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Papers by Federico Arcamone
Journal of the Chemical Society, Chemical Communications, 1978
The nocardicin skeleton has been s'iereospecifically synthesised from readily available penicilli... more The nocardicin skeleton has been s'iereospecifically synthesised from readily available penicillin derivatives.
Nucleic Acids Research, Jun 1, 1997
Conjugation of an anthracycline to a triplex-forming oligonucleotide (TFO) allows delivery of thi... more Conjugation of an anthracycline to a triplex-forming oligonucleotide (TFO) allows delivery of this drug to a specific DNA site, preserving the intercalation geometry of this class of anticancer agents. Conjugate 11, in which the TFO is linked via a hexamethylene bridge to the O-4 on the D ring of the anthraquinone moiety, affords the most stable triple helix, through intercalation of the planar chromophore between DNA bases and binding of both the TFO and the amino sugar to the major and the minor groove respectively.
Biochemical Pharmacology, Feb 15, 1991
In this study we analyse the effects of the anti-tumor compound distamycin on the binding of nucl... more 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-y) mimicking a putative regulatory region of the human HLA-DRo~ 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-y 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.
J Am Chem Soc, 1980
... lo Studio e la Cura dei Tumori, Milan, Italy, and are reported here by the courtesy of A. Di ... more ... lo Studio e la Cura dei Tumori, Milan, Italy, and are reported here by the courtesy of A. Di Marco and A ... Federico Arcamone,* Guiseppe Cassinelli Franco DiMatteo, Salvatore Forenza, M. Clara Ripamonti Cioranni Rivola, Aristide Vigevani Farmitalia, C. Erba Spa Via Dei Gracchi ...
Cancer chemotherapy reports. Part 1
Il Farmaco; edizione scientifica
Antiviral Chemistry and Chemotherapy, 1997
Molecular Pharmacology
The comparative binding affinities for poly(dA-dT) and poly(dG-dC) of novel antitumor anthracycli... more 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.
Anti-cancer drug design
A series of doxorubicin and daunorubicin analogues have been investigated in aqueous solution and... more 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.
Il Farmaco
New series of monobactam antibiotics, bearing thio-and dithiocarbamate derivatives as C-4 side ch... more New series of monobactam antibiotics, bearing thio-and dithiocarbamate derivatives as C-4 side chain, were synthesized. Some compounds were found to have good antibacterial activity against Gram-negative bacteria.
Molecular Pharmacology
5-Iodo-2'-deoxy-L-uridine (L-IdU) and (E)-5-(2-bromovinyl)-2'-deoxy-L-uridine (L-... more 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.
Nucleic Acids Symposium Series
Journal of the Chemical Society, Chemical Communications, 1978
The nocardicin skeleton has been s'iereospecifically synthesised from readily available penicilli... more The nocardicin skeleton has been s'iereospecifically synthesised from readily available penicillin derivatives.
Nucleic Acids Research, Jun 1, 1997
Conjugation of an anthracycline to a triplex-forming oligonucleotide (TFO) allows delivery of thi... more Conjugation of an anthracycline to a triplex-forming oligonucleotide (TFO) allows delivery of this drug to a specific DNA site, preserving the intercalation geometry of this class of anticancer agents. Conjugate 11, in which the TFO is linked via a hexamethylene bridge to the O-4 on the D ring of the anthraquinone moiety, affords the most stable triple helix, through intercalation of the planar chromophore between DNA bases and binding of both the TFO and the amino sugar to the major and the minor groove respectively.
Biochemical Pharmacology, Feb 15, 1991
In this study we analyse the effects of the anti-tumor compound distamycin on the binding of nucl... more 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-y) mimicking a putative regulatory region of the human HLA-DRo~ 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-y 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.
J Am Chem Soc, 1980
... lo Studio e la Cura dei Tumori, Milan, Italy, and are reported here by the courtesy of A. Di ... more ... lo Studio e la Cura dei Tumori, Milan, Italy, and are reported here by the courtesy of A. Di Marco and A ... Federico Arcamone,* Guiseppe Cassinelli Franco DiMatteo, Salvatore Forenza, M. Clara Ripamonti Cioranni Rivola, Aristide Vigevani Farmitalia, C. Erba Spa Via Dei Gracchi ...
Cancer chemotherapy reports. Part 1
Il Farmaco; edizione scientifica
Antiviral Chemistry and Chemotherapy, 1997
Molecular Pharmacology
The comparative binding affinities for poly(dA-dT) and poly(dG-dC) of novel antitumor anthracycli... more 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.
Anti-cancer drug design
A series of doxorubicin and daunorubicin analogues have been investigated in aqueous solution and... more 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.
Il Farmaco
New series of monobactam antibiotics, bearing thio-and dithiocarbamate derivatives as C-4 side ch... more New series of monobactam antibiotics, bearing thio-and dithiocarbamate derivatives as C-4 side chain, were synthesized. Some compounds were found to have good antibacterial activity against Gram-negative bacteria.
Molecular Pharmacology
5-Iodo-2'-deoxy-L-uridine (L-IdU) and (E)-5-(2-bromovinyl)-2'-deoxy-L-uridine (L-... more 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.
Nucleic Acids Symposium Series