The interactions of DAPI with natural DNA and synthetic polymers have been investigated by hydrodynamic, DNase I footprinting, spectroscopic, binding, and kinetic methods. Footprinting results at low ratios (compound to base pair) are similar for DAPI and distamycin. At high ratios, however, GC regions are blocked from enzyme cleavage by DAPI but not by distamycin. Both poly[d(G-C)]2 and poly[d(A-T)]2 induce hypochromism and shifts of the DAPI absorption band to longer wavelengths, but the effects are larger with the GC polymer. NMR shifts of DAPI protons in the presence of excess AT and GC polymers are significantly different, upfield for GC and mixed small shifts for AT. The dissociation rate constants and effects of salt concentration on the rate constants are also quite different for the AT and the GC polymer complexes. The DAPI dissociation rate constant is larger with the GC polymer but is less sensitive to changes in salt concentration than with the AT complex. Binding of DAPI to the GC polymer and to poly[d(A-C)].poly[d(G-T)] exhibits slight negative cooperativity, characteristic of a neighbor-exclusion binding mode. DAPI binding to the AT polymer is unusually strong and exhibits significant positive cooperativity. DAPI has very different effects on the bleomycin-catalyzed cleavage of the AT and GC polymers, a strong inhibition with the AT polymer but enhanced cleavage with the GC polymer. All of these results are consistent with two totally different DNA binding modes for DAPI in regions containing consecutive AT base pairs versus regions containing GC or mixed GC and AT base pair sequences. The binding mode at AT sites has characteristics which are similar to those of the distamycin-AT complex, and all results are consistent with a cooperative, very strong minor groove binding mode. In GC and mixed-sequence regions the results are very similar to those observed with classical intercalators such as ethidium and indicate that DAPI intercalates in DNA sequences which do not contain at least three consecutive AT base pairs.

Thirty-eight 2-(aryl or heteroaryl)quinolin-4-amines, N,N-disubstituted, N-monosubstituted, and without a substituent at the amino group have been synthesized with use of novel chemistries developed by us recently. Some of these derivatives show anti-HIV-1 activity at a concentration level of 1 microM and low cell toxicity in vitro. The most active and least toxic compounds are derivatives of 2-(3-pyridyl)quinoline. The results of the quantitative structure-activity relationship analyses, including several classical, linear regression correlations and a Free-Wilson approach of de novo model, provide guidelines for the design of new active compounds of this class.

Phenothiazin‐5‐ium tetraiodide hydrate (2), the suggested oxidation product of phenothiazine with iodine, is treated with two equivalents of a dialkylamine to give 3‐(dialkylamino)phenothiazin‐5‐ium triiodides, 3‐6. 3,7‐Disubstituted phenothiazin‐5‐ium iodides, 7‐9, are obtained by the reaction of 3‐6 with an amine.

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A set of 21 polyheteroaromatic compounds substituted with flexible cationic groups and of similar molecular size has been analyzed for binding with DNA and for effects of the bleomycin-mediated degradation of the DNA double helix. Increases in apparent rates of the DNA digestion were observed in all cases under the experimental conditions of noncompetitive binding of these compounds and bleomycin to DNA. Surprisingly, the quantitative structure-activity relationship analysis revealed two distinct correlations despite close structural similarities for the set of bleomycin amplifiers. These unusual results are explained in terms of the formation of two stereochemically different ternary complexes of activated bleomycin-DNA-amplifier. The relevance of this finding for the design of new bleomycin amplifiers is discussed.