Natural polyamines are nitrogen-bearing aliphatic chains that play an essential role in cell growth and differentiation and represent physiological sources of polycations necessary for stabilization of DNA topologies. Polyamine content in the cells is tightly regulated: in addition to synthesis, mammalian cells are equipped with an efficient polyamine uptake system, whose activity is proportional to cell proliferation. Polyamines analogues and derivatives can suppress proliferation of cancer cells by inhibition of the biosynthesis of natural polyamines and can exert cytotoxic activity due to their DNA-binding properties. Many tumour types have been shown to contain elevated level of an active polyamine transporter (PAT) for importing exogenous polyamines. In the present study, a bis(benzyl)polyamine analogue (MDL 27695), known to exert antiproliferative activity, has been used as a template where to inserte a well-known DNA-intercalator group (aromatic core) to combine the ability to use the polyamine uptake system with the property to intercale and bind tightly the double-stranded DNA. For this purpose two groups of polyamine derivatives (symmetric or non-symmetric) were synthesized: each group includes 9 compounds which differ for the number of C atom (n=2-10) in the lateral chain to verify the best lenght of the amino-alkyl chain. All derivatives were tested for antiproliferative activity in human breast cancer (SKBR-3) and leukemia (CEM) in vitro in a range of concentrations beetween 0.1 and 10 μM. The MTT assay was used to determine growth inhibition after up 72 h of treatment. Results indicate that the symmetric derivatives are more effective than the corresponding non-symmetric ones in both cell lines. All the symmetric compounds cause a significant dose- and time-dependent growth inhibition in the range of concentration tested. The compound with n=3 emerges as the most potent among the symmetric derivatives, with an IC50 (72h) of 0.35 and 0.17 μM in leukemic and breast cancer cells respectively. The present preliminary results document that some of these polyamine derivatives are more active than polyamine DNA-Intercalator conjugates against human leukemia or than oxa-polyamines derivatives against breast cancer. The pharmacokinetics and pharmacodynamics of the active compounds are now under study.

NEWLY SYNTHESIZED POLYAMINE DERIVATIVES AS POTENTIAL ANTICANCER AGENTS

GASPERI CAMPANI, ANNA;BAIOCCHI, DANIELA;RONCUZZI, LAURA;GILLI, ELENA;MILELLI, ANDREA;TUMIATTI, VINCENZO
2008

Abstract

Natural polyamines are nitrogen-bearing aliphatic chains that play an essential role in cell growth and differentiation and represent physiological sources of polycations necessary for stabilization of DNA topologies. Polyamine content in the cells is tightly regulated: in addition to synthesis, mammalian cells are equipped with an efficient polyamine uptake system, whose activity is proportional to cell proliferation. Polyamines analogues and derivatives can suppress proliferation of cancer cells by inhibition of the biosynthesis of natural polyamines and can exert cytotoxic activity due to their DNA-binding properties. Many tumour types have been shown to contain elevated level of an active polyamine transporter (PAT) for importing exogenous polyamines. In the present study, a bis(benzyl)polyamine analogue (MDL 27695), known to exert antiproliferative activity, has been used as a template where to inserte a well-known DNA-intercalator group (aromatic core) to combine the ability to use the polyamine uptake system with the property to intercale and bind tightly the double-stranded DNA. For this purpose two groups of polyamine derivatives (symmetric or non-symmetric) were synthesized: each group includes 9 compounds which differ for the number of C atom (n=2-10) in the lateral chain to verify the best lenght of the amino-alkyl chain. All derivatives were tested for antiproliferative activity in human breast cancer (SKBR-3) and leukemia (CEM) in vitro in a range of concentrations beetween 0.1 and 10 μM. The MTT assay was used to determine growth inhibition after up 72 h of treatment. Results indicate that the symmetric derivatives are more effective than the corresponding non-symmetric ones in both cell lines. All the symmetric compounds cause a significant dose- and time-dependent growth inhibition in the range of concentration tested. The compound with n=3 emerges as the most potent among the symmetric derivatives, with an IC50 (72h) of 0.35 and 0.17 μM in leukemic and breast cancer cells respectively. The present preliminary results document that some of these polyamine derivatives are more active than polyamine DNA-Intercalator conjugates against human leukemia or than oxa-polyamines derivatives against breast cancer. The pharmacokinetics and pharmacodynamics of the active compounds are now under study.
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88
Gasperi-Campani A.; Baiocchi D.; Roncuzzi L.; Gilli E.; Milelli A.; Tumiatti V.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11585/70483
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