220465-97-4Relevant academic research and scientific papers
A novel heterocumulenic Pauson-Khand reaction of alkynylcarbodiimides: A facile and efficient synthesis of heterocyclic ring-fused pyrrolinones
Saito, Takao,Shiotani, Masahiro,Otani, Takashi,Hasaba, Satoshi
, p. 1045 - 1048 (2007/10/03)
The first examples of the heterocumulenic Pauson-Khand reaction are described. Alkynylcarbodiimides undergo an intramolecular Pauson-Khand cycloaddition upon heating in the presence of Mo(CO)6 and DMSO to afford 4,5-dihydro-1H-pyrrolo[2,3-b]pyrrolin-2-ones and 1H-pyrrolo[2,3-b]indol-2-ones.
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.
Biradicals from thermolysis of N-[2-(1-alkynyl)phenyl]-N'- phenylcarbodiimides and their subsequent transformations to 6H-indolo[2,3- b]quinolines
Shi, Chongsheng,Zhang, Quan,Wang, Kung K.
, p. 925 - 932 (2007/10/03)
Thermolysis of the carbodiimide 9a in γ-terpinene at 138 °C produced 2-(phenylamino)quinoline (11a, 49%) and the parent 6H-indolo[2,3-b]quinoline (14a, 16%). Apparently, 11a was produced via the biradical 10a followed by hydrogen-atom abstraction from γ-terpinene. A two-step biradical pathway through 12a or a one-step intramolecular Diels-Alder reaction could furnish 13a, which then underwent tautomerization to give 14a. With the carbodiimide 9b having a trimethylsilyl substituent at the acetylenic terminus, thermolysis in refluxing p-xylene at 138 °C produced the 6H-indolo[2,3- b]quinoline 14b (86%) exclusively. Treatment of 14b with 6 N NaOH in refluxing ethanol then furnished 14a in 92% yield. Similarly, the 6H- indolo[2,3-b]quinolines 14c-f were obtained from thermolysis of the carbodiimides 9c-f. The use of the aza-Wittig reaction between 4- methoxyphenyl isocyanate and the iminophosphoranes 2d and 2f to produce the corresponding carbodiimides followed by thermolysis furnished the 6H- indolo[2,3-b]quinolines 16d and 16f having a methoxy substituent at the C-2 position. Thermolysis of the carbodiimides 25a and 25b produced 26a and 26b having two indoloquinoline units connected at the 11 and 11' positions with either a three-carbon or a five-carbon tether. Using 1,4-phenylene diisocyanate for the aza-Wittig reaction with 2 equiv of the iminophosphorane 2g followed by thermolysis furnished 31 (66%) having two indoloquinoline units incorporated in the seven fused rings.
