Synthesis and biological activity of new dimers in the 7H-pyrido[4,3-c] carbazole antitumor series.
Ditercalinium (NSC 366241) is a 7H-pyrido[4,3-c]carbazole dimer with a diethylbipiperidine rigid chain linking the two heterocyclic rings. Ditercalinium is characterized by a high DNA affinity and bisintercalating ability, associated with potent antitumor properties, involving an original mechanism of action. Unfortunately as ditercalinium is hepatotoxic, its clinical evaluation has been interrupted. In order to eliminate or at least minimize the serious drawbacks related to its toxic effects, several chemical modifications have been made to the structure of ditercalinium, and their influence has been evaluated by measuring the DNA affinities, intercalation properties, and toxicity toward leukemia cells of the newly synthesized dimers. Reduction of the pyridinic moieties of ditercalinium, in order to suppress the permanent charges provided by the quaternizing chain, led to an almost complete loss of activity, although the DNA bisintercalating property of the dimer was preserved. Dimerization of the 7H-pyrido[4,3-c]carbazole rings by introduction of the rigid spacer on the N7- or C6-positions corresponding to the convex face of the pyridocarbazole, instead of the N2-position in ditercalinium, led to DNA bisintercalating dimers practically devoid of antitumor properties. However after quaternarization of the N2 atoms, the dimer linked by the N7 atoms exhibited a very high DNA affinity (greater than 10(9) M-1) and recovered antitumor activity, supporting the requirement of positive charges for the emergence of antitumor activity in these dimers. Introduction on the C6 of the 7H-pyridocarbazole ring of an aminomethyl or carboxyl group, a sugar residue, or C or N free amino acids such as Lys or Glu has also been carried out, in order to increase the hydrophilic properties of the molecules or to enable them to use amino acid transport systems. Although some of these compounds were active, none of them exhibited the pharmacological potency of ditercalinium.
Garbay-Jaureguiberry
C
C
Département de Chimie Organique, U266 INSERM-UA498 CNRS, Paris, France.
Barsi
M C
MC
Jacquemin-Sablon
A
A
Le Pecq
J B
JB
Roques
B P
BP
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D002227:Carbazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism; D007939:Leukemia L1210 / Q000188:drug therapy; D051379:Mice; D008811:Mice, Inbred DBA; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D002227:Carbazoles; D004273:DNA, Neoplasm; C042804:ditercalinium