Biomedical subjects

F A Tanious

Publications and source records attributed to F A Tanious.

24 records · Page 2Linked to original sources

PubMed1990

The interaction with DNA of unfused aromatic systems containing terminal piperazino substituents. Intercalation and groove-binding.

A number of unfused tricyclic aromatic intercalators have shown excellent activity as amplifiers of the anticancer activity of the bleomycins and the 4',6-diphenylpyrimidines, 2a and 2b, with terminal basic functions (4-methylpiperazino groups) have been synthesized to test the structural requirements for amplifier-DNA interactions. The terminal piperazine rings are bulky, have limited flexibility, and are twisted out of the phenyl ring plane in both 2a and 2b. With 2a the pyrimidine is unsubstituted at position 5 and the conformation predicted by molecular mechanics calculations has a 25-30 degrees twist between the phenyl and pyrimidine ring planes. With 2b the 5-position is substituted with a methyl group and this causes a larger twist angle (50-60 degrees) between the phenyl and pyrimidine planes. These conformational variations lead to markedly different DNA interactions for 2a and 2b. Absorption, CD and NMR spectral, viscometric, flow dichroism and kinetics results indicate that 2a binds strongly to DNA by intercalation while 2b binds more weakly in a groove complex. The general structure and conformation of 2a, a slightly twisted, unfused-aromatic system with terminal piperazino groups is more similar to groove-binding agents such as Hoechst 33258 than to intercalators. The fact that 2a forms a strong intercalation complex with DNA is unusual but in agreement with studies on other amplifiers of anticancer drug action. Molecular modeling studies provide a second unusual feature of the 2a intercalation complex. While most well-characterized intercalators bind with their bulky and/or cationic substitutents in the DNA minor groove, the cationic piperazino groups of 2a are too large to bind in the minor groove in an intercalation complex but can form strong interactions with DNA in the major groove. The tricyclic aromatic ring system of 2a stacks well with adjacent base-pairs in the major-groove complex and the piperazino groups have good electrostatic and van der Waals interactions with the DNA backbone.

Animals↗

PubMed1990

The interaction of unfused polyaromatic heterocycles with DNA: intercalation, groove-binding and bleomycin amplification.

A number of unfused-aromatic cations have been found to bind to DNA by intercalation and to amplify the bleomycin catalysed cleavage of DNA. These molecules are more similar in structure to unfused minor-groove binding compounds such as netropsin and DAPI than to fused-ring intercalators such as proflavine. An analysis of DAPI interactions with specific sequence DNA polymers has indicated that the binding modes for the molecule are sequence dependent: minor groove binding in sequences of three or more AT base pairs and intercalation in mixed or pure GC base pair sequences. As with other unfused intercalators which bind with their cationic side chains in the major groove, the amidinium groups of DAPI are in the major groove in the GC intercalation complex. DAPI is, thus, a good bleomycin amplifier in GC sequences but its minor-groove binding mode in AT sequences leads to bleomycin inhibition.

Base Sequence↗

PubMed1989

Interaction of unfused tricyclic aromatic cations with DNA: a new class of intercalators.

Unfused tricyclic aromatic ring systems 1-6 with one or two cationic side chains have been synthesized and their interactions with DNA and synthetic polymers probed with a variety of techniques. Molecular mechanics calculations indicate that the torsional angle between ring planes in the minimum energy conformation of the tricyclic molecules can range from 0 degree to as high as 50 degrees depending on the type of rings and substituents. Viscometric titrations with linear and supercoiled DNA, linear dichroism, and NMR studies indicated that all compounds with torsional angles of approximately 20 degrees or less bind to DNA by intercalation. The more highly twisted intercalators caused significant perturbation of DNA structure. Unfused intercalators with twist angles of approximately 20 degrees have reduced binding constants, suggesting that they could not form an optimum interaction with the DNA base pairs. Unfused intercalators with twist less than 20 degrees formed strong complexes with DNA. The structures of these unfused intercalators are more analogous to typical groove-binding molecules, and an analysis of their interaction with DNA provides a better understanding of the subtle differences between intercalation and groove-binding modes for aromatic cations. The results indicate that intercalation and groove-binding modes should be viewed as two potential wells on a continuous energy surface. The results also suggest design strategies for intercalators that can optimally complement DNA base pair propeller twist or that can induce bends in DNA at the intercalation site.

Cations↗

PubMed1988

Molecular basis for bleomycin amplification: conformational and stereoelectronic effects in unfused amplifiers.

Sixteen unfused heterobiaromatic and biphenyl compounds substituted with an amino side chain (protonated in water) have been tested for (i) binding with DNA and (ii) their effect on the digestion of the DNA double helix by a bleomycin-iron complex. Only the DNA intercalating molecules amplify the digestion of DNA. One 2,2'-bipyridine derivative tested is an inhibitor of the bleomycin reaction because it removes ferrous ion from the bleomycin complex. Polarity of the intercalating unfused biaromatic system is of primary importance for effective binding of the molecule with native DNA and, at the same time, for its amplification activity. The molecules that have the biaromatic system polarized extensively in the direction of the side cationic chain, so that the intercalating sites constitutes a positive part of the dipole, show strong binding with DNA and good amplification activity. For strong intercalative forces that determine the amplification activity, it is important that both the heteroaromatic subsystems of the molecule have positive ends of their dipoles positioned away from the side chain. This work provides general guidelines for synthesis of new highly effective bleomycin amplifiers.

Bleomycin↗

PubMed1987

Amplification of bleomycin-mediated degradation of DNA.

Three simple and independent tests have been introduced for studying the effect of DNA intercalating compounds on the bleomycin-mediated digestion of DNA in vitro. These methods are based on hyperchromic changes of DNA solution, changes in viscosity of DNA solution, and HPLC quantitative analysis of the four bases released from digested DNA. All three tests give comparable results. However, the viscometric method is technically the simplest and at the same time the most sensitive. The amplification of the bleomycin-mediated degradation of DNA by three unfused heteropolyaromatic intercalator molecules, namely N-[2''-(dimethylamino)ethyl]-4-thien-2'-ylpyrimidin-2-amine (1N), N,N-dimethyl-2-[(4'-thien-2''-ylpyrimidin-2'-yl)thio] ethylamine (1S), and newly synthesized 2,5-bis[2'-[[2''-(dimethylamino)ethyl]thio]pyrimidin-4'yl]thiophene (2) correlates well with the respective DNA binding constants for these compounds and is concentration dependent. The amplification activity of these compounds increases with increasing concentrations. The strongly binding compound 2 is the best amplifier of bleomycin in vitro found so far. Fused heteropolyaromatic systems, like ethidium bromide, are modest amplifiers of bleomycin at low concentrations but strongly inhibit the bleomycin chemistry at high concentrations.

Animals↗

PubMedDate not supplied

Synthesis and anti-Pneumocystis carinii pneumonia activity of novel dicationic dibenzothiophenes and orally active prodrugs.

Dicationic carbazoles have been found to be highly active against a rat model of Pneumocystis carinii pneumonia (PCP). Unfortunately, amidoxime derivatives, designed as prodrugs, were inactive against PCP even though the corresponding amidines were highly active. In the present work, a series of 2,8- and 3,7-bis cationic dibenzothiophenes was synthesized and assayed for anti-PCP activity. Three of the compounds proved to be more potent and less toxic than a standard anti-PCP drug (pentamidine) when given intravenously. Unlike the carbazoles, a dibenzothiophene amidoxime prodrug given orally reduced the parasite load by more than 99%. While no quantitative correlation was seen between anti-PCP activity and DNA binding, a strong level of DNA binding was found to be necessary for antimicrobial activity.

Animals↗