Synthesis, DNA binding properties and biol. activity of a series of bis-benzoheterocycle derivs. , structurally related to the natural dipyrrole antitumor agent netropsin, and tethered to a benzoyl nitrogen mustard (BAM) as alkylating moiety is reported and structure-activity relationships detd. These compds. have been evaluated for sequence selective alkylating properties and cytotoxicity against murine L1210 and human K562 leukemia cells. Using as target sequence a portion of the long terminal repeat of the type-1 human immunodeficiency virus, we found that these compds. induce similar patterns of DNA fragmentation. In addn., the results obtained indicate that all synthesized compds. retain a good antiproliferative activity in the submicromolar range, and generally are more active against L1210 than K562 cells. With respect to both these cell lines, compds. showed the greatest potency, ranging from 0.3 to 1 M, while some other compds. exhibit the lowest activity (IC50 = 2 - 12 M). Among compds., the deriv. was found to be the most potent member of this class and it is 5 and 10-fold less active than the bis-pyrrole counterpart it against K562 and L1210 cell lines, resp. For another compd., the substitution of the C-terminus benzofurane with N-methylindole and indole led to a decrease in cytotoxicity, which is more evident against the K562 cell line. Finally, differences were found among compds. in induction of K562 differentiation. Some of them are potent inducers of erythroid differentiation of K562 cells, and could be proposed for differentiation anti-cancer therapy.

Benzoyl nitrogen mustard derivatives of benzoheterocyclic analogues of netropsin: Synthesis and biological activity

BARALDI, Pier Giovanni
Primo
;
ROMAGNOLI, Romeo
Secondo
;
BIANCHI, Nicoletta
Penultimo
;
GAMBARI, Roberto
Ultimo
2003

Abstract

Synthesis, DNA binding properties and biol. activity of a series of bis-benzoheterocycle derivs. , structurally related to the natural dipyrrole antitumor agent netropsin, and tethered to a benzoyl nitrogen mustard (BAM) as alkylating moiety is reported and structure-activity relationships detd. These compds. have been evaluated for sequence selective alkylating properties and cytotoxicity against murine L1210 and human K562 leukemia cells. Using as target sequence a portion of the long terminal repeat of the type-1 human immunodeficiency virus, we found that these compds. induce similar patterns of DNA fragmentation. In addn., the results obtained indicate that all synthesized compds. retain a good antiproliferative activity in the submicromolar range, and generally are more active against L1210 than K562 cells. With respect to both these cell lines, compds. showed the greatest potency, ranging from 0.3 to 1 M, while some other compds. exhibit the lowest activity (IC50 = 2 - 12 M). Among compds., the deriv. was found to be the most potent member of this class and it is 5 and 10-fold less active than the bis-pyrrole counterpart it against K562 and L1210 cell lines, resp. For another compd., the substitution of the C-terminus benzofurane with N-methylindole and indole led to a decrease in cytotoxicity, which is more evident against the K562 cell line. Finally, differences were found among compds. in induction of K562 differentiation. Some of them are potent inducers of erythroid differentiation of K562 cells, and could be proposed for differentiation anti-cancer therapy.
2003
Baraldi, Pier Giovanni; Romagnoli, Romeo; Bianchi, Nicoletta; Gambari, Roberto
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11392/516755
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