The pyrrolo[2,1-C][1,4]benzodizepines (PBDs) are a family of sequence-selective DNA-binding anti tumor antibiotics that bind exclusively to the exocyclic N2 of guanine in the minor groove of DNA. Footprinting-type studies have shown that the adduct span 3 base-pairs with a rank order of preference for 5'-Pu-G-Pu>5'->Pu-G-Py or 5'-Py-G-Pu>5'-Py-G-Py sequences. In a project aimed to design new analogues lacking both cardiotoxicity and tissue necrosis, we have substituted theA benzene ring of the PBD skeleton with different heterocycle nucleus such as substituted pyrazoles, pyridine and pyrimidine. The rationale behind the synthesis of the heterocyclic analogues reported here has been to design molecules with the following features:i)a possibly higher binding affinity and modified sequence selectivity for the DNAminor groove, due to the potential new hydrogen bonds that might occur between the A-ring atoms and DNA bases;ii)a reduced cardiotoxicity due to the impossibility of C9-quinone formation as occurs with anthramycin. The synthesized compounds were evaluated for cytotoxicity by growth inhibition studies in L1210 murine leukemia and its L1210/L-PAM sublime cells resistant to melphalan (L-PAM) and LoVo human coloncarcinoma and its sublime (LoVo/DX) resistant to Doxorubicin(DX). Among the most cytotoxic compounds containing the pyrazole ring it is interesting to note that:1)substitution at N7 increases cytotoxicity with respect to the N6 substituted compounds in L1210 and L1210/L-PAM cell lines;2)the N7 benzyl or N7 substituted benzyl compounds are similar or superior to N7 methyl or ethyl substituted compounds in terms of cytotoxicity; 3)with the same substituent at N6 replacement of the C8 methyl group with a carboxy methyl ester does not increase cytotoxicity.4)in the L1210 cell line, the introduction of a sterically demanding substituent at C8leads to a decrease in citotoxicity compared to the C8-methyl compound.

SYNTHESIS AND CYTOTOXICITY OF DNA-INTERACTIVE PYRROLO[2,1-C][1,4]BENZODIAZEPINONE HETEROCYCLIC-ANALOGS

CACCIARI, Barbara;
1995

Abstract

The pyrrolo[2,1-C][1,4]benzodizepines (PBDs) are a family of sequence-selective DNA-binding anti tumor antibiotics that bind exclusively to the exocyclic N2 of guanine in the minor groove of DNA. Footprinting-type studies have shown that the adduct span 3 base-pairs with a rank order of preference for 5'-Pu-G-Pu>5'->Pu-G-Py or 5'-Py-G-Pu>5'-Py-G-Py sequences. In a project aimed to design new analogues lacking both cardiotoxicity and tissue necrosis, we have substituted theA benzene ring of the PBD skeleton with different heterocycle nucleus such as substituted pyrazoles, pyridine and pyrimidine. The rationale behind the synthesis of the heterocyclic analogues reported here has been to design molecules with the following features:i)a possibly higher binding affinity and modified sequence selectivity for the DNAminor groove, due to the potential new hydrogen bonds that might occur between the A-ring atoms and DNA bases;ii)a reduced cardiotoxicity due to the impossibility of C9-quinone formation as occurs with anthramycin. The synthesized compounds were evaluated for cytotoxicity by growth inhibition studies in L1210 murine leukemia and its L1210/L-PAM sublime cells resistant to melphalan (L-PAM) and LoVo human coloncarcinoma and its sublime (LoVo/DX) resistant to Doxorubicin(DX). Among the most cytotoxic compounds containing the pyrazole ring it is interesting to note that:1)substitution at N7 increases cytotoxicity with respect to the N6 substituted compounds in L1210 and L1210/L-PAM cell lines;2)the N7 benzyl or N7 substituted benzyl compounds are similar or superior to N7 methyl or ethyl substituted compounds in terms of cytotoxicity; 3)with the same substituent at N6 replacement of the C8 methyl group with a carboxy methyl ester does not increase cytotoxicity.4)in the L1210 cell line, the introduction of a sterically demanding substituent at C8leads to a decrease in citotoxicity compared to the C8-methyl compound.
1995
Baraldi, Pg; Beria, I; Cacciari, Barbara; Leoni, A; Spalluto, G.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11392/1198459
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