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Biomedical subjects

F Arcamone

Publications and source records attributed to F Arcamone.

At least 55 records · Page 3Linked to original sources
PubMed1986

Synthesis, DNA binding and antiviral activity of distamycin analogues containing different heterocyclic moieties.

A series of novel distamycin analogues possessing an additional benzene or heterocyclic ring have been synthesised and tested for selective DNA binding properties and antiviral activity. Inhibition of herpes virus in cell culture appears to be related to AT base pair specificity. Some of the new compounds are also more potent than the parent distamycin against Moloney sarcoma virus.

Animals↗
PubMed1985

New anthracycline glycosides obtained by the nitrous acid deamination of daunorubicin, doxorubicin and their configurational analogues.

The new anthracyclines 7-O-(2,3,5-trideoxy-3-C-formyl-alpha-L-threo-pentofuranosyl)daunomyci none (8) and -adriamycinone (10) have been obtained upon nitrous acid deamination of daunorubicin and doxorubicin respectively. Deamination of the L-ribo analogue of daunorubicin (6) gave a mixture of 2,3,6-trideoxy-L-glycero-hexopyranosid-4-ulose (alpha-L-cinerulosyl) (11) and 2,6-dideoxy-alpha-L-arabino-hexopyranosyl (12) glycosides. The corresponding adriamycinone glycosides 13 and 14, obtained by deamination of the doxorubicin L-ribo analogue 7, were found to display an outstanding antileukemic activity in mice.

Animals↗
PubMed1985

Properties of antitumor anthracyclines and new developments in their application: Cain memorial award lecture.

The established efficacy of doxorubicin in the medical treatment of cancer is hampered by dose limiting side effects and lack of activity on major clinical tumors. The new derivative epirubicin (4'-epidoxorubicin) is already available clinically as a better tolerated drug, with confirmed efficacy on doxorubicin responsive diseases. Because of the different orientation of the 4'-hydroxyl, the compound is partially detoxified in the human body by beta-glucuronidation. The other clinically studied analogue, idarubicin (4-demethoxydaunorubicin), has shown clinical activity in leukemias and in breast tumors also when given p.o. The properties of idarubicin may be related to electronic factors and to the extensive bioconversion to 13(S)-idarubicinol. New lines of investigation are introduced. The first is represented by the irreversible DNA binding derivatives and is exemplified by the highly potent cyanomorpholino analogues. The second is based on the finding that certain structural modifications, such as in the 6-deoxy derivatives, are accompanied by resistance to enzymic reductive deglycosidation, a reaction that converts the anthracyclines to inactive compounds in hypoxic conditions. The third line of investigation deals with the very lipophilic doxorubicin analogues, among which 4'-deoxy-4'-iododoxorubicin has been selected for further preclinical development because of the extended spectrum of activity also after p.o. administration and of the cytotoxicity exhibited on doxorubicin-resistant murine leukemia cells.

Antibiotics, Antineoplastic↗
PubMed1984

[Adriamycin and its analogs].

Among the biologically active metabolites produced by Streptomyces peucetius adriamycin (syn. doxorubicin) appeared the most effective anthracycline. Because of the low yield of the biosynthetic process, the chemical conversion of daunorubicin to adriamycin represent the key-step of the development of the drug. The therapeutic importance of adriamycin prompted us to begin since 1972 a research program aimed to the development of the second generation anthracyclines. The studies carried out during this research program allowed to discover three new synthetic anthracyclines, which, for the time being, are under clinical investigation: 4'- epidoxorubicin ( epirubicin ), 4-demethoxydaunorubicin ( idarubicin ) and 4'-deoxydoxorubicin ( esorubicin ). These compounds, like daunorubicin and doxorubicin, show affinity to DNA, but some of their pharmacological properties and metabolism in animals as well as in humans are different in respect to those of the parent drugs. Herein the stages of the search for new analogs and the outlooks of further progress in the filed of the antitumor anthracyclines are shortly reported.

Animals↗
PubMed1984

Self-association of doxorubicin and related compounds in aqueous solution.

The dimerization of doxorubicin, daunorubicin, and their 4-demethoxy, 4'-epi, and 4'-deoxy analogues was studied spectrophotometrically. Self-association was found to be influenced by buffer composition and ionic strength. Kd values were 1.3 X 10(4) and 2.3 X 10(4) M-1 for doxorubicin and daunorubicin, respectively, and ranged from 3.8 X 10(3) to 6.1 X 10(3) M-1 for the 4-demethoxy analogues. For 4'-epi- and 4'-deoxydoxorubicin, tetramerization has also been considered. On this basis, values of 2.0 X 10(4) and 2.2 X 10(4) M-1 were found, respectively, for the formation constant of the dimerization process. Stability of the dimeric species appears to be strongly influenced by substitution of the chromophore moiety.

Chemistry, Pharmaceutical↗
PubMed1984

Radioactive species in rat urines and tissues after [14C] AD 32 administration.

[14-14C]N-Trifluoroacetyldoxorubicin-14-valerate [( 14C]AD 32) was synthesized and administered IV to male rats at 9.09 mg/kg. Urinary radioactivity excreted in the 0-24 h interval was only 2.3% of the dose, N-trifluoroacetyldoxorubicin (AD 41), 13-dihydro-N-trifluoroacetyldoxorubicin (AD 92), and doxorubicin being the major urinary metabolites identified. Doxorubicin and AD 32 were the main radioactive species extracted from tissues at 24 h after treatment. The amount of doxorubicin present in the analysed tissue samples is in agreement with the relatively low toxicity of AD 32 compared with doxorubicin.

Animals↗
PubMed1984

Disposition of 14C-labelled 4'-epidoxorubicin and doxorubicin in the rat. A comparative study.

The disposition of 4'-epi-[14-14C]doxorubicinHCl (4'-epi-[14C]DXR) and [14-14C]doxorubicinHCl [( 14C]DXR) was studied in male Sprague-Dawley rats given 1 mg/kg body weight IV. Most of the radioactivity administered was recovered in the faeces (two-thirds of the dose within 6 days after administration), urine accounting for 15% of the 14C given during the same period. A significant amount of radioactivity was also found in expired air. Significantly higher levels of radioactivity were recorded in the plasma (40 min and 4 h) and liver (40 min) in [14C]DXR-treated animals, whereas in animals treated with 4'-epi-[14C]DXR a higher specific radioactivity was found in the kidneys (40 min and 4 h) and bone marrow (40 min). The total tissue residual radioactivity was greater (P less than 0.05) at 24 h for [14C]DXR (45.8%) than for 4'-epi-[14C]DXR (38.6%). The main radioactive species in urines were the unchanged drugs. Minor metabolites were represented by a polar fraction, 13-dihydroderivatives, and aglycones. Whereas aglycones represent an important fraction of extractable tissue radioactivity in liver samples of many of the treated animals, the unchanged drug was invariably the major radioactive component in spleen, lung, and kidney. Liver extraction studies showed the presence of significant amounts of bound radioactivity that could be recovered in soluble form only after incubation with deoxyribonuclease. The main radioactive species present in the bile were the unchanged drug and a polar fraction. The amount of the former was higher in [14C]DXR-treated than in 4'-epi-[14C]DXR-treated animals. On the other hand, partial glucuronidation of 4'-epi-[14C]DXR was deduced on the basis of results of enzymic hydrolysis of bile samples.

Animals↗
PubMed1983

Chain length-dependent association of distamycin-type oligopeptides with A X T and G X C pairs in polydeoxynucleotide duplexes.

Different binding affinities of various distamycin analogs including the deformylated derivative with poly(dA-dC) X poly(dG-dT) were investigated using CD measurements. The inhibitory effect of distamycins on the DNAase I cleavage activity of DNA duplexes strongly supports the binding data. The base specificity of the ligand interaction with duplex DNA depends on the chain length of distamycin analogs. Netropsin, distamycin-2 and the deformylated distamycin-3 show no binding to dG X dC containing sequences at moderate ionic strength and are classified as highly dA X dT specific. In contrast distamycin having three, four or five methylpyrrolecarboxamide groups also forms more or less stable complexes with dG X dC-containing duplexes. These ligands possess a lower basepair specificity. The correlation between binding behavior and oligopeptide structure shows that presence of the number of hydrogen acceptor and donor sites determines the basepair and sequence specificity. The additional interaction with dG X dC pairs becomes essential when the number of hydrogen acceptor sites exceeds n = 3.

Animals↗
PubMed1983

Synthesis, biological and biochemical properties of new anthracyclines modified in the aminosugar moiety.

New 4'-C-methyl analogues of daunorubicin, synthesized by the coupling reaction of daunomycinone with 1-chloroderivatives of protected 4-C-methyldaunosamine analogues, were chemically transformed to the corresponding doxorubicin analogues. Their cytotoxic effect against HeLa cells, ability to bind to DNA, and in vivo toxicity and antitumor activity were compared with those of daunorubicin, doxorubicin, and their 4'-O-methyl analogues. The cytotoxic effect of the new anthracyclines could be correlated with their ability to bind to DNA and with their toxicity in experimental animals; however, the antitumor effectiveness did not seem to be related to these parameters. In general all the compounds retained a remarkable antitumor activity at their optimal doses. The most active compound against P388 leukemia was 4'-O-methyldoxorubicin, which was also more active than doxorubicin against L1210 leukemia.

Animals↗
PubMed1982

New anthracycline glycosides: 4-O-demethyl-11-deoxydoxorubicin and analogues from Streptomyces peucetius var. aureus.

The new anthracyclines 4-O-demethyl-11-deoxydoxorubicin, 4-O-demethyl-11-deoxydaunorubicin along with its 13-dihydro and 13-deoxo analogues are the main components of the anthracycline complex produced by cultures of Streptomyces peucetius var. aureus. They were isolated by solvent partition, separated by column chromatography and characterized by chemical and physical methods. Among these new anthracyclines, displaying antibacterial and cytotoxic activity "in vitro", 4-O-demethyl-11-deoxydoxorubicin and the corresponding daunorubicin analogue were also active against experimental tumors.

Animals↗
PubMed1982

o-Methylation on anthracyclines and anthracyclinones. New o-methyl ethers of daunorubicin and its analogues.

The synthesis of four new ethers of daunorubicin, namely 6-, 9-, 11-monomethyl and 6,9-dimethyl, along with the 4'-methyl ethers of 11-deoxydaunorubicin and 11-deoxydoxorubicin is reported. While the methylation of any of the mentioned hydroxyl groups of the aglycone moiety of daunorubicin resulted in a practically complete loss of bioactivity, the methylation of the aminosugar hydroxyl group of 11-deoxydaunorubicin and 11-deoxydoxorubicin increased their effectiveness on P 388 leukemia in mice.

Animals↗
PubMed1982

Metabolism of metergoline in the rat.

[19,10-3H] Metergoline was administered orally to female rats and radioactive metabolites were recovered form urine and bile. Besides unchanged drug, the presence of 1-demethylmetergoline (II) was confirmed both in urine and bile. Two other urinary metabolites were identified, namely 8 beta-aminomethyl-6-methylergoline (IX) and 8 beta-acetylaminomethyl-6-methylergoline (VI). A third metabolite, 1,6-dimethyl-8 beta-aminomethylergoline (VIII), was identified only in bile. Beside these metabolites, further polar and so far unidentified biotransformation products are present both in bile and urine, accounting for about half of the radioactivity present in these excreta.

Administration, Oral↗