The Experts below are selected from a list of 270 Experts worldwide ranked by ideXlab platform
Pier Giovanni Baraldi - One of the best experts on this subject based on the ideXlab platform.
-
hybrid molecules between DistAmycin A And Active moieties of Antitumor Agents
ChemInform, 2007Co-Authors: Pier Giovanni Baraldi, Delia Preti, Francesca Fruttarolo, Mojgan Aghazadeh Tabrizi, Romeo RomagnoliAbstract:The DNA minor groove is An AttrActive tArget for the design And development of molecules Able to specificAlly recognize predetermined DNA sequences. The pyrrole-Amide skeleton of DistAmycin A hAs been Also used As DNA sequence selective vehicle for the delivery of AlkylAting functions to DNA tArgets. Selectivity for specific sequences mAy be of pArticulAr importAnce in Affecting the Activity of regulAtory genes (oncogenes And tumor suppressor genes). Recent work on A number of hybrid compounds, in which known Antitumor compounds or simple Active moieties of known Antitumor Agents hAve been tethered to DistAmycin frAme or hAirpin polyAmides derived from DistAmycin, is reviewed. The DNA AlkylAting And growth inhibition Activities AgAinst severAl tumor cell lines Are reported And discussed in terms of their structurAl differences in relAtion to both the number of N-methyl pyrrolic rings And the type of the AlkylAting unit tethered to the oligopyrrolic frAme.
-
hybrid molecules bAsed on DistAmycin A As potentiAl Antitumor Agents
Arkivoc, 2005Co-Authors: Pier Giovanni Baraldi, Abdel Naser Zaid, Delia Preti, Francesca Fruttarolo, Mojgan Aghazadeh Tabrizi, Antonietta Iaconinoto, Maria Giovanna Pavani, Maria Dora Carrion, Carlota Lopez Cara, Romeo RomagnoliAbstract:MAny nAturAl And synthetic AnticAncer Agents with the Ability to interAct with DNA hAve been discovered, but most of them hAve relAtively low therApeutic index. This is probAbly relAted to the fAct thAt these derivAtives cAuse DNA dAmAge in An unspecific mAnner, inducing unselective growth inhibition And deAth, both in neoplAstic And in highly proliferAtive normAl tissues. For these reAsons, there hAs been considerAble interest in finding smAll molecules Able to AlkylAte the DNA with A much higher degree of sequence specificity And to modify the function of nucleic Acids irreversibly. AnAlogues of nAturAlly occurring Antitumor Agents, such As DistAmycin A, which bind in the minor groove of DNA, represent A new clAss of AnticAncer compounds currently under investigAtion. DistAmycin A hAs driven reseArcher's Attention not only for the biologicAl Activity, but Also for its non intercAlAtive binding to the minor groove of double- strAnded B-DNA, where it forms strong reversible complex preferentiAlly At the nucleotide sequences consisting of 4-5 AdjAcent AT bAse pAirs. The pyrrole-Amide skeleton of DistAmycin A hAs Also been used As DNA sequence selective vehicle for the delivery of AlkylAting functions to DNA tArgets, leAding to A shArp increAse of its cytotoxicity, in compArison to thAt, very weAk, of DistAmycin itself. The DNA AlkylAting And cytotoxic Activities AgAinst severAl tumor cell lines Are reported And discussed in terms of their structurAl differences in relAtion to both the number of N-methyl pyrrole rings And the type of the AlkylAting unit tethered to the oligopeptidic frAme.
-
dnA minor groove binders As potentiAl Antitumor And AntimicrobiAl Agents
Medicinal Research Reviews, 2004Co-Authors: Pier Giovanni Baraldi, Delia Preti, Francesca Fruttarolo, Mojgan Aghazadeh Tabrizi, Maria Giovanna Pavani, Andrea Bovero, Romeo RomagnoliAbstract:DNA minor groove binders constitute An importAnt clAss of derivAtives in AnticAncer therApy. Some of these compounds form noncovAlent complexes with DNA (e.g., DistAmycin A, Hoechst 33258, And pentAmidine) while others DNA-binding compounds (such As CC-1065) cAuse cleAvAges in the DNA bAckbone. In this Article, we hAve reviewed the minor groove binders currently in preclinicAl evAluAtion in the lAst yeArs. DiArylAmidines such As DAPI, berenil, And pentAmidine; bis-benzimidAzoles such As Hoechst 33258; ecteinAscidins, pyrrololo [2,1-c]-[1,4]-benzodiAzepines (PBDs), CC-1065, And DistAmycins Are the clAsses discussed in this review Article. A speciAl section hAs been dedicAted to hybrid molecules resulted by the combinAtion of two minor groove binders, especiAlly for derivAtives of nAturAlly occurring Antitumor Agents, such As AnthrAmycin or the AlkylAting unit of the Antibiotic CC-1065, And DistAmycin frAmes.
-
cytotoxic α hAlogenoAcrylic derivAtives of DistAmycin A And congeners
Journal of Medicinal Chemistry, 2004Co-Authors: Italo Beria, Paolo Cozzi, Marina Caldarelli, Cristina Geroni, Pier Giovanni Baraldi, Nicola Mongelli, Sergio Marchini, Romeo RomagnoliAbstract:The mechAnism of Action of mAny Antitumor Agents involves DNA dAmAge, either by direct binding of the drug to DNA or to DNA-binding proteins. However, most of the DNA-interActing Agents hAve only A limited degree of sequence specificity, which implies thAt they mAy hit All the cellulAr genes. DNA minor groove binders, Among which the derivAtives of DistAmycin A plAy An importAnt role, could provide significAnt improvement in cAncer mAnAgement, increAsing gene specificity, due to high selectivity of interAction with thymine-Adenine (TA) rich sequences. We now report And discuss the synthesis, the in vitro And in vivo Activities, And some mechAnistic feAtures of AlphA-hAlogenoAcrylAmido derivAtives of DistAmycin A. The finAl result of this work wAs the selection of brostAllicin 17 (PNU-166196). BrostAllicin, presently in phAse II clinicAl triAls, shows A broAd spectrum of Antitumor Activity And An Apoptotic effect higher thAn DistAmycin derivAtive tAllimustine. An importAnt in vitro toxicologicAl feAture of brostAllicin is the very good rAtio between myelotoxicity on humAn hAemAtopoietic progenitor cells And cytotoxicity on tumor cells, in compArison with clinicAlly tested DNA minor groove binders. A peculiArity of brostAllicin is its in vitro reActivity in the DNA AlkylAtion AssAys only in the presence of glutAthione. Moreover brostAllicin's Antitumor Activity, both in in vitro And in vivo tumor models, is higher in the presence of increAsed levels of glutAthione/glutAthione-S-trAnferAses. These findings contribute to the definition of brostAllicin As A novel AnticAncer Agent thAt differs from other minor groove binders And AlkylAting Agents for both the profile of Activity And the mechAnism of Action And to clAssify the AlphA-bromoAcrylAmido derivAtives of DistAmycin As A new clAss of cytotoxics. Moreover, due to its interAction with glutAthione, brostAllicin mAy hAve A role for the tAilored treAtment of tumors chArActerized by constitutive or therApy-induced overexpression of glutAthione/glutAthione-S-trAnferAse levels.
-
DistAmycin A As stem of dnA minor groove AlkylAting Agents
Current Topics in Medicinal Chemistry, 2004Co-Authors: Pier Giovanni Baraldi, Antonio Espinosa, Maria Del Carmen Nunez, Romeo RomagnoliAbstract:AnAlogues of nAturAlly occurring Antitumor Agents, such As DistAmycin A, which bind in the minor groove of DNA, represent A new clAss of AnticAncer compounds currently under investigAtion. DistAmycin A hAs driven reseArcher's Attention not only for their biologicAl Activity, but Also for its non intercAlAtive binding to the minor groove of double-strAnded B-DNA, where it forms strong reversible complex preferentiAlly At the nucleotide sequences consisting of 4-5 AdjAcent AT bAse pAirs. The pyrrole-Amide skeleton of DistAmycin A hAs been Also used As DNA sequence selective vehicles for the delivery of AlkylAting functions to DNA tArgets, leAding to A shArp increAse of its cytotoxicity, in compArison to thAt, very weAk, of DistAmycin itself. In the lAst few yeArs, severAl hybrid compounds, in which known Antitumor derivAtives or simple Active moieties of known Antitumor Agents hAve been tethered to DistAmycin frAmes, hAve been designed, synthesized And tested. SeverAl efforts hAve been mAde to modify DNA sequence selectivity And stAbility of the DistAmycin And the structurAl modificAtions hAve been bAsed on replAcement of pyrrole by other heterocycles And/or benzoheterocycles obtAining A novel clAss of minor groove binding molecules cAlled lexitropsins. The role of the Amidino moiety, by meAns of the substitution with vArious groups, which includes ionizAble, Acid or bAsic, And non-ionizAble groups, hAs been Also studied. The synthesis of A hybrid deriving Among the combinAtion of the DistAmycin A And nAturAlly occurring AlkylAting Agent hAs been Also reported. SeverAl clAsses of DistAmycin derivAtives thAt hAve been reported in the published literAture hAve been described in this review Article.
Romeo Romagnoli - One of the best experts on this subject based on the ideXlab platform.
-
hybrid molecules between DistAmycin A And Active moieties of Antitumor Agents
ChemInform, 2007Co-Authors: Pier Giovanni Baraldi, Delia Preti, Francesca Fruttarolo, Mojgan Aghazadeh Tabrizi, Romeo RomagnoliAbstract:The DNA minor groove is An AttrActive tArget for the design And development of molecules Able to specificAlly recognize predetermined DNA sequences. The pyrrole-Amide skeleton of DistAmycin A hAs been Also used As DNA sequence selective vehicle for the delivery of AlkylAting functions to DNA tArgets. Selectivity for specific sequences mAy be of pArticulAr importAnce in Affecting the Activity of regulAtory genes (oncogenes And tumor suppressor genes). Recent work on A number of hybrid compounds, in which known Antitumor compounds or simple Active moieties of known Antitumor Agents hAve been tethered to DistAmycin frAme or hAirpin polyAmides derived from DistAmycin, is reviewed. The DNA AlkylAting And growth inhibition Activities AgAinst severAl tumor cell lines Are reported And discussed in terms of their structurAl differences in relAtion to both the number of N-methyl pyrrolic rings And the type of the AlkylAting unit tethered to the oligopyrrolic frAme.
-
liposomes And micellAr dispersions for delivery of benzoheterocyclic derivAtives of DistAmycin A
Drug Delivery, 2007Co-Authors: Rita Cortesi, Romeo Romagnoli, Abdel Naser Zaid, Elisabetta Esposito, I Cuccu, Enea Menegatti, Claudio NastruzziAbstract:In this Article we describe the production And chArActerizAtion of speciAlized delivery systems for some DistAmycin derivAtives (DD), nAmely liposomes And micellAr dispersions. All the formulAtions were designed to increAse the solubility of DD in An Aqueous environment And to reduce the possible toxicity problems relAted to the AdministrAtion of these drugs. For instAnce, liposomes were prepAred by reverse phAse evAporAtion technique followed by extrusion through polycArbonAte filters, then chArActerized in terms of dimensions, morphology, And encApsulAtion efficAcy. The AnAlysis of their in vitro AntiproliferAtive Activity on cultured humAn And mouse leukemic cells demonstrAted thAt liposomes And micellAr dispersions contAining DD exert quite different effects. These effects were compAred with those shown by the free drug depending on type of drug And Also cell line used.
-
hybrid molecules bAsed on DistAmycin A As potentiAl Antitumor Agents
Arkivoc, 2005Co-Authors: Pier Giovanni Baraldi, Abdel Naser Zaid, Delia Preti, Francesca Fruttarolo, Mojgan Aghazadeh Tabrizi, Antonietta Iaconinoto, Maria Giovanna Pavani, Maria Dora Carrion, Carlota Lopez Cara, Romeo RomagnoliAbstract:MAny nAturAl And synthetic AnticAncer Agents with the Ability to interAct with DNA hAve been discovered, but most of them hAve relAtively low therApeutic index. This is probAbly relAted to the fAct thAt these derivAtives cAuse DNA dAmAge in An unspecific mAnner, inducing unselective growth inhibition And deAth, both in neoplAstic And in highly proliferAtive normAl tissues. For these reAsons, there hAs been considerAble interest in finding smAll molecules Able to AlkylAte the DNA with A much higher degree of sequence specificity And to modify the function of nucleic Acids irreversibly. AnAlogues of nAturAlly occurring Antitumor Agents, such As DistAmycin A, which bind in the minor groove of DNA, represent A new clAss of AnticAncer compounds currently under investigAtion. DistAmycin A hAs driven reseArcher's Attention not only for the biologicAl Activity, but Also for its non intercAlAtive binding to the minor groove of double- strAnded B-DNA, where it forms strong reversible complex preferentiAlly At the nucleotide sequences consisting of 4-5 AdjAcent AT bAse pAirs. The pyrrole-Amide skeleton of DistAmycin A hAs Also been used As DNA sequence selective vehicle for the delivery of AlkylAting functions to DNA tArgets, leAding to A shArp increAse of its cytotoxicity, in compArison to thAt, very weAk, of DistAmycin itself. The DNA AlkylAting And cytotoxic Activities AgAinst severAl tumor cell lines Are reported And discussed in terms of their structurAl differences in relAtion to both the number of N-methyl pyrrole rings And the type of the AlkylAting unit tethered to the oligopeptidic frAme.
-
dnA minor groove binders As potentiAl Antitumor And AntimicrobiAl Agents
Medicinal Research Reviews, 2004Co-Authors: Pier Giovanni Baraldi, Delia Preti, Francesca Fruttarolo, Mojgan Aghazadeh Tabrizi, Maria Giovanna Pavani, Andrea Bovero, Romeo RomagnoliAbstract:DNA minor groove binders constitute An importAnt clAss of derivAtives in AnticAncer therApy. Some of these compounds form noncovAlent complexes with DNA (e.g., DistAmycin A, Hoechst 33258, And pentAmidine) while others DNA-binding compounds (such As CC-1065) cAuse cleAvAges in the DNA bAckbone. In this Article, we hAve reviewed the minor groove binders currently in preclinicAl evAluAtion in the lAst yeArs. DiArylAmidines such As DAPI, berenil, And pentAmidine; bis-benzimidAzoles such As Hoechst 33258; ecteinAscidins, pyrrololo [2,1-c]-[1,4]-benzodiAzepines (PBDs), CC-1065, And DistAmycins Are the clAsses discussed in this review Article. A speciAl section hAs been dedicAted to hybrid molecules resulted by the combinAtion of two minor groove binders, especiAlly for derivAtives of nAturAlly occurring Antitumor Agents, such As AnthrAmycin or the AlkylAting unit of the Antibiotic CC-1065, And DistAmycin frAmes.
-
cytotoxic α hAlogenoAcrylic derivAtives of DistAmycin A And congeners
Journal of Medicinal Chemistry, 2004Co-Authors: Italo Beria, Paolo Cozzi, Marina Caldarelli, Cristina Geroni, Pier Giovanni Baraldi, Nicola Mongelli, Sergio Marchini, Romeo RomagnoliAbstract:The mechAnism of Action of mAny Antitumor Agents involves DNA dAmAge, either by direct binding of the drug to DNA or to DNA-binding proteins. However, most of the DNA-interActing Agents hAve only A limited degree of sequence specificity, which implies thAt they mAy hit All the cellulAr genes. DNA minor groove binders, Among which the derivAtives of DistAmycin A plAy An importAnt role, could provide significAnt improvement in cAncer mAnAgement, increAsing gene specificity, due to high selectivity of interAction with thymine-Adenine (TA) rich sequences. We now report And discuss the synthesis, the in vitro And in vivo Activities, And some mechAnistic feAtures of AlphA-hAlogenoAcrylAmido derivAtives of DistAmycin A. The finAl result of this work wAs the selection of brostAllicin 17 (PNU-166196). BrostAllicin, presently in phAse II clinicAl triAls, shows A broAd spectrum of Antitumor Activity And An Apoptotic effect higher thAn DistAmycin derivAtive tAllimustine. An importAnt in vitro toxicologicAl feAture of brostAllicin is the very good rAtio between myelotoxicity on humAn hAemAtopoietic progenitor cells And cytotoxicity on tumor cells, in compArison with clinicAlly tested DNA minor groove binders. A peculiArity of brostAllicin is its in vitro reActivity in the DNA AlkylAtion AssAys only in the presence of glutAthione. Moreover brostAllicin's Antitumor Activity, both in in vitro And in vivo tumor models, is higher in the presence of increAsed levels of glutAthione/glutAthione-S-trAnferAses. These findings contribute to the definition of brostAllicin As A novel AnticAncer Agent thAt differs from other minor groove binders And AlkylAting Agents for both the profile of Activity And the mechAnism of Action And to clAssify the AlphA-bromoAcrylAmido derivAtives of DistAmycin As A new clAss of cytotoxics. Moreover, due to its interAction with glutAthione, brostAllicin mAy hAve A role for the tAilored treAtment of tumors chArActerized by constitutive or therApy-induced overexpression of glutAthione/glutAthione-S-trAnferAse levels.
Nicola Mongelli - One of the best experts on this subject based on the ideXlab platform.
-
cytotoxic α hAlogenoAcrylic derivAtives of DistAmycin A And congeners
Journal of Medicinal Chemistry, 2004Co-Authors: Italo Beria, Paolo Cozzi, Marina Caldarelli, Cristina Geroni, Pier Giovanni Baraldi, Nicola Mongelli, Sergio Marchini, Romeo RomagnoliAbstract:The mechAnism of Action of mAny Antitumor Agents involves DNA dAmAge, either by direct binding of the drug to DNA or to DNA-binding proteins. However, most of the DNA-interActing Agents hAve only A limited degree of sequence specificity, which implies thAt they mAy hit All the cellulAr genes. DNA minor groove binders, Among which the derivAtives of DistAmycin A plAy An importAnt role, could provide significAnt improvement in cAncer mAnAgement, increAsing gene specificity, due to high selectivity of interAction with thymine-Adenine (TA) rich sequences. We now report And discuss the synthesis, the in vitro And in vivo Activities, And some mechAnistic feAtures of AlphA-hAlogenoAcrylAmido derivAtives of DistAmycin A. The finAl result of this work wAs the selection of brostAllicin 17 (PNU-166196). BrostAllicin, presently in phAse II clinicAl triAls, shows A broAd spectrum of Antitumor Activity And An Apoptotic effect higher thAn DistAmycin derivAtive tAllimustine. An importAnt in vitro toxicologicAl feAture of brostAllicin is the very good rAtio between myelotoxicity on humAn hAemAtopoietic progenitor cells And cytotoxicity on tumor cells, in compArison with clinicAlly tested DNA minor groove binders. A peculiArity of brostAllicin is its in vitro reActivity in the DNA AlkylAtion AssAys only in the presence of glutAthione. Moreover brostAllicin's Antitumor Activity, both in in vitro And in vivo tumor models, is higher in the presence of increAsed levels of glutAthione/glutAthione-S-trAnferAses. These findings contribute to the definition of brostAllicin As A novel AnticAncer Agent thAt differs from other minor groove binders And AlkylAting Agents for both the profile of Activity And the mechAnism of Action And to clAssify the AlphA-bromoAcrylAmido derivAtives of DistAmycin As A new clAss of cytotoxics. Moreover, due to its interAction with glutAthione, brostAllicin mAy hAve A role for the tAilored treAtment of tumors chArActerized by constitutive or therApy-induced overexpression of glutAthione/glutAthione-S-trAnferAse levels.
-
cytotoxic hAlogenoAcrylic derivAtives of DistAmycin A
ChemInform, 2000Co-Authors: Paolo Cozzi, Italo Beria, Marina Caldarelli, Laura Capolongo, Cristina Geroni, Nicola MongelliAbstract:The design, synthesis, in vitro And in vivo Activities of A series of hAlogenoAcrylic derivAtives of DistAmycin A Are described. The structure-Activity relAtionships indicAte A key role of the reActivity of AlphA-hAlogenoAcrylic moiety. The reActivity And the putAtive AlkylAting mechAnism of these compounds Are different from those of the nitrogen mustArds And possibly bAsed on A MichAel type reAction. This supports the hypothesis thAt these compounds represent A clAss of minor groove binders mechAnisticAlly different from tAllimustine.
-
novel benzoyl nitrogen mustArd derivAtives of pyrAzole AnAlogues of DistAmycin A synthesis And Antileukemic Activity
Bioorganic & Medicinal Chemistry, 1999Co-Authors: Pier Giovanni Baraldi, Paolo Cozzi, Cristina Geroni, Romeo Romagnoli, Nicola Mongelli, Giampiero SpallutoAbstract:AbstrAct The design And synthesis of novel benzoic Acid mustArd (BAM) derivAtives of DistAmycin A beAring one or more pyrAzole rings replAcing the pyrrole rings of the lAtter Are described. In vitro And in vivo Activities AgAinst L1210 leukemiA Are reported And discussed. Some of these compounds show An Activity profile compArAble to tAllimustine 1 . All the compounds beAring the pyrAzole ring close to the BAM moiety show reduced cytotoxicity in compArison to derivAtives chArActerized by the BAM linked to A pyrrole: the sAme effect hAs not been observed when occurring At the Amidine terminus of the oligopeptidic frAme. ©
-
Design, synthesis And biologicAl Activity of A pyrrolo [2,1-c][1,4]benzodiAzepine (PBD)-DistAmycin hybrid.
Bioorganic & medicinal chemistry letters, 1998Co-Authors: Pier Giovanni Baraldi, David E. Thurston, Philip W. Howard, Barbara Cacciari, A. Guiotto, Alberto Leoni, Romeo Romagnoli, Giampiero Spalluto, Nicola Mongelli, Nicoletta BianchiAbstract:We report the synthesis of A new hybrid 13 which is A combinAtion of the nAturAlly occurring Antitumor Agent DistAmycin A 1 And the pyrrolo[2,1-c][1,4]benzodiAzepine 11, relAted to the nAturAlly occurring AnthrAmycin 2. The Antitumor Activity of the hybrid 13 wAs tested in vitro And compAred to the nAturAl product DistAmycin 1 And the PBD 11.
-
structure Activity relAtionship of novel DistAmycin A derivAtives synthesis And Antitumor Activity
Bioorganic & Medicinal Chemistry Letters, 1994Co-Authors: Roberto Dallessio, Giovanni Biasoli, Cristina Geroni, Enrico Pesenti, Maria Grandi, Nicola MongelliAbstract:AbstrAct Synthesis And biologicAl evAluAtion of A group of DistAmycin A derivAtives beAring new AlkylAting moietis is presented.
Cristina Geroni - One of the best experts on this subject based on the ideXlab platform.
-
cytotoxic α hAlogenoAcrylic derivAtives of DistAmycin A And congeners
Journal of Medicinal Chemistry, 2004Co-Authors: Italo Beria, Paolo Cozzi, Marina Caldarelli, Cristina Geroni, Pier Giovanni Baraldi, Nicola Mongelli, Sergio Marchini, Romeo RomagnoliAbstract:The mechAnism of Action of mAny Antitumor Agents involves DNA dAmAge, either by direct binding of the drug to DNA or to DNA-binding proteins. However, most of the DNA-interActing Agents hAve only A limited degree of sequence specificity, which implies thAt they mAy hit All the cellulAr genes. DNA minor groove binders, Among which the derivAtives of DistAmycin A plAy An importAnt role, could provide significAnt improvement in cAncer mAnAgement, increAsing gene specificity, due to high selectivity of interAction with thymine-Adenine (TA) rich sequences. We now report And discuss the synthesis, the in vitro And in vivo Activities, And some mechAnistic feAtures of AlphA-hAlogenoAcrylAmido derivAtives of DistAmycin A. The finAl result of this work wAs the selection of brostAllicin 17 (PNU-166196). BrostAllicin, presently in phAse II clinicAl triAls, shows A broAd spectrum of Antitumor Activity And An Apoptotic effect higher thAn DistAmycin derivAtive tAllimustine. An importAnt in vitro toxicologicAl feAture of brostAllicin is the very good rAtio between myelotoxicity on humAn hAemAtopoietic progenitor cells And cytotoxicity on tumor cells, in compArison with clinicAlly tested DNA minor groove binders. A peculiArity of brostAllicin is its in vitro reActivity in the DNA AlkylAtion AssAys only in the presence of glutAthione. Moreover brostAllicin's Antitumor Activity, both in in vitro And in vivo tumor models, is higher in the presence of increAsed levels of glutAthione/glutAthione-S-trAnferAses. These findings contribute to the definition of brostAllicin As A novel AnticAncer Agent thAt differs from other minor groove binders And AlkylAting Agents for both the profile of Activity And the mechAnism of Action And to clAssify the AlphA-bromoAcrylAmido derivAtives of DistAmycin As A new clAss of cytotoxics. Moreover, due to its interAction with glutAthione, brostAllicin mAy hAve A role for the tAilored treAtment of tumors chArActerized by constitutive or therApy-induced overexpression of glutAthione/glutAthione-S-trAnferAse levels.
-
cytotoxic hAlogenoAcrylic derivAtives of DistAmycin A
ChemInform, 2000Co-Authors: Paolo Cozzi, Italo Beria, Marina Caldarelli, Laura Capolongo, Cristina Geroni, Nicola MongelliAbstract:The design, synthesis, in vitro And in vivo Activities of A series of hAlogenoAcrylic derivAtives of DistAmycin A Are described. The structure-Activity relAtionships indicAte A key role of the reActivity of AlphA-hAlogenoAcrylic moiety. The reActivity And the putAtive AlkylAting mechAnism of these compounds Are different from those of the nitrogen mustArds And possibly bAsed on A MichAel type reAction. This supports the hypothesis thAt these compounds represent A clAss of minor groove binders mechAnisticAlly different from tAllimustine.
-
synthesis And Antitumor Activity of new benzoheterocyclic derivAtives of DistAmycin A
Journal of Medicinal Chemistry, 2000Co-Authors: Pier Giovanni Baraldi, Paolo Cozzi, Italo Beria, Cristina Geroni, Romeo Romagnoli, Nicoletta Bianchi, N. Mongelli, Carlo Mischiati, Roberto GambariAbstract:The design, synthesis, And in vivo And in vitro Antileukemic Activity of A novel series of compounds (13−22 And 34), in which different benzoheterocyclic rings, beAring A nitrogen mustArd or A benzoyl nitrogen mustArd or An α-bromoAcryloyl group As AlkylAting moieties, Are tethered to A DistAmycin frAme, Are reported, And structure−Activity relAtionships Are discussed. The new derivAtives were prepAred by coupling nitrogen mustArd-substituted, benzoyl nitrogen mustArd-substituted, or α-bromoAcryloyl-substituted benzoheterocyclic cArboxylic Acids 23−32 with desformylDistAmycin (33) or in one cAse with its two-pyrrole AnAlogue 35. With very few exceptions, the Activities of compounds beAring the sAme AlkylAting moiety Are slightly Affected by the kind of the heteroAtom present on the benzoheterocyclic ring. All novel compounds, with one exception, showed in vitro Activity AgAinst L1210 murine leukemiA cell line compArAble to or better thAn thAt of tAllimustine. The compounds in which the nitrogen mustArd An...
-
Phenyl sulfur mustArd derivAtives of DistAmycin A.
Bioorganic & Medicinal Chemistry Letters, 2000Co-Authors: Paolo Cozzi, Italo Beria, Marina Caldarelli, Laura Capolongo, Cristina Geroni, Stefania Mazzini, Enzio RaggAbstract:The design, synthesis, And cytotoxic Activity of novel benzoyl And cinnAmoyl sulfur mustArd derivAtives of DistAmycin A Are described And structure Activity relAtionships Are discussed. These sulfur mustArds Are more potent cytotoxics thAn corresponding nitrogen mustArds in spite of the lower AlkylAting power, while their sulfoxide AnAlogues Are substAntiAlly inActive. CinnAmoyl sulfur mustArd derivAtive (7) proved to be one of the most Active DistAmycin-derived cytotoxics, About 1000 times more potent thAn melphAlAn.
-
α bromoAcryloyl derivAtive of DistAmycin A pnu 151807 A new non covAlent minor groove dnA binder with AntineoplAstic Activity
British Journal of Cancer, 1999Co-Authors: Sergio Marchini, Paolo Cozzi, Cristina Geroni, Maurizio Dincalci, Marco Ciro, F Gallinari, Massimo BrogginiAbstract:PNU 151807 is A new synthetic α-bromoAcryloyl derivAtive of DistAmycin A. In the present study we investigAted the DNA interAction And the mechAnism of Action of this compound in pArAllel with the DistAmycin AlkylAting derivAtive, tAllimustine. PNU 151807 possesses A good cytotoxic Activity in in vitro growing cAncer cells, even superior to thAt found for tAllimustine. By footprinting experiments we found thAt PNU 151807 And tAllimustine interAct non-covAlently with the sAme AT-rich DNA regions. However, differently from tAllimustine, PNU 151807 fAiled to produce Any DNA AlkylAtion As Assessed by TAq stop AssAy And N3 or N7-Adenine AlkylAtion AssAy in different DNA sequences. PNU 151807, like tAllimustine, is Able to induce An ActivAtion of p53, And consequently of p21 And BAX in A humAn ovAriAn cAncer cell line (A2780) expressing wild-type p53. However, disruption of p53 function by HPV16-E6 does not significAntly modify the cytotoxic Activity of the compound. Flow cytometric AnAlysis of cells treAted with equitoxic concentrAtions of PNU 151807 And tAllimustine showed A similAr induction of AccumulAtion of cells in the G2 phAse of the cell cycle but with A different time course. When tested AgAinst recombinAnt proteins, only the compound PNU 151807 (And not tAllimustine or DistAmycin A) is Able to Abolish the in vitro kinAse Activity of CDK2–cyclin A, CDK2–cyclin E And cdc2–cyclin B complexes. The results obtAined showed thAt PNU 151807 seems to hAve A mechAnism of Action completely different from thAt of its pArent compound tAllimustine, possibly involving the inhibition of cyclin-dependent kinAses Activity, And cleArly indicAte PNU 151807 As A new non-covAlent minor groove binder with cytotoxic Activity AgAinst cAncer cells. © 1999 CAncer ReseArch CAmpAign
Nicoletta Bianchi - One of the best experts on this subject based on the ideXlab platform.
-
synthesis And growth inhibition Activity of α bromoAcrylic heterocyclic And benzoheterocyclic derivAtives of DistAmycin A modified on the Amidino moiety
Bioorganic & Medicinal Chemistry, 2003Co-Authors: Pier Giovanni Baraldi, Paolo Cozzi, Italo Beria, Nicoletta Bianchi, Roberto Gambari, Romeo RomagnoliAbstract:AbstrAct The design, synthesis And in vitro Activities of novel α-bromoAcryloyl pyrAzole, imidAzole And benzoheterocyclic derivAtives of DistAmycin A, in which the Amidino moiety hAs been replAced by moieties of different physico-chemicAl feAtures Are described, And the structure–Activity relAtionships Are discussed. In spite of the relevAnce of these modificAtions on the DistAmycin frAme, these derivAtives showed significAnt growth inhibitory Activity AgAinst mouse leukemiA L1210 cells. Therefore, the presence of the Amidino moiety, And in generAl of A bAsic moiety, is not An Absolute requirement for biologicAl Activity of α-bromoAcrylic derivAtives of DistAmycin.
-
synthesis And Antitumor Activity of new benzoheterocyclic derivAtives of DistAmycin A
Journal of Medicinal Chemistry, 2000Co-Authors: Pier Giovanni Baraldi, Paolo Cozzi, Italo Beria, Cristina Geroni, Romeo Romagnoli, Nicoletta Bianchi, N. Mongelli, Carlo Mischiati, Roberto GambariAbstract:The design, synthesis, And in vivo And in vitro Antileukemic Activity of A novel series of compounds (13−22 And 34), in which different benzoheterocyclic rings, beAring A nitrogen mustArd or A benzoyl nitrogen mustArd or An α-bromoAcryloyl group As AlkylAting moieties, Are tethered to A DistAmycin frAme, Are reported, And structure−Activity relAtionships Are discussed. The new derivAtives were prepAred by coupling nitrogen mustArd-substituted, benzoyl nitrogen mustArd-substituted, or α-bromoAcryloyl-substituted benzoheterocyclic cArboxylic Acids 23−32 with desformylDistAmycin (33) or in one cAse with its two-pyrrole AnAlogue 35. With very few exceptions, the Activities of compounds beAring the sAme AlkylAting moiety Are slightly Affected by the kind of the heteroAtom present on the benzoheterocyclic ring. All novel compounds, with one exception, showed in vitro Activity AgAinst L1210 murine leukemiA cell line compArAble to or better thAn thAt of tAllimustine. The compounds in which the nitrogen mustArd An...
-
synthesis of hybrid DistAmycin cysteine lAbeled with 99mtc A model for A novel clAss of cAncer imAging Agents
Bioorganic & Medicinal Chemistry Letters, 2000Co-Authors: Pier Giovanni Baraldi, Romeo Romagnoli, Nicoletta Bianchi, Adriano Duatti, Cristina Bolzati, A Piffanelli, Carlo Mischiati, Roberto GambariAbstract:AbstrAct The synthesis of A hybrid constituted by DistAmycin A And cysteine lAbeled with the γ-emitting rAdionuclide 99m Tc to Afford the conjugAte complex 5 is reported. This new rAdiophArmAceuticAl is of potentiAl interest As tumor imAging Agent in diAgnostic nucleAr medicine. The prepArAtion of the hybrid DistAmycin A-cysteine 4 hAs been Achieved by coupling deformylDistAmycin A And Boc-Dmt-OH. Compound 4 wAs then successfully lAbeled with 99m Tc by reAction with the novel, high-electrophilic, metAl-contAining frAgment [ 99m Tc(N)(PP)] 2+ (PP=diphosphine ligAnd) yielding the 1:1 complex 5 .
-
Design, synthesis And biologicAl Activity of A pyrrolo [2,1-c][1,4]benzodiAzepine (PBD)-DistAmycin hybrid.
Bioorganic & medicinal chemistry letters, 1998Co-Authors: Pier Giovanni Baraldi, David E. Thurston, Philip W. Howard, Barbara Cacciari, A. Guiotto, Alberto Leoni, Romeo Romagnoli, Giampiero Spalluto, Nicola Mongelli, Nicoletta BianchiAbstract:We report the synthesis of A new hybrid 13 which is A combinAtion of the nAturAlly occurring Antitumor Agent DistAmycin A 1 And the pyrrolo[2,1-c][1,4]benzodiAzepine 11, relAted to the nAturAlly occurring AnthrAmycin 2. The Antitumor Activity of the hybrid 13 wAs tested in vitro And compAred to the nAturAl product DistAmycin 1 And the PBD 11.