Modulation of the antitumor activity by methyl substitutions in the series of 7H-pyridocarbazole monomers and dimers

Abstract

The structure of the dimeric antitumor drug ditercalinium (NSC 366241) [2,2'-([4,4'-bipiperidine]-1,1'-diyldi-2,1-ethanediyl)bis[10 -methoxy-7H-pyrido[4,3-c]carbazolium] tetramethanesulfonate] was modified by introduction of methyl groups in various positions of the aromatic ring. Monomeric analogues with the nitrogen atom of the pyridinic ring in different positions have also been synthesized. Pharmacological properties and DNA interactions of the new compounds are reported. In contrast with the monomeric analogue of ditercalinium, which was inactive, methyl substitutions on the 10-methoxy-7H-pyrido[4,3-c]carbazolium in positions 6 or 7 led to monomers endowed with small but significant activity. As expected, dimerization of the methyl-substituted pyridocarbazoles yielded DNA bisintercalators with affinity slightly higher than that of the unsubstituted parent compounds. These dimers, characterized by a relatively better therapeutic index, have the same mechanism of action as ditercalinium. Otherwise, in monomeric and dimeric series, methyl substitution in position 4 or 5 provided inactive compounds unable to intercalate into DNA. All these results are in agreement with the previously proposed geometry for the complex of ditercalinium with DNA.

Effects of Cationic Charge on Three-Dimensional Structures of Intercalative Complexes Structure of a bis-Intercalated DNA Complex Solved by MAD Phasing

“…Structures of tetracationic ditercalinium [16,17] Each compound in this ditercalinium sub-family is composed of two monocationic 7H-pyridocarbazole units and a charged linker. Structure-activity studies indicate that the cationic charges [20] and linker rigidity [20][21][22][23][24] are critical to activity. Ditercalinium has a rigid diethylbipiperidine linker and is active in both prokaryotes and eukaryotes [23].…”

Drug-induced DNA repair: X-ray structure of a DNA-ditercalinium complex.

“…Strong antitumor activity is observed only when 7H-pyridocarbazoles are dimerized (5). Other important factors include the position and hybridization of the nitrogen substituted with the linker (5,6) and the rigidity (5) and length (7) of the linker. Furthermore, the drug is inactivated when the N-7 position, or to a lesser extent the C-6 position, is substituted with alkyl groups larger than methyl (8), or when the position of the nitrogen at the 7 position within the chromophore is altered (5).…”

Synthesis and Cytotoxic Activity of Dimeric Analogs of Acronycine in the Benzo[b]pyrano[3,2-h]acridin-7-one Series

“…Ditercalinium (1), resulting from the dimerization of two pyridocarbazole units related to natural alkaloids ellipticine (2) and olivacine (3) is an excellent example of this approach. [7][8][9] Benzo [b]acronycine derived antitumor derivatives, developed from the model of natural acronycine (4), [10][11][12][13][14] are exemplified by diacetate 5, currently under phase I clinical trials under the code S23906-1. 15,16) These compounds displayed a particularly impressive broad antitumor spectrum, when evaluated against aggressive orthotopic models of human ovarian, lung, and colon cancers.…”