5O4.H2O, Mr = 445.52, triclinic, P1, a = 9.500 (2), b = 11.753 (3), c = 13.328 (2) A, alpha = 62.84 (1), beta = 66.60 (2), gamma = 77.58 (2) degrees, V = 1214.1 A3, Z = 2, Dx = 1.172 Mg m-3, Cu K alpha, lambda = 1.54178 A, mu = 0.640 mm-1, F(000) = 476, T = 294 K, final R = 0.063 for 1100 unique observed reflections. Both crystal structures have extended conformations for the 1,3-diaryltriazene groups, with a cisoid arrangement of phenyl rings. The terminal N--N bonds of each triazene are non-equivalent, and a hydrogen atom has been located in the N==N--NH moiety. Extensive molecular-orbital (MNDO) calculations on the model core 1,3-diphenyltriazene system have confirmed that this geometry is energetically favoured, and have revealed the shape of the energy surface for rotation about the N--NH bond in the triazene linkage.

S. Neidle

Papers

Studies on 1,3-diaryltriazene analogues of berenil: molecules with potential GC base-pair selectivity.