DNA intercalating compounds

In this paper we report some of our work with stabilized liposomes containing boronated DNA intercalating compounds. 

Queiroz synthesized diarylamines in the benzothiophene series, where the ligand BINAP was used to achieve the Pd-catalyzed amination in medium to high yields [156]. The diarylamines 96 were used in materials with electronic or luminescent properties. These compounds were further cyclized to provide substituted thienocarbazoles, which are bioisosteres of natural antitumoral DNA intercalating compounds. The presence of fluorine atoms increased the solubility of these molecules [156]. 

Antineoplastic Drugs. Cyclophosphamide (193) produces antineoplastic effects (see Chemotherapeutics, anticancer) via biochemical conversion to a highly reactive phosphoramide mustard (194) it is chiral owing to the tetrahedral phosphoms atom. The therapeutic index of the (3)-(-)-cyclophosphamide [50-18-0] (193) is twice that of the (+)-enantiomer due to increased antitumor activity the enantiomers are equally toxic (139). The effectiveness of the DNA intercalator dmgs adriamycin [57-22-7] (195) and daunomycin [20830-81-3] (196) is affected by changes in stereochemistry within the aglycon portions of these compounds. Inversion of the carbohydrate C-1 stereocenter provides compounds without activity. The carbohydrate C-4 epimer of adriamycin, epimbicin [56420-45-2] is as potent as its parent molecule, but is significandy less toxic (139). 

Multimolecular helical inclusion networks formed by rigid alicyciic diols, urea, deoxycholic acid, and tri-o-thymotide are described and contrasted, followed by discussion of DNA intercalates, amylose compounds, and other inclusion systems formed by helical polymers. 

Another way in which Pt could bind to DNA is through the formation of intercalation compounds. The parallel here is with the hydrocarbon carcinogens and the nucleic acid stains, the acridines. It has been shown that metal chelates will form this same type of jt-complex. For example, palladium oxinate will form exactly the same type of -complexes as anthracene (88). 

The thienothienopyridines are a relatively little-known class of compound. Interest in these systems arose through the possibility that they occurred in coal-derived products and their extended 7i-systems initiated interest for their interesting optical properties. Additionally, several differently substituted examples have antitumor activity <2002CPB656>, and may serve as DNA intercalating agents <2005MOL279>. 

Indolopyridopyridazinium salts such as 498 can be prepared by treatment of the iV-aminopyridoindolium salt 497 with a 1,2-diketone (Equation 218). These compounds can act as DNA intercalators <1996BML1453, 1999JOC3907>. 

RNA, (ii) the screening for antiviral compounds that do not bind to RNA but bind specifically to target RNA polymerases, (hi) the evaluation of the binding of aminoglycosides to RNA, and (iv) the evaluation of the binding of DNA intercalators and minor groove binders to RNA. 

Table 2.3 GPC spin column/ESI-MS non-covalent binding studies of RNA with model RNA and DNA binding compounds (intercalators).

Ethidium is a model compound for these studies. In human pharmacology, two classes of natural products (actinomyces, anthracyclines) provide prototypic molecules as DNA intercalating agents. (Planar molecules tend to insert well into the stacked nucleic acids, which accounts for the carcinogenic potential of polyaromatic hydrocarbons see figure 7.5.)... 

A high-throughput assay for bacterial RNA polymerase has been successfully developed and validated using a 96-well, automated format [70], The reaction mixture contained a DNA template, nucleotide substrates (NTPs), supplemented with a-33P-labeled CTP in Tris-acetate buffer (pH 6.8). The polymerase reaction was carried out at 34°C for 40 min (providing linear kinetics). The effect of dimethylsulfoxide (DMSO), the usual solvent for test compounds used in a screen, was taken into consideration. The radiolabeled RNA transcripts were allowed to bind diethyl aminoethyl (DEAE) beads, which were then separated via filtration, and radioactivity associated with the wells was quantitated to measure the RNA polymerase activity. The standard deviation of the measured activity was typically < 15% of the average. Use of this assay to screen for RNA polymerase inhibitors from chemical libraries and natural products led to the identification of DNA intercalators (known to inhibit RNA polymerase activity), rifampicin (a known inhibitors of RNA polymerase), and several derivatives of rifampicin from Actinomycetes extracts. Therefore this assay can be reliably utilized to detect novel inhibitors of bacterial RNA polymerase. 

A variety of plant substances with planar, polycyclic, aromatic structures can intercalate with DNA, examples being the quinoline alkaloid camptothecin and the furanocoumarin phenolic psoralen (Table 12.1). A variety of plant-derived anthraquinones and naphthoquinones bind to DNA and it is notable that the structurally related anthraquinones mitox-antrone and adriamycin are clinically employed as anticancer drugs (Table 12.1). DNA-binding compounds that interfere with DNA repair, DNA replication and gene expression are cytotoxic and have potential as anticancer agents (see Chapter 9). 

DNA can also be a target for alkaloids planar and lipophilic alkaloids, such as berberine and sanguinarine (Figure 1.6) are intercalating compounds that assemble between the stacks of paired nucleotides in the DNA double helix [2,3,18,23]. DNA intercalation can disturb replication, DNA repair, and DNA topoisomerases. Frameshift mutations are one of the adverse consequences of intercalating compounds. Some alkaloids, such as pyrrolizidine alkaloids, aristolochic acids, cycasin, and furoquinoline alkaloids, are known to form covalent adducts with DNA bases. Mutations and tumor formation can be the result of such interactions. DNA alkylation occurs in some alkaloids only after activation by liver enzymes, such as cytochrome p450 oxidases (pyrrolizidine alkaloids, aristolochic acids) [17,18,24]. 

The antitumor activities and DNA affinities of several 1-alkylamino derivatives 113-117 of 9-methoxyellipticine (2) have been measured (Table IV) (72). These compounds are cytotoxic and have some antitumor properties, but there does not appear to be a correlation between their cytotoxicity and DNA intercalating ability. Moreover, these derivatives tend to accumulate in the cytoplasm rather than in the nuclei of the cells. Compound 118, with a longer alkyl chain, is not taken up by the cells, presumably owing to the hydrophobic nature of the decyl chain. From the DNA binding data, the authors conclude that only 113-115 behave as true intercalators. 

Figure 2 The three boronated DNA intercalators WSA-1, WSP-1, WSN-1 and the DNA staining compound ethidium bromide.

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