DNA daunomycin

Several electron donors form molecular complexes with menadione, which then suppress its photodecomposition in aqueous solutions (107). DNA-daunomycin complexes exposed to UV irradiation are reported by Gray and Philips (127) to be more stable than daunomycin alone. The photostability of nifedipine increases on the addition of PVP (64,128). However, the rate of photobleaching of riboflavin by VIS radiation is considerably enhanced by PVP (28). 

Gray PJ, Philips DR. Ultraviolet photoirradiation of daunomycin and DNA-daunomycin complexes. Photochem Photobiol 1981 (33) 297-303. 

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). 

Fig. 12. Representation of the DNA-drug intercalation model showing locations of excluded sites which are not available for further intercalation, for (a) two separate mono-intercalators such as daunomycin 28 (b) one tris-intercalator such as compound 29...

P. Cieplak, S. N. Rao, P. D. J. Grootenhuis, and P. A. Kollman, Free energy calculation on base specificity of drug-DNA interactions Application to daunomycin and acridine intercalation into DNA, Biopol. 29 717 (1990). 

The effect of the position of side chains on the intercalation kinetics of anthra-quinones,101 which are related to the aromatic moiety of daunomycin (13), was studied with the stopped flow SDS sequestration technique. Guest molecules 14—17 can have two different intercalation modes, a classic mode where both side chains are located in the same groove of the DNA helix (14 and 16) or a threading mode where the side chains are located in opposite grooves of the DNA (15 and 17) (Scheme 7). The relative position of intercalated 14 with respect to the DNA bases was suggested to be the same as for 13. 

Perhaps a bit more subtle than those agents that react chemically with DNA are those that insert themselves between the stacked bases of the DNA double helix— intercalation. This alters the regular structure of the DNA molecule and may lead, for instance, to inhibition of mRNA synthesis. The structures of the intercalcating agents are generally quite complex and I will spare you the complexity. However, three names may be familiar—dactinomycin (Actinomycin D), daunorubicin (daunomycin), and doxorubicin (Adriamycin)— and intercalation is how they work. All three are natural products and were isolated from the fermentation broths of Streptomyces species. 

The effects of intercalators (see also p. 262) are illustrated here using the example of the daunomycin-DNA complex, in which two daunomycin molecules (red) are inserted in the double helix (blue). The antibiotic s ring system inserts itself between G/C base pairs (bottom), while the sugar moiety occupies the minor groove in the DNA (above). This leads to a localized change of the DNA conformation that prevents replication and transcription. 

In the thermodynamic study of duplex formation, a variety of complementary pairs of relatively simple, well-defined oligonucleotides are employed, " while the intercalation thermodynamics was examined with more complex or natural DNA duplexes. " Typical intercalating agents examined are acridine orange, acriflabine, actinomycin, daunomycin, ethidium bro-... 

Figure 5-23 Stereoscopic drawing showing a molecule of daunomycin (Fig. 5-22) intercalated between two base pairs in a molecule of double-helical DNA, d(CGTACG). Nitrogen and oxygen atoms are shown as dots. From Quigley et al.220 Both daunomycin and adriamycin (doxorubicin 14-hydroxy-daunomycin) are important but seriously toxic anticancer drugs.

Yoshikawa, Y., Yoshikawa, K. and Kanbe, T. (1996c) Daunomycin unfolds compactly packed DNA. Biophys. Chem., 61, 93-100. 

Daunorubicin (Daunomycin and Cerubidine) and doxorubicin (Adriamycin) bind to and cause the intercalation of the DNA molecule, thereby inhibiting DNA template function. They also provoke DNA chain scission and chromosomal damage. Daunorubicin is useful in treating patients with acute lymphocytic or acute granulocytic leukemia. Adriamycin is useful in cases of solid tumors such as sarcoma, metastatic breast cancer, and thyroid cancer. These agents cause stomatitis, alopecia, myelosuppression, and cardiac abnormalities ranging from arrhythmias to cardiomyopathy. 

Daunorubicin (Daunomycin and Cerubidine) and doxorubicin (Adriamycin) bind to and cause the intercalation of the DNA molecule, thereby inhibiting DNA template function. They also provoke DNA chain scission and chromosomal damage. 

Simulation Study of the Molecular Mechanism of Intercalation of the Anti-Cancer Drug Daunomycin into DNA... 

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