Synthesis and Biological Evaluation of Novel Naphthocarbazoles as Potential Anticancer Agents

Abstract

We report the efficient synthesis involving palladium-catalyzed reactions and biological evaluation of new naphthocarbazoles designed as potential anticancer agents. The use of 5- and 6-benzyloxyindoles generated three substitution sites which were successively exploited to introduce several hydrophilic side chains. The cytotoxicity of the newly designed compounds was evaluated on three cell lines. Several compounds showed a marked cytotoxicity with IC(50) values in the sub-micromolar range. This is the case for the 3-hydroxy-naphthopyrrolocarbazoledione 37, bearing a dimethylaminoethyl side chain, which is extremely cytotoxic to L1210 and DU145 cells (IC(50): 36 nM, 108 nM) and induces an accumulation of L1210 cells in the G2+M phases of the cell cycle. Some of the most cytotoxic compounds were tested for inhibition of CDK-5, GSK-3 and topoisomerase I, and their interaction with DNA was also evaluated. Interaction with DNA was detected, suggesting that nucleic acids represent a privileged target for these molecules.

Topological Polar Surface Area: A Useful Descriptor in 2D-QSAR

“…The negative contribution of the indicator variable I XNCH3 suggests that NCH 3 substitution is not favorable for the activity. This is consistent with the SAR observation of Routier et al [43] that N-hydrophilic substitution increases the cytotoxicity compared to NCH 3 .…”

“…Routier et al [43] reported some naphthocarbazoles (IV) with significant cytotoxic properties toward cancer cells. IV is one of the modified structures obtained from the indolocarbazole skeleton found in indolo [2,3-]pyrrolo [3,4-c]carbazole alkaloids, some of which have been found to have significant antitumor, antiviral and antimicrobial activity.…”

“…Routier et al [43] proposed that binding of IV to DNA leads to the antiproliferative activity. IV failed to show any significant activity against CDK-5, GSK-3 or topoisomerases (IC 50 > 10 M).…”

“…IV failed to show any significant activity against CDK-5, GSK-3 or topoisomerases (IC 50 > 10 M). We used the reported in vitro antiproliferative activity (IC 50 ) against a human prostate cancer cell line (DU145) for the present QSAR analysis [43]. Table 4) explains 74.8% of the variance in the observed activity.…”

New Efficient Route to Fused Aryltetrahydroindolizinones via N‐Acyliminium Intermediates

“…Molecular modelling and crystallographic data have shown, in particular, the crucial role of one specific carbonyl group, which engages in direct interaction with the Leu83 residue, in the active site. [9][10][11] Another class of potent CDK inhibitors has also emerged from molecular modelling and topological binding similarity. The diarylurea scaffold was proposed and, interestingly, during the optimization of the aryl counterpart it was additionally shown that the tetrahydropyrrolo[2,1-a]- isoindol-5-one framework II (Figure 2) can also bind with the enzyme (IC 50 42 n).…”