Adriamycin structure

Hyaluronic acid is a linear polysaccharide found in the highest concentrations in soft connective tissues where it fills an important structural role in the organization of the extracellular matrix (23,24). It has been used in ophthalmic preparations to enhance ocular absorption of timolol, a beta blocker used for the treatment of glaucoma (25), and in a viscoelastic tear formulation for conjunctivitis (26). The covalent binding of adriamycin and daunomycin to sodium hy-aluronate to produce water-soluble conjugates was recently reported (27). 

The DNA forms stable complexes with doxorubicin (Adriamycin, ADR) and daunorubicin (DNR). Doxorubicin and DNR, although structurally similar, show distinctly different properties ADR is more toxic and active than DNR in the treatment of various human solid tumors the apparent binding affinity of ADR to DNA is about 1.8 times higher than that of DNR to DNA. Trouet et al. [229] found the ADR-DNA complex to be more active than ADR, DNR, or DNR-DNA in subcutaneously inoculated leukemic mice, whereas the DNR-DNA complex showed the highest... 

Das, T.K. and Mazumdar, S., 2000, Effect of Adriamycin on the boundary hpid structure of cytochrome c oxidase pico-second time-resolved fluorescence depolarization studies. Biophys. Chem. 86 15-28... 

A compound of a very similar structure is phenazinomycin (67), which has been isolated from mycelial extracts of Streptomyces sp. WK-2057 by Omura et al. [69]. This compound possesses in vivo antitumor activity against experimental murine tumor cells and cytotoxic activity against adriamycin-resistant... 

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. 

In 1997, Chakrabarty et al. reported the isolation of 9-carbethoxy-3-methylcarba-zole (5) and 9-formyl-3-methylcarbazole (6) from the roots of M. koenigii (17). These metabolites are the first 9-formyl and 9-carbethoxy carbazole derivatives obtained from plant sources. 9-Formyl-3-methylcarbazole (6) showed weak cytotoxicity against both mouse melanoma B16 and adriamycin-resistant P388 mouse leukemia cell lines. The structural assignment of these two alkaloids was based on the IR- and H-NMR spectra which were lacking any signal of an NH group. Additional structural support for 9-carbethoxy-3-methylcarbazole (5) was provided by the similarity of the UV absorption spectrum with that of a synthetic sample, obtained by reaction of 3-methylcarbazole with ethyl chloroformate in the presence of base. Further structural support for 9-formyl-3-methylcarbazole (6) was derived from a comparison of the UV spectrum and the IR carbonyl absorption (1696 cm ) with those of an authentic sample of 9-formyl-3-methylcarbazole (1700 cm ), prepared by the treatment of 3-methylcarbazole (2) with 98% formic acid (17) (Scheme 2.3). 

The anthracycline antibiotics are fermentation products of Streptomyces peucetius. Daunorubicin (Cerubidine) is used to treat acute leukemias, while its structural analogue, doxorubicin (Adriamycin) is extensively employed against a broad spectrum of cancers. Although... 

Anthracyclines are antitumor quinone containing antibiotics produced by different strains of Streptomyces. Some of them, such as adriamycin doxorubicin), and daunorubicin are broad spectrum antitumor compounds. They act by binding to DNA and interfering with DNA replication and gene transcription. Their limitations for clinical use are cardiac toxicity and drug resistance phenomena. Consequently, intense structure-activity relationship studies have been performed to improve the pharmacological profile as well as to enhance the affinity for DNA. In particular, a number of fluorinated anthracyclines have been prepared with introduction of fluorine atoms into D or A cycles, and into the aglycone side chain linked atC-14. ... 

Fig. 9. Synthesis of a targetable dextran-adriamycin conjugate. Note that amino groups were introduced into the dextran structure, whereas the amino group of adriamycin was converted into a carboxylic group. According to [54]...

Synthesis of an adriamycin-HPMA copolymer-galactosamine conjugate is shown in Fig. 10. Attachment/release points at the side-chain termini are created by incorporation of tailor-made comonomers into the copolymer structure. 

Yokoyama, M., T. Okano, Y. Sakurai, and K. Kataoka. 1994. Improved synthesis of adriamycin-conjugated poly(ethylene oxide)-poly(aspartic acid) block copolymer and formation of unimodal micellar structure with controlled amount of physically entrapped adriamydirControl. Rel.32 269-277. 

Therapeutic Function Antineoplastic Chemical Name Adriamycin, trifluoroacetyl-, 14-valerate Common Name Valrubicin Structural Formula ... 

The modulation of synaptosomal plasma membranes (SPMs) by adriamycin and the resultant effects on the activity of membrane-bound enzymes have been reported [58]. Again DPH was used as fluorescence probe. Adriamycin increased the lipid fluidity of the membrane labeled with DPH, as indicated by the steady-state fluorescence anisotropy. The lipid-phase separation of the membrane at 23.3 °C was perturbed by adriamycin so that the transition temperature was reduced to 16.2 °C. At the same time it was found that the Na+,K+-stimulated ATPase activity exhibits a break point at 22.8 °C in control SPMs. This was reduced to 15.8 °C in adriamydn-treated SPMs. It was proposed that adriamycin achieves this effect through asymmetric perturbation of the lipid membrane structure and that this change in the membrane fluidity may be an early key event in adriamycin-induced neurotoxicity. 

Both aclacinomycin (ACM) and adriamycin (ADM) are antitumor and antibiotic drugs that bind to DNA. Figure 6-12 shows their structures, and Fig. 6-13 shows the RR spectra of these drugs mixed with poly(dA-dT) and poly(dG-dC) obtained by Nonaka et al. (25). It is seen that the fluorescence background is prominent in ADM-poly(dA-dT) but is quenched in ADM-poly(dG-dC). On the other hand, a strong fluorescence background is observed for ACM-poly(dG-dC) but is quenched for ACM-poly(dA-dT). These results suggest that ADM is intercalated between the G-C/C-G sequence, whereas ACM is intercalated between the A-T/T-A sequence of DNA. 

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). 

Macrolides and polyethers such as erythromycin A (4), FK 506, rapamycin or avermectin A (5, Scheme 1) are products of modular type I polyketide-synthases. These compounds are distinguished by extraordinary structural diversity and complexity [1,2]. Because of their biological potency, members of this structural class as well as the aromatic polycyclic products of type II polyketide-synthases, tetracyclines and anthara-cyclines, e.g. adriamycin (6), became useful as pharmaceuticals (antibiotics, cytostatics, immunosuppressives) [1,2],... 

The phenothiazines, such as chlorpromazine, used in the treatment of schizophrenia, the tricyclic antidepressant drugs such as imipramine and amitryp-tUine, antimalarials such as quinacrine, and the anticancer agent adriamycin are structural analogs of riboflavin (see Figure 7.6) and inhibit flavokinase. In experimental animals, administration of these drugs at doses equivalent to those used clinically results in an increase in the EGR activation coefficient (Section 7.5.2) and increased urinary excretion of riboflavin, with reduced tissue concentrations of riboflavin phosphate and FAD, despite feeding diets providing more riboflavin than is needed to meet requirements (Pinto et al., 1981). 

Figure 7.6. Drugs that are structural analogs of riboflavin and may cause deficiency. Relative molecular masses (Mr) riboflavin, 376.4 quinacrine, 472.9 (dihydrochloride) chlorpromazine, 318.9 imipramine, 280.4 amitryptyline, 277.4 and adriamycin (doxorubicin), 543.5.

The effect of adriamycin, an anti-tumor chemical, on cardiolipin (CL), a phospholipid specific to the inner mitochondrial membrane, was studied by ATR-IR spectroscopy. It was shown that in the very stable complex the structures of both adriamycin and cardiolipin are different from those of the pure substances (Goormaghtigh et al., 1987). 

Furthermore, the method can be applied to the synthesis of 4-demethoxyadriamy-cinone, which is the key structure of the anti-cancer drugs, the adriamycins such as idarubicin and aimamycin (52) (Eq. 3.69). The ruthenium-catalyzed oxidation of allyl acetate SO gives the corresponding a-hydroxyketone 51 in 60% yield (Eq. 3.69) [129]. 

Frederick CA, Williams LD, Ughetto G, Van der Marel GA, Van 76. Boom JH, Rich A, Wang AHJ. Structural comparison of anticancer drug-DNA complexes adriamycin and daunomycin. Biochemistry... 

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