Drug action intercalation

Drug Action - The action of a drug or poison refers to its biochemical mechanism. How does it interact on a molecular level A drug may interferewith membrane permeability, for example. Or it may be an enzyme inhibitor, hormone analogue and competitor, or DNA intercalator. Let us consider some specific drug actions. 

Dactinomycin is an antitumor antibiotic isolated from a Streptomyces organism. It binds tightly to double-stranded DNA through intercalation between adjacent guanine-cytosine base pairs and inhibits all forms of DNA-dependent RNA synthesis, with ribosomal RNA formation being most sensitive to drug action. 

In 1984, Giibble et al. reported for the first time a novel l,10-bis-(6-methyl-5H-benzo[fc]carbazol-ll-yl)decane (469) which has potential bifunctional nucleic acid intercalating properties (406). To function as anti-tumor active drugs, one of the most important cytostatic mechanisms of action of coplanar annelated polycyclic compounds is their intercalation with DNA (405). Ten years later, Kucklander et al. studied a series of 5H-benzo[ 7]carbazole quinone derivatives for their cytotoxic activity against colon and lung cancer cells, and found that the heteroannelated 5H-benzo[ 7]carbazole quinone derivative 470 was the most active among the various analogs (407) (Scheme 4.2). 

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... 

The intercalating drugs and nucleic acid synthesis inhibitors discussed in the preceding sections interfere indirectly with every phase of nucleic acid action because the DNA is rendered nonfunctional. Other drugs, discussed below, affect the regulation of protein synthesis even when the genome, the DNA structure, is intact. Such activity can be the result of interference either with transcription of messenger RNA or with translation of the mRNA to protein. 

Wink, M. (2007) Molecular modes of action of cytotoxic alkaloids - from DN A intercalation, spindle poisoning, topoisomerase inhibition to apoptosis and multiple drug resistance, in The Alkaloids (ed. G. CordeU), Vol. 64. Academic Press, San Diego,... 

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). 

The exact mode of action of oxamniquine is unknown [83]. The drug exhibits anticholinergic action its action on neuromuscular transmission has been demonstrated [119]. It has been suggested that oxamniquine (14) is converted enzymatically into a phosphate or sulphate ester (50), which then dissociates non-enzymatically to form the chemically reactive species 51. This intermediate then alkylates essential macromolecules of the schistosomes like DNA to give a Drug-DNA complex (52) (Scheme 5) [1,120,121]. The antischistosomal activity of oxamniquine is due to its ability to alkylate DNA. It does not intercalate with DNA, because the drug molecule is not planar, an essential structural requirement for intercalation. The lower mutagenic property of oxamniquine may, therefore, be due to the fact that it is not a DNA inter-calator [1],... 

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