DNA intercalating activity

The active-site metal ion plays an accepted role in the catalytic function of IN, although its role in inhibition is poorly understood. The role of the metal ion in inhibition has been a topic of speculation since the first inhibitors began to appear in the literature in 1993. Early work identified some DNA-binding and DNA-intercalating molecules as IN inhibitors (18). These early inhibitors include doxorubicin (Fig. 2,1), caffeic acid phenethyl ester (CAPE, Fig. 2,2), and quercetin (Fig. 2,3). This work established, however, that there was no clear relationship between DNA-binding or DNA-intercalating activities and inhibition. It was noted that active inhibitors contained polyhydroxylated aromatic regions that... 

Polyheterocyclic structures such as benzimidazoquinazoUnes 91 made up of two fused heterocyclic rings often possess potent biological activity, like antiproliferative and DNA-intercalator activity [62], antifertiUty activity [63], anticonvulsant activity, and myorelaxant activity [64]. These benzimid-azoquinazoline compounds 91 have been obtained by the condensation of... 

All alkaloids were found to have little activity compared to the reference compound. The strong DNA intercalating activity of 37 is believed to be responsible for its high degree of antiplasmodial activity... 

Topoisomerase I inhibitor apoptosis induction in S-phase Weak DNA intercalation activation of caspase-3 DNA fragmentation depolarization of mitochondrial membranes apoptotic Cell-cycle arrest in G2/M phase PARP cleavage cytochrome c release upregulation of p53 DNA intercalation activation of caspase-3, -9 PARP cleavage DNA fragmentation apoptotic clastogenic potential... 

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). 

The AMAPs (2-[ arylmethyl amino]-l,3-propanediols) are a class of planar polycyclic aromatic derivatives, which contain polar side-chains. They are known to be DNA intercalators and possess broad spectrum antitumour activity. An approach to C-radiolabelled AMAP derivative 40 used the Bucherer reaction as an initial starting reaction. 2-Naphthol was reacted with 4-bromophenylhydrazine 38 in the presence of sodium metabisulfite and HCl to afford 39. Subsequent derivatisation of 39 afforded 40. 

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>. 

So we are still left with two models of the stereochemistry of DNA alkylated by a PAH diol epoxide the PAH either lies in a groove of DNA or else tries to intercalate between the bass of DNA. Since it is covalently bonded to a base it must cause considerable distortion if it tries to lie between the bases. However, the stacking observed in the crystalline state seems to argue for partial intercalation. We will need crystal structures of at least one appropriately alkylated polynucleotide before this problem can be resolved. And when this is done it will be just the beginning of the answer to the problem of alkylation of DNA by activated carcinogens. The subsequent question is, what is the lesion in DNA that is important in carcinogenesis, and then what does it cause to happen so that tumor formation is initiated ... 

Recent structure-activity studies of 1-alkylbenzo[a]pyrenes also suggest that DNA intercalation of benzo[a]pyrene (BP) metabolites plays a role in the mechanism of BP carcinogenesis (38). The addition of bulky alkyl groups at the 1-position of BP, which inhibit DNA intercalation of 1-alkyl-BP metabolites (19), causes a reduction in carcinogenic activity. 

Kumar A, Brown DT, Leno GH (2004) DNA intercalators differentially affect chromatin structure and DNA repUcation in Xenopus egg extract. Anticancer Drugs 15(6) 633—639 Kuo MT (1981) Preferential damage of active chromatin by bleomycin. Cancer Res 41(6) 2439—2443 Kuo MT, Sarny TS (1978) Effects of neocarzinostatin on mammalian nuclei release of nucleosomes. Biochim Biophys Acta 518(1) 186—190... 

Ellipticine inhibits DNA, RNA and protein synthesis. The inhibition is not reversible by removal of the alkaloid. It has no appreciable effects on thymidine and uridine kinases or on RNA polymerase, but it markedly inhibits DNA polymerase activity [240, 241]. The actual mechanism of action of ellipticine and related compounds has not yet been elucidated. Ellipticine and derivatives have been found to interact with bacterial membranes [242]. Many investigators have categorized these compounds as DNA-interacting or intercalating agents [230, 235, 237,243-246]. It has recently been postulated that mammalian DNA topoisomerase II may be a common target of these antitumour compounds [247],... 

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