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F Arcamone

Publications and source records attributed to F Arcamone.

At least 19 recordsLinked to original sources
PubMed1995

2-Substituted penems with amino acid-related side chains: synthesis and antibacterial activity of a new series of beta-lactam antibiotics.

A new series of 6-(hydroxyethyl)penems 2-substituted with amino acid-related side chains was synthesized. The nature of the amino acyl derivative proved to be crucial both from a synthetic point of view, as beta-lactam ring opening can compete with C-2 nucleophilic substitution, and for antibacterial activity. Primary amino acid amides emerged as the most suitable side chains for enhancing permeability through a Gram-negative outer membrane. In vitro activity of the new 2-[(aminoamido)methyl]penems 3a-u was influenced by the nature and position of the amide moiety, the ring size for cyclic amides, and the configuration of the amino acid. Compounds bearing amides derived from small N-methyl amino acids (such as 3a) or from cyclic amino acids (such as prolinamide 3p and 4-hydroxyprolinamide 3r) showed broad spectrum in vitro activity against both Gram-positive and Gram-negative microorganisms.

Amino Acids↗
PubMed1995

Synthesis and biological evaluation of novel NK-1 tachykinin receptor antagonists: the use of cycloalkyl amino acids as a template.

In the course of a program aimed at synthesizing novel, potent NK-1 tachykinin receptor antagonists, we developed upon a bioactive model by comparing the low energy structures of a series of peptide and nonpeptide Substance P antagonists. The comparison was based on the superimposition of the aromatic rings, assuming that the rest of the molecule behaves predominantly as a template to arrange the key aromatic groups in the right spatial position. A series of 2-aminocyclohexane carboxylic acid analogues were then selected as the best templates for reproducing the postulated bioactive structure, leading to several pseudo-peptides with interesting biological activity. According to the molecular modeling, these compounds exhibit a neat parallel facing of the indolyl and naphthyl groups at about 3 A distance. Ultraviolet absorption and steady state fluorescence measurements support this conclusion, showing a linear correlation between the spectral properties and the binding affinity of these analogues. Stacking of the indole ring with naphthalene gives rise to a complex characterized by a well-defined molar extinction coefficient. Consistently, steady state and lifetime fluorescence measurements suggest that the quenching process is ascribable to ground-state interactions between the chromophores. Implications of the pi stacking propensity of aromatic groups in the biological activity of the compounds examined are briefly discussed.

Amino Acids↗
PubMed1995

5-Iodo-2'-deoxy-L-uridine and (E)-5-(2-bromovinyl)-2'-deoxy-L-uridine: selective phosphorylation by herpes simplex virus type 1 thymidine kinase, antiherpetic activity, and cytotoxicity studies.

5-Iodo-2'-deoxy-L-uridine (L-IdU) and (E)-5-(2-bromovinyl)-2'-deoxy-L-uridine (L-BVdU) have been prepared and found to inhibit herpes simplex virus type 1 (HSV-1) thymidine kinase (TK) with activities comparable to those of their analogs with the natural D-sugar configuration. The mechanism of inhibition is purely competitive for L-IdU (Ki = 0.24 microM) and mixed-type for L-BVdU (Ki = 0.13 microM). High performance liquid chromatographic analysis of the reaction products demonstrated that the viral enzyme phosphorylates both L-enantiomers to their corresponding monophosphates with efficiency comparable to that for D-enantiomers. Neither L-enantiomer inhibits the human cytosolic TK. In contrast to their D-enantiomers, L-IdU and L-BVdU have no effect on human thymidylate synthase, either in HeLa cells or in TK-deficient HeLa cells transformed with the HSV-1 TK gene. Both L-enantiomers (i) have no effect on HeLa cell growth, (ii) are 1000-fold less cytotoxic toward TK-deficient HeLa cells transformed with the HSV-1 TK gene than are their D-enantiomers, (iii) in contrast to their D-enantiomers, are fully resistant to hydrolysis by nucleoside phosphorylase, and, (iv) in spite of their much lower cytotoxicity, most probably due to the very low affinity of L-BVdU monophosphate and L-IdU monophosphate for thymidylate synthase, are only 1 or 2 orders of magnitude less potent than their D-enantiomers in inhibiting viral growth, with potency comparable to that of acyclovir.

Antineoplastic Agents↗
PubMed1992

L-thymidine is phosphorylated by herpes simplex virus type 1 thymidine kinase and inhibits viral growth.

We have demonstrated that herpes simplex 1 (HSV1) thymidine kinase (TK) shows no stereospecificity for D- and L-beta-nucleosides. In vitro, L enantiomers are not recognized by human TK, but function as specific substrates for the viral enzyme in the order: L-thymidine (L-T) >> 2'-deoxy-L-guanosine (L-dG) > 2'-deoxy-L-uridine (L-dU) > 2'-deoxy-L-cytidine (L-dC) > 2'-deoxy- L-adenosine (L-dA). HSV1 TK phosphorylates both thymidine enantiomers to their corresponding monophosphates with identical efficiency and the Ki of L-T (2 microM) is almost identical to the Km for the natural substrate D-T (2.8 microM). The L enantiomer reduces the incorporation of exogenous [3H]T into cellular DNA in HeLa TK-/HSV1 TK+ but not in wild-type HeLa cells, without affecting RNA, protein synthesis, cell growth, and viability. L-T markedly reduces HSV1 multiplication in HeLa cells. Our observations could lead to the development of a novel class of antiviral drugs characterized by low toxicity.

Cell Division↗
PubMed1991

Distamycin inhibits the binding of a nuclear factor to the -278/-256 upstream sequence of the human HLA-DR alpha gene.

In this study we analyse the effects of the anti-tumor compound distamycin on the binding of nuclear factor(s) to a synthetic oligonucleotide (GTATA/IFN-gamma) mimicking a putative regulatory region of the human HLA-DR alpha gene. This region contains the sequence (GTATA), that is required for nuclear protein binding and is likely to interact with distamycin. The present results, by showing that distamycin inhibits the interaction between nuclear factors and the GTATA/IFN-gamma oligonucleotide, suggest that distamycin might alter the binding of transacting factors to cis-elements containing AT/TA sequences. Alterations of nuclear protein binding to specific target sequences could be one of the molecular mechanism(s) by which distamycin exerts its antiproliferative activity on living cells.

Antineoplastic Agents↗
PubMed1989

Correlation between growth inhibition and intranuclear doxorubicin and 4'-deoxy-4'-iododoxorubicin quantitated in living K562 cells by microspectrofluorometry.

Intranuclear drug concentration in cells treated with doxorubicin (DXR) or with 4'-deoxy-4'-iododoxorubicin (IDX) was measured by means of a quantitative microspectrofluorometric technique recently developed by us. Resolution of free and bound drug contributions in fluorescence emission spectra, as collected from a microvolume of single living cell nuclei, provided concentration data with about 10% indetermination. Uptake of DXR and IDX into the nucleus of K562 cells and DXR-resistant K562/DXR cells could then be studied with a sensitive, nondestructive technique. Growth inhibitory concentrations of K562 and K562/DXR cells, when measured with respect to drug content in the medium, differed by a factor of 25 in the case of DXR and by a factor of three in the case of IDX. By contrast, intranuclear drug concentrations measured at corresponding growth inhibitory concentrations are found to be nearly constant, i.e., independent of cellular-resistant phenotype and of anthracycline structure. This result supports an identical mechanism of action for the two drugs, most probably targeted to the nucleus, and ascribes to intracellular transport the different potency of the two drugs in the two cell lines.

Algorithms↗
PubMed1989

Association of anthracyclines and synthetic hexanucleotides. Structural factors influencing sequence specificity.

The equilibrium and kinetic aspects of the interaction between four anthracyclines and two synthetic self-complementary hexanucleotides was investigated by fluorescence detection. Two of the studied anthracyclines are widely used antitumor drugs: doxorubicin (1, formerly adriamycin) and daunorubicin (2, formerly daunomycin). The other two, 9-deoxydoxorubicin (3) and 3'-deamino-3'-hydroxy-4'-epidoxorubicin (4), are doxorubicin analogues with modifications of the chemical groups that have been proposed as responsible for sequence specificity (Chen, K.-X., Gresh, N. and Pullman, B. (1985). J. Biomol. Struct. Dyn. 3, 445-466). One of the oligonucleotides, d(CGTACG), is identical to that used in the high resolution x-ray structure determination of the daunorubicin intercalative complex (Wang, A. H.-J., Ughetto, G., Quigley, G. J. & Rich, A. (1987). Biochemistry 26, 1152-1163). Binding to this hexanucleotide is compared with intercalation into the d(CGCGCG) duplex, revealing sequence preferences of the four anthracyclines. Taking into account the anthracycline aggregation and the dissociation of the hexanucleotide double standard form, results can be interpreted with a model that assumes complete fluorescence quenching at intercalative sites containing the CG base pair, and a large residual fluorescence after intercalation within the TpA fragment. All four anthracyclines show preferential intercalation at sites near the ends of both hexanucleotide duplexes, partly as a result of positive cooperativity in the formation of di-intercalated species at these sites. Within the limits of experimental error, complete site specificity for the CpG fragment is found in the intercalation of 1 and 2 into d(CGTACG) duplex, whereas analogues 3 and 4 give increasing evidence of intercalation at other sites including the fluorescence-preserving TpA fragment. Site specificity is less pronounced in the association with d(CGCGCG), when cooperativity is taken into account. Kinetic data corroborate the results of equilibrium studies and are interpreted with a mechanism that includes formation of an intermediate bound species followed by drug redistribution to preferential sites. Finally, from a comparison of pertinent site binding constants, approximate free energy contributions to sequence specific DNA interaction, due to C9-OH on the aglycone and -NH3+ on daunosamine, are estimated not to exceed 2 kcal/mol.

Antibiotics, Antineoplastic↗
PubMed1989

Joint experimental and theoretical investigation of the comparative DNA binding affinities of intercalating anthracycline derivatives.

The comparative binding affinities for poly(dA-dT) and poly(dG-dC) of novel antitumor anthracyclines are reported. The data concern, besides the parent compound adriamycin (ADM), 4-demethoxy 6-deoxy 6-aminodaunomycin (II), 9-deoxy-ADM (III), 4-demethyl-6-O-methyl-ADM (IV), and 3'-deamino-3'-hydroxy-4'-epi-ADM (IV). Theoretical computations are performed in parallel for their comparative binding affinities to model double-stranded hexanucleotides, d(GCGCGC)2, d(TATATA)2, and d(CGTACG)2, using the SIBFA (sum of interactions between fragments computed ab inito) procedure. The computations reproduce in a very satisfactory manner the most salient features of the experimental comparative binding affinities. These encompass, in particular, a higher affinity for the d(TATATA)2 oligomer of II than that of ADM, despite the absence of the 14-OH substituent in II, a marked reversal of the CG versus TA sequence selectivity of the neutral compound V, favoring the d(CGCGCG)2 oligomer over the d(TATATA)2 one; and the deleterious effect incurred on the binding affinities by the presence of an O-methyl substituent at position 6 of the chromophore.

Antibiotics, Antineoplastic↗
PubMed1988

Studies of anthracycline--DNA complexes by circular dichroism.

A series of doxorubicin and daunorubicin analogues have been investigated in aqueous solution and as DNA-bound forms by means of circular dichroism (c.d.) spectroscopy. The structural variants comprise modifications on the amino sugar, on the aliphatic ring and the side chain of the aglycone moiety, and of the substitution pattern of the anthraquinone chromophore. Results with compounds having conformational constraints interfering with optimal fitting to DNA indicate that stereochemistry and conformation of the aliphatic ring predominantly affect c.d. spectra of anthracyclines in DNA-bound as well as in free form. Conformational correspondence with the known structure of the daunorubicin-oligonucleotide complex is inferred from the spectra of derivatives with modifications at position 6 or 11 in the anthraquinone chromophore. On the other hand, a different binding geometry is postulated for compounds either lacking the 4-methoxy group of daunorubicin (idarubicin and derivatives) or having a phenolic function in its place (carminomycin and derivatives). A possible relation with cytotoxic activity is discussed at a speculative level.

Antibiotics, Antineoplastic↗
PubMed1987

Chemical and biological characterization of 4'-iodo-4'-deoxydoxorubicin.

4'-Iodo-4'-deoxydoxorubicin is a doxorubicin (DXR) analogue with greater lipophilicity and reduced basicity of the amino group. In vitro 4'-iodo-4'-deoxydoxorubicin is more cytotoxic than DXR against a panel of human and murine cell lines and is characterized by a higher and faster uptake. In vivo, the spectrum of activity of 4'-iodo-4'-deoxydoxorubicin is comparable to that of DXR, but the new compound has higher activity against murine P388 leukemia resistant to DXR and against pulmonary metastases from Lewis lung carcinoma. Moreover, the new analogue exhibits antitumor activity also after p.o. administration and shows no cardiotoxicity in experimental systems.

Administration, Oral↗
PubMed1986

Disposition and metabolism of [14-14C] 4-demethoxydaunorubicin HCl (idarubicin) and [14-14C]daunorubicin HCl in the rat. A comparative study.

The disposition of [14-14C]4-demethoxydaunorubicin HCl ([14-14C]idarubicin HCl, [14C]IDR) and of [14-14C]daunorubicin HCl ([14C]DNR) was studied in male Sprague Dawley rats. [14C]IDR was administered either IV at 0.25 mg/kg body weight or PO at 1 mg/kg body weight, whereas [14C]DNR was dosed IV at 1 mg/kg body weight. The main elimination route for both compounds was the bile, fecal excretion representing 0.75-0.8 times the total dose at 72 h. Radioactivity due to [14C]IDR-derived species is released by the tissues at a slower rate than activity derived from [14C]DNR. After IV treatment comparable plasma levels are obtained, but tissue radioactivity is markedly lower with [14C]IDR, in keeping with the lower dosage. The ratio of plasma to tissue radioactivity is even higher in animals treated PO with [14C]IDR, because of the more extensive metabolism after this route of administration. The 13-dihydro derivatives of both [14C]IDR and [14C]DNR are the main metabolites in tissues, but in the case of the former, products of phase II reactions become more important at later times in liver and kidney and in excreta.

Administration, Oral↗
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↗