450381-16-5Relevant articles and documents
Synthesis, cytotoxicity, and antiplasmodial and antitrypanosomal activity of new neocryptolepine derivatives
Jonckers, Tim H. M.,Van Miert, Sabine,Cimanga, Kanyanga,Bailly, Christian,Colson, Pierre,De Pauw-Gillet, Marie-Claire,Van den Heuvel, Hilde,Claeys, Magda,Lemière, Filip,Esmans, Eddy L.,Rozenski, Jef,Quirijnen, Ludo,Maes, Louis,Dommisse, Roger,Lemière, Guy L. F.,Vlietinck, Arnold,Pieters, Luc
, p. 3497 - 3508 (2007/10/03)
On the basis of the original lead neocryptolepine or 5-methyl-5H-indolo[2,3-b]quinoline, an alkaloid from Cryptolepis sanguinolenta, derivatives were prepared using a biradical cyclization methodology. Starting from easily accessible educts, this approach allowed the synthesis of hitherto unknown compounds with a varied substitution pattern. As a result of steric hindrance, preferential formation of the 3-substituted isomers over the 1-substituted isomers was observed when cyclizing N-(3-substituted-phenyl)-N′-[2-(2-trimethylsilylethynyl)phenyl] carbodiimides. All compounds were evaluated for their activity against chloroquine-sensitive as well as chloroquine-resistant Plasmodium falciparum strains, for their activity against Trypanosoma brucei and T. cruzi, and for their cytotoxicity on human MRC-5 cells. Mechanisms of action were investigated by testing heme complexation using ESI-MS, inhibition of β-hematin formation, DNA interactions (DNA-methyl green assay and linear dichroism), and inhibition of human topoisomerase II. Neocryptolepine derivatives with a higher antiplasmodial activity and a lower cytotoxicity than the original lead have been obtained. This selective antiplasmodial activity was associated with inhibition of β-hematin formation. 2-Bromoneocryptolepine was the most selective compound with an IC50 value against chloroquine-resistant P. falciparum of 4.0 μM in the absence of cytotoxicity (IC50 > 32 μM). Although cryptolepine, a known lead for antimalarials also originally isolated from Cryptolepis sanguinolenta, was more active (IC50 = 2.0 μM), 2-bromoneocryptolepine showed a low affinity for DNA and no inhibition of human topoisomerase II, in contrast to cryptolepine. Although some neocryptolepine derivatives showed a higher antiplasmodial activity than 2-bromocryptolepine, these compounds also showed a higher affinity for DNA and/or a more pronounced cytotoxicity. Therefore, 2-bromoneocryptolepine is considered as the most promising lead from the present work for new antimalarial agents. In addition, 2-bromo-, 2-nitro-, and 2-methoxy-9-cyanoneocryptolepine exhibited antitrypanosomal activity in the micromolar range in the absence of obvious cytotoxicity.
