Intercalating agent

Intercalating drugs are compounds which are capable of slipping between the layers of nucleic acid base pairs and disrupting the shape of the double helix. This disruption prevents replication and transcription. One example is the antibacterial agent proflavine (Fig. 6.6). 

Drugs which work in this way must be flat in order to fit between the base pairs, and must therefore be aromatic or heteroaromatic in nature. Some drugs prefer to approach the helix via the major groove, whereas others prefer access via the minor groove. 

Several antibiotics such as the antitumour agents actinomycin D and adriamycin (Fig. 6.7) operate by intercalating DNA. 

Actinomycin D contains two cyclic pentapeptides, but the important feature is the flat, tricyclic, heteroaromatic structure which is able to slide into the double helix. It 

The highly effective antimalarial agent chloroquine—a drug developed from quinine—can attack the malarial parasite by blocking DNA transcription as part of its action. Once again a flat heteroaromatic structure is present which can intercalate DNA (Fig. 6.8). 

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ON A alkylating agents, intercalating agents, wrong substrates (Trofan horses, e.g, S-fluorouracil)... 

Intelligent material Inter am Intercalates Intercalating agents Intercalation... 

Figure 12.16), can insert between the stacked base pairs of DNA. The bases are forced apart to accommodate these so-called intercalating agents, causing an unwinding of the helix to a more ladderlike structure. The deoxyribose-phosphate backbone is almost fully extended as successive base pairs are displaced 0.7 nm from one another, and the rotational angle about the helix axis between adjacent base pairs is reduced from 36° to 10°. 

FIGURE 12.16 The structures of ethidiutn bromide, acridine orange, and actinomycin D, three intercalating agents, and their effects on DNA structure. 

Cassytha filiformis L., mentioned earlier, contains aporphine alkaloids such as actin odaphnine, cassythine, and dicentrine, which effectively bind to DNA and behave as typical intercalating agents and interfere with the catalytic activity of topoisomerases (3,10,11). 

Examples of acridin alkaloids used in therapeutics as antineoplastic agents is amsacrine (Amsa P-D ), which is used for the treatment of acute leukemia in adults and malignant lymphomas, refractory to conventional therapy. Amsacrin is an intercalating agent and topoisomerase II inhibitor. 

Zhu, X.Q., Chilton, N.B., Beveridge, I. and Gasser, R.B. (1998a) Detection of sequence variation in parasite ribosomal DNA by electrophoresis in agarose gels supplemented with a DNA-intercalating agent. Electrophoresis 19, 671-674. 

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>. 

Daunorubicin -anthracycline antitumor antibiotic DNA intercalating agent -bone marrow suppression -nausea and vomiting—mild to moderate -mucocutaneous effects (mucositis, stomatitis, diarrhea) -vesicant if extravasated —cardiotoxicity (550 mg/M2) -Liposomal daunorubicin there is significantly less bone marrow suppression, nausea and vomiting, stomatitis, and cardiotoxicity... 

Biver, T., De Biasi, A., Secco, E, Venturing M., and Yarmoluk, S. (2005) Cyanine dyes as intercalating agents Kinetic and thermodynamic studies on the DNA/Cyan40 and DNA/CCyan2 systems. Biophys. J. 89, 374-383. 

Hydrophobic stacking provides stability. Intercalating agents stack between bases. 

Intercalating agents are hydrophobic, planar structures that can fit between the DNA base pairs in the center of the DNA double helix. These compounds (ethidium bromide and actinomycin D are often-used examples) take up space in the helix and cause the helix to unwind a little bit by increasing the pitch. The pitch is a measure of the distance between successive base pairs. 

Luminescent bacteria also allow detection of the carcinogenic effect of ge-notoxics. A dark mutant of a Photobacterium or Vibrio strain that can revert back to luminescence at an increased rate in the presence of base-substitutes or frame-shifts agents, DNA-damaging agents, DNA synthesis inhibitors, and DNA intercalating agents can be employed [171, 172],... 

Nucleic acids flexibility torsion dynamics helix structure deformation due to intercalating agents photocleavage accessibility carcinogenesis... 

Significant increase in triplex stability can be achieved by using intercalating agents, either by conjugate attachment to the third strand TFO or as a separate adjunct ligand, if binding of this residue can preferentially stabilize a... 

WARNING Administer only under sup vision of a healthcare provider experienced in leukemia and in an institution w/ resources to maintain a pt compromised by drug tox Uses Acute leukemias CML in blast crisis, breast CA Action DNA intercalating agent i DNA topoisom ases I II Dose (Per protocol) 10-12 mg/mVd for 3-4 d 4- in renal/hepatic impairment Caution [D, -] Contra Bilirubin >5 mg/dL, PRO Disp Inj 1 mg/mL (5, 10, 20 mg vials) SE X BM, cardiotox, N/V, mucositis, alopecia, IV site Rxns, rarely -1- renal/hepatic Fxn Interactions Myelo-suppression W/ antineoplastic drugs and radiation therapy -1- effects OF live virus vaccines EMS Monitor for S/Sxs of Infxn OD May cause N/V, t Infxn risk and cardio/GI tox symptomatic and supportive... 

Intercalating agents are aromatic compounds that fit between the base pairs in the core of DNA structure and lead to insertions and deletions of one or more base pairs upon replication. 

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