Synthesis and in vitro anticancer evaluation of 1,8-naphthalimide N(4) and S(4)-derivatives combining DNA intercalation and alkylation capabilities

Abstract

Research on DNA binding antitumor agents has been classically steered by either non-covalent (DNA intercalation) or covalent (DNA alkylation) interactions. In this context bi-functional anticancer molecules are particularly attractive since they are capable of sequential DNA intercalation followed by DNA alkylation. Here we describe the synthesis and in vitro anticancer activity of bi-functional 1,8-naphthalimide N(4) and S(4)-derivatives. Cell viability assays indicate that our amonafide-N-mustard chimeras are selective, effective only on certain tumor cell lines, and less toxic toward nonmalignant cells than the drug amonafide. The biological activities of the bi-functional derivatives presented here are encouraging and the compounds are suitable for further optimization and in vivo studies. Graphical Abstract Here we describe the synthesis and in vitro anticancer activity of three bi-functional 1,8-naphthalimide N(4) and S(4)-derivatives presenting both DNA intercalation and alkylation capabilities. Cell viability assays indicate that these amonafide-N-mustard chimeras are effective only on certain tumor cell lines and are less toxic towards non-malignant cells than their parent drug: amonafide.Electronic supplementary material The online version of this article (

Biolabile peptidyl delivery systems toward sequential drug release

“…Indeed, a sample of pure CLB shows considerable degradation at all tested pH values (Fig. ) CLB is least stable at pH 5, whereas at pH 2 the protonation of the mustard tertiary amine may partially prevent the formation of the aziridinium intermediate, reducing the reactivity of the mustard moiety . Considering the observed reactivity, the hydrolysis of CLB may become an important factor contributing to the loss of 9a before the cleavage of any of the amide or carbamate linkers.…”

Synthesis, DNA Binding, and Anticancer Properties of Bis-Naphthalimide Derivatives with Lysine-Modified Polyamine Linkers

“…Though some of its derivatives were approved for clinical trials, all of the trials were terminated due to the toxic side effects [ 2 , 3 , 4 , 5 , 6 , 7 ]. Therefore, to improve the antitumor activity and reduce the side effects, modifications on the naphthalimide structure have been carried out in recent decades; some naphthalimide derivatives with different side chains, aromatic ring systems, and substituents on the ring have been designed and synthesized [ 8 , 9 , 10 , 11 ].…”