Synthesis and Preliminary Biological Evaluation of a New Pyridocarbazole Derivative Covalently Linked to a Thymidine Nucleoside as a Potential Targeted Antitumoral Agent. I

Abstract

The therapy of human cancer is one of the more pursued goals by medicinal chemistry research. Most of the compounds clinically used as a treatment owe their efficacy to their cytotoxic interaction (direct or indirect) with nuclear DNA. This interaction results in the inhibition of DNA synthesis and the degradation of nucleic strands. Ellipticine is a naturally occurring 6H-pyrido[4,3-b]carbazole alkaloid endowed with antitumor activity, and several ellipticine derivatives have been used in clinical trials. We previously reported some 1,4-dimethyl-9H-carbazole derivatives structurally related to ellipticine. The purpose of our research was to transform the pyridocarbazole in a prodrug so that it would have more penetration in the tumor cells and block their replication. Our prodrug is slowly hydrolyzed in human plasma in the corresponding acid. From these preliminary results, we deduce that our compound can block cellular replication. Our hypothesis is that the antitumoral activity is probably related to the induction of damage to DNA, without cellular lysis in the short term.

Inhibition of Human Topoisomerase II by N,N,N‐Trimethylethanammonium Iodide Alkylcarbazole Derivatives

“…The organic layer was dried over anhydrous MgSO 4 , filtered and the solvent removed by evaporation. The resulting residue was purified by silica gel column chromatography in petroleum ether/ethyl acetate (1:9) to give a white/yellow solid in 67 % yield ( 2 a – g ) …”

“…The resulting residue was purified by silica gel column chromatography in petroleum ether/ethyl acetate (1:9) to give aw hite/ yellow solid in 67 %yield (2a-g). [16,49,63] General method for the synthesis of compounds 3a-g:1 -[2-(Dimethylamino)ethyl]piperazine (l.35 mmol) and Na 2 CO 3 (2.7 mmol) were dissolved in DMF (10 mL). As olution of N-bromoalkyl-substituted carbazole (2a-g,1 .35 mmol) in DMF (10 mL) was added at room temperature.…”

“…Moreover, their antiproliferative activity was evaluated with two breast cancer cell lines: MCF‐7 and MDA‐MB‐231. The solubility of the synthesized compounds was improved through the formation of salts, as in the case of 9‐hydroxy‐2‐methylellipticinium acetate (celiptium), which possesses higher DNA affinity than ellipticine and lacks toxicity at therapeutic doses . Some of these compounds showed notable cytotoxic activity against breast tumor cells, due to the inhibition of hTopo II and activation of apoptosis.…”

“…Thesolubility of the synthesized compounds was improved through the formation of salts, as in the case of 9-hydroxy-2-methylellipticinium acetate (celiptium), which possesses higher DNA affinity than ellipticine and lacks toxicity at therapeutic doses. [24,48,49] Someo ft hese compounds showedn otable cytotoxic activity against breast tumor cells, due to the inhibition of hTopo II and activationo fa poptosis. Overall,t hese compounds can be considered new and important tools exploring the signalingp athways involved in breast cancer growth and progression.…”

1-Hydroxy-3-methyl-9H-carbazole-2-carbaldehyde

“…For related literature, see: Borek-Dohalska et al (2004); Chakraborty (1977); Chakraborty & Roy (1991); Chmielewski et al (2004); Hagg et al (2004); Hedin et al (2000); Hirata et al (1999); Knolker & Reddy (2002); Saturnino et al (2003); Thomas et al (2001); Van Dijken et al (2004); Wang et al (2005).…”