Daunomycin derivatives

The inhibitory effect of the various daunomycin derivatives on viral oncogenesis by FL VandRSVis shown in Table 15. FLV suspensions, prepared as described above, were incubated with and without the antibiotic (50 pg/ml) for 1 h at 37 °C and 0.1 ml of this suspension (ID90) was injected intraperito-neally into mice. Each experimental group contained six animals five of the six control animals died after 13 days of infection at which time all the animals... 

The inhibitory activity of daunomycin and its structural analogues on viral oncogenesis by FLV and RSV, and on in vitro transformation by MSV (M) suggests that it is the activity of the virus-associated enzymes which is sensitive to these antibiotics. The RNA-dependent DNA polymerase of the virions is responsible for the synthesis of viral DNA. Table 16 shows how the reverse-transcriptase activity of MSV (M), FLV and RSV is inhibited by various daunomycin derivatives. 

Table 16. Inhibition of reverse-transcriptase activity of RNA tumor viruses by daunomycin derivatives. Figures in brackets are percentages...

Table 17 shows how template-dependent DNA polymerase activity of FLV is inhibited by various daunomycin derivatives. The reactions catalyzed by poly-(dA-dT) and poly (rA) (dT)i2 are highly sensitive to the action of daunomycin and its derivatives. Here again, daunomycin and adriamycin are most effective, and the N-acetyl derivative is completely inactive. It is interesting that the poly (dA-dT)-and poly (rA) (dT)i2-dependent reactions are more sensitive to these antibiotics than the endogenous reaction (see Table 17), while the DNA polymerase reaction catalyzed by poly (dl-dC) is completely insensitive. The most active derivatives (daunomycin, adriamycin and dihydro daunomycin) slightly stimulate 3H-dGMP incorporation catalyzed by poly (dl-dC). This stimulation is particularly noticeable in the case of dihydro daunomycin. Surprisingly, the N-acetyl derivative was found to inhibit this reaction. The mechanism of this inhibition is not understood. 

The inhibition of template-dependent DNA polymerase activity of MSV (M) by various daunomycin derivatives was also studied. Like the FLV system, the MSV poly (dA-dT)-and poly (rA) (dT)i2-dependent reactions were extremely sensitive to daunomycin derivatives. In both cases the N-acetyl derivative was completely ineffective. Again as with the FLV system, we found that the poly (dl-dC) - catalyzed incorporation of 3H-dGMP was not inhibited by any of the derivatives. In this system, unlike the FLV system, the N-acetyl derivative did not inhibit 3H-dGMP incorporation into DNA. Dihydro daunomycin here too greatly stimulated 3H-dGMP incorporation in the presence of poly (dl-dC).. 

The results show that the inhibition exerted by daunomycin derivatives against DNA polymerase from RNA tumor viruses is selectively dependent on... 

Table 18. Inhibition of growth of some transplanted tumors by daunomycin derivatives. Tumor suspensions were in-cubated with 50 jUg/ml of the antibiotic at 37 °C for 1 h...

Since Brockman s discovery of toxic pigments produced by Streptomyces in the early 1960s [8], thousands of new daunomycin derivatives have been obtained, either by synthesis involving glycosidic bond reassembly or by directed biogenesis. Early discussions on structure-activity relationships are presented in a fundamental account elaborated by Arcamone [3,92]. Over the years, as the methods for evaluation of drug candidates became more so-... 

A review of the synthesis of anthracyclinones by elaboration of anthraquinones includes a section on the use of sugars as chiral templates. Glycosylations of the daunomycinones (46)-(48) led to the corresponding daunomycin derivatives (49)-(51). The L-fyxo-, L-arabino- and L-nfeo-isomers of the isorhodomycin compounds (52) have been made and tested for cytotoxicity. Several analogues of the anthracycline antibiotics, eg. (53), having a 1,2,3-triazolyl moiety in the sugar, have been described. ... 

An electrochemical assay for biotin has been described (96). This assay involves an electroactive biotinyl-5 -daunomycin derivative. Upon binding to avidin the biotinyldaunomycin loses its electrochemical properties. Therefore free biotin will compete for binding to avidin and will increase the electrode response. This method has the advantage that separation of bound and free biotin is not necessary. The sensitivity was good (0.1 Xg range) for biotin, but the response was not linear. 

Since most P-gp effectors are hydrophobic, it was of interest to study flavonoids substituted with different hydrophobic groups, for example the isoprenyl group [210]. Isoprenylated flavonoids are natural compounds which constitute a class of plant secondary metabolites. Comte et al. [210] have synthesized a series of C- or O-substituted hydrophobic derivatives of chrysin (22). Increasing the hydrophobicity of substituents at positions 6, 7, or 8 increased the affinity of binding to the purified cytosolic domain of P-gp. Isoprenylated derivatives also increased intracellular daunomycin (78) accumulation in K562/R7 leukemic cells. 

Table 14. Effect of daunomycin and its derivatives on the thermal transition temperature (Tm) and viscosity of DNA...

The derivatives substituted in the amino sugar moiety were ineffective. Oncogenesis by RSV in chickens was similarly inhibited by daunomycin and its analogues, mean survival time being prolonged from 12.3 days to 28.3 days by adriamycin. Daunomycin was even more effective but, the other derivatives had no significant effect. 

Daunomycin and related derivatives were found to affect cell proliferation and MSV (M) foci production differently. In both tests, the activity of daunomycin and adriamycin was found to be a linear function of the dose. However, as the dose-effect curve of foci inhibition has a steeper slope than that of cell proliferation, the two lines cross over. Hence higher doses give greater inhibition of foci formation than of cell proliferation. Almost total inhibition of foci formation could be achieved by treatment with daunomycin or adriamycin at about 0.025 jug/ml. 

Daunomycin and adriamycin at 10 jug/reaction mixture (0.25 ml) inhibit the reverse-transcriptase reaction by 60—70%. The dihydro derivative is also quite effective whereas the N-guanidine derivative has moderate activity. The N-acetyl derivative was completely ineffective in the MSV (M) and FLV systems but moderately inhibited the RSV system. 

The antitumor activity of some derivatives of daunomycin at the amino and methyl ketone functions has been studied by Yamamoto etal. 43 Their studies were carried out mainly on leukemia 1210 in mice. At 2 mg/kg dose, the N-piperidinoimine derivative was found to have the same antitumor activity as daunomycin other derivatives were not active at this dose level. The N-acetyl derivative was found to posses only a little antitumor activity, but displayed no accute toxicity even at very high doses. According to our experience, the N-acetyl derivative was in most of the cases ineffective against tumor growth (Table 18). 

Berbamine was shown to have a similar but weaker effect than isotetrandrine or tetrandrine on overcoming resistance in the multidrug-resistant subline, ChR-24, derived from human KB carcinoma cells to various antineoplastic drugs. Berbamine partially overcomes the resistance of CHR24 cells to daunomycin [183]. 

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