Distamycins compound

First, yeast RNA and (in the case of distamycin-A) apurinic and apyrimidinic DNA at r- 0.025 did not change the characteristic absorption band of the free compounds. The absorption spectrum of distamycin-5 was enhanced in the presence of RNA. 

The cytotoxicity of distamycin derivatives was estimated on the basis of the morphological modifications induced in HeLa cell cultures, after incubation for 40 h in Hanks saline solution + 0.5 % lactalbumin hydrolysate + 5 % calf serum (HLS). Assay on vaccinia virus Cultures of HeLa cells (grown in HLS medium) or mouseembryo cells (grown in HLS medium plus 0.1 % yeastolate) infected with vaccinia virus (Strain WR/ATCC) were used. Preliminary assays were made according to Herrmann et al.° Subsequent studies were carried out by assessing the inhibition of plaque formation (ECP) as well as the inhibition of infectious virus production in test tube cultures treated with the compounds for 40 h after the absorption of the virus. 

The cytotoxicity and antiviral activity of distamycin derivatives containing 2, 3, 4 and 5 pyrrole rings is shown in Table 1. The cytotoxicity of the derivatives with 2 and 3 pyrrole residues is the same. However, compounds containing 4 and 5 pyrrole rings (distamycin/4 and distamycin/5) are less toxic. The cytotoxicities of distamycin/4 and distamycin/5 are only 50% and 25% of the natural antibiotic (distamycin/A) respectively. It seems therefore, that the cytotoxicity decreases as the number of pyrrole rings increases. This is at least true for distamycin/A, distamycin/4 and distamycin/5. Our studies on dista-mycin/6 (distamycin with 6 pyrrole rings) have, however, shown that no such relationship strictly exists. Distamycin/6 was found to be as toxic as distamycin/4. 

The results, reported in Fig. 8, show that treatment with distamycin/A, distamycin/4 and distamycin/5 reduces the number of MSV-foci produced in vitro. The inhibitory activity was dependent on the dose used, and increased according to the number of pyrrole residues in the molecule. The cytotoxic activity of these compounds increases at higher doses however, it was always less than their antiviral activity. 

Activity calculated with respect to that of compound I (distamycin A) considered = 100. 

Chandra et al.4> have shown that the antiviral activity of distamycin and their action on the template activity of DNA are dependent on the number of pyrrole rings in the molecule. The distamycin derivative with 5 pyrrole rings (distamycin/5) has 10 times higher antiviral activity than distamycin A (with 3 pyrrole rings), and is a better inhibitor of the RNA-polymerase reaction. It was therefore interesting to study the correlation between the antiviral activity and the inhibition of RNA-polymerase reaction by compounds I, II, III and IV. The effect of an equimolar concentration (8 x 10-5 M) of the distamycin derivatives on the template activity of DNA is shown in Table 9. The derivatives were added into the reaction mixture as described above. The highest inhibition was obtained with the natural antibiotic (distamycin A) followed by compounds IV, II and III, respectively. The cyclopentylpropionyl derivative, having no... 

Other examples are symmetrical bradykinin antagonists and symmetrical lexitropsins (netropsine, distamycine), active against HTV-I viruses. Non-symmetrical polymethylenic thromboxane synthetase inhibitors are described by Press et al The compounds contain a thiophene-2-carboxamide moiety, separated from an imidazole ring by 3-8 methylene units. Surprisingly, whereas most of the compounds show... 

A number of synthetic analogues of distamycin and netropsin have been found to have excellent antitumor activity. For example, FCE 24517 (41), which is a nitrogen mustard-distamycin hybrid, is in clinical trials . The distamycin derivative (42) has increased water solubihty and enhanced cellular uptake <95H(4l)337>, and (43) is one of several related antitumor compounds with... 

DNA cleaving activity of PYML(6)-(4/ -APA)-distamycin was found to be more potent than that of PYML(6)-bleomycin and dramatic change in the base sequence specificity was observed. Evidently, PYML(6)-4R-APA)-distamycin predominantly cleaved AT rich regions which were not cleaved by BLM (Fig. 21B). The difference in the cleavage pattern between Dervan s compound and our compound remains to be explored in more detail. The inspection of the manmade BLM with a molecular model strongly suggests that the molecule bends at the 4R-APA linker to orient the metal center exactly to the observed cleavage site. 

This mechanism of action is not unique. In fact, there are several natural products that can similarly read the edge of the minor groove of DNA through hydrogen bond interactions. One such compound is distamycin A, which, as shown below, contains three peptide bond-linked pyrroles that can also target AT-rich regions of DNA. 

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