Potential antitumor agents. 39. Anilino ring geometry of amsacrine and derivatives: relationship to DNA binding and antitumor activity

Abstract

The clinical antileukemic drug amsacrine and analogues are thought to exert their biological activity by binding tightly but reversibly to DNA, with the acridine chromophore intercalated and the anilino group making additional binding contact in the minor groove of the double helix. In this binding model the steric environment around the 3'- and 5'-positions of the anilino ring is crucial. Two 3',5'-disubstituted analogues of amsacrine have been prepared, and their conformation, DNA binding properties, and antitumor activity were determined and compared with corresponding unsubstituted and 3'-substituted compounds. Addition of 3'- and 3',5'-substituents have little effect on minimum-energy conformations of the anilino side chain but have significant effects on DNA binding and biological activity. Monosubstitution lowers binding constants several-fold, but intercalative binding with extensive drug-base pair overlap is retained. Disubstitution lowers binding further, and although the binding is still intercalative as assessed by unwinding angles, it appears to occur with little drug-base pair overlap, as determined by high-field NMR studies of DNA imino proton shifts. These changes in DNA binding are accompanied by an abrupt change in biological activity, with the 3',5'-disubstituted analogues proving inactive and nontoxic even though other physicochemical properties, such as lipophilicity and stability, remain within acceptable limits. This study provides further evidence that the binding of drugs to DNA has a critical influence on their biological activity.

Molecular modeling of tricyclic compounds with anilino substituents and their intercalation complexes with DNA sequences

“…Interesting differences were observed for dihedral angle values. In the case of acridine derivatives, ta was around À808 while in compound series 6 and 7, it was around À608/À708, except in 4 0 -substituted derivatives (-NH 2 and -OCH 3 substituents), where the values were around À548/À688, in close agreement with experimental data for 9-anilinoacridines [20,21].…”

Benzoquinazoline derivatives as new agents affecting DNA processing

“…4), revealed that a large variation on dihedral angle between acridine nucleus and aniline side chain was required to allow interaction with DNA, according to other experimental observations. 14 On the contrary, for the benzoquinazoline derivatives bearing the same aniline side chain of m-AMSA, a lower variation of the dihedral angle between intercalated and isolated structures was observed (data not shown). Thus, in the case of benzoquinazoline derivatives, a lower penalty for dihedral free energy variation was observed with respect to m-AMSA.…”

“…Owing to the known instability of 4-chloro derivatives, 16 compound 15 was immediately submitted to substitution step, but any attempt to carry out the reaction gave only the starting quinazolin-1-one (14), due to the ease of hydrolysis of chlorine group which was competitive with the substitution reaction.…”

Synthesis and characterization of para-nitro substituted 2,6-bis(phenylimino)pyridyl Fe(II) and Co(II) complexes and their ethylene polymerization properties

“…All other chemicals were purchased from commercial resources and used without further purification. 2,6-Dimethyl-4-nitroaniline, 2,6-diisopropyl-4-nitroaniline [21,22] and 2,6-diacetylpyridine(2,6-diisopropylanil)FeCl 2 were prepared by established procedures [3]. …”