Synthesis and Biological Evaluation of Novel Phenylcarbazoles as Potential Anticancer Agents

Abstract

We here report the synthesis and biological evaluation of new phenylcarbazole derivatives designed as potential anticancer agents. Indole and hydroxyindole were used to generate three scaffolds that were successively exploited to introduce various substituents on the maleimide moiety. The synthesis includes a final intramolecular key Heck-type reaction, which was carried out with a triflate derivative or with a bromophenyl derivative. Each step was optimized and the complete chemical strategy is detailed. Several compounds showed a marked cytotoxicity against CEM human leukemia cells with IC(50) values in the 10-100 nM range. Precise structure-activity relationships were delineated. Cell cycle analysis, topoisomerase I inhibition, and interaction with DNA were evaluated, and inhibition of CDK activity was also investigated. Although binding of the drugs to DNA likely contributes to the cytotoxic action, the exact molecular targets of these molecules remain undiscovered. The efficient chemical routes reported here for the design of highly cytotoxic compounds provide novel opportunities to identify antitumor agents in the phenylcarbazole series.

Human protein kinase inhibitor screening by capillary electrophoresis using transverse diffusion of laminar flow profiles for reactant mixing

“…They were used to validate the universality of the described CE methodology. The comparison of the IC 50 values obtained by CE to those reported in the literature [16][17][18]34,36,37] will enable to evaluate the quality of the incapillary mixing by TDLFP and thus the efficiency of the CE method developed for assaying human kinase inhibitors. Some of the tested molecules had a wide range of IC 50 values going from a few nanomolars to micromolars.…”

“…Human DYRK1A, Woodtide and phosphoglycogen synthase peptide-2 (PGSP2), syringes and hydrophilic polyvinylidene fluoride (PVDF) Millex-HV Syringe Filters, pore size 0.45 m, were purchased from Millipore (Molsheim, France). Compounds 6 to 13 were synthesized as reported elsewhere [16][17][18]. The name, CAS number and molecule based structure of the 13 inhibitors (1 to 13) tested are as follows: 1*: Roscovitine (CAS 186692-46-6); 2*: Purvalanol A (CAS 212844-53-6); 3: …”

“…This incubation time was optimized from 0 to 30 min. It was found that 10 min of incubation time (versus 30 min used for conventional methods) [16,18,34] was enough to produce about 5 M of ADP in the absence of any inhibitor. Moreover, the reaction time of 10 min is higher than the time required for transverse diffusion (t r ).…”

Synthesis and biological evaluation of novel series of aminopyrimidine derivatives as urease inhibitors and antimicrobial agents

“…Carprofen, a nonsteroidal anti-inflammatory drug (NSAID), is a selective COX-2 inhibitor 31 . More recently, a series of phenylcarbazole ( Figure 1) molecules have been reported as antitumour agent 32 , carbazole sulphonamides ( Figure 1) are a novel class of antimitotic agents against solid tumours 33 . Syutkin et al 34 have reported carbazole containing chalcones and pyrimidines as light emitting diodes.…”

A Direct Palladium‐Catalyzed Route for the Synthesis of Benzo[a]carbazoles through Sequential C–C Bond Formation and C–H Bond Functionalization

“…[3] Benzo [a]carbazole ring systems are of considerable interest because they can exhibit antifungal and antitumor activities, [4] antiestrogenic properties, [5] or kinase inhibitory activities. [6] For example, 1 has been shown to block estrogen receptors in breast tumor cells. [5] Benzo[a]carbazoles 2 and 3 exhibit antitumor activity against leukemia, renal tumor, colon cancer, and melanoma ( Figure 1).…”