Synthesis and Biological Evaluation of Novel .BETA.-Carbolines as Potent Cytotoxic and DNA Intercalating Agents

Abstract

901Regular Article b-Carboline alkaloids represent a large number of naturally and synthetic indole alkaloids associated with a broad spectrum of biochemical effects and pharmaceutical properties.1) Previous investigations focused on the effects of b-carboline alkoloids on the central nervous system (CNS). 2-9)Recent reports [10][11][12][13][14][15][16][17] have pointed out b-carbolines as a class of potential antitumor agents, which was discovered to function their antitumor activity through multiple mechanisms, such as intercalating into DNA, 11,18) and kinesin Eg5. 25)Recently, our group investigations 26-31) on the synthesis of a variety of b-carboline derivatives and the evaluation of their antitumor activities unraveled that b-carbolines had potent antitumor activities and the activities were correlated to both the planarity of the molecule and the presence of the ring substituents. Structure-activity relationships (SARs) analysis suggested that the introduction of appropriate substituents into position-2, 3 and 9 played a vital role in determining their antitumor effects, and the n-butyl, benzyl or phenylpropyl substituents at position-9 was suitable pharmacophoric group giving rise to some potent antitumor agents.In continuing search for novel and effective antitumor agents, we designed and synthesized a series of water-soluble b-carbolines bearing a flexible alkylamino side chain at position-3 and a alkyl or arylated alkyl substituent at position-9, respectively. The selective introduction of a methyl, n-butyl, benzyl, 4-fluorobenzyl and phenylpropyl substituents into position-9 of b-carboline nucleus was based on the previous SARs analysis results, and the design of the amino substituents was limited to diethylaminoethylamino, dimethylaminopropylamino diethylaminopropylamino and diethylaminobutylamino group. The purpose of this study was to investigate effect of the flexible amino side chain moiety on the antitumor activity, with the ultimate aim of developing novel antitumor b-carbolines with improved water solubility and bioavailability. ChemistryThe synthetic routes of novel b-carbolines 1a, 2a-d, 3a-d, 4a-d, 5a-d and 6a-d are outlined in Chart 1. 1-Methyl-b-carboline-3-carboxaldehydes 1-6 were prepared from the L-tryptophan via six steps including the Pictet-Spengler condensation, esterification, aromatization, N-alkylation or N-arylation, reduction and oxidation as previously described. [26][27][28] The reaction of compounds 1-6 with the corresponding diamines to form schiff bases took place readily at room temperature in good yield. The crude schiff bases without further purification were directly reduced with NaBH 3 CN in anhydrous methanol to give the target b-carbolines 1a, 2a-d, 3a-d, 4a-d, 5a-d and 6a-d (Table 1) in 40-78% yield. The chemical structures of all the synthesized compounds were characterized by MS, IR, 1 H-NMR, and 13 C-NMR spectra. Results and DiscussionCytotoxic Activity in Vitro The cytotoxic potential of all newly synthesized b-carbolines was evaluated in vitro against a pa...

One-pot reaction of pyranoindolones with phenylisocyanates: a simple and regioselective approach to β-carbolines

“…1) are widespread in both the plant and animal kingdom, mostly marine microorganisms, with high affinity for benzodiazepine, serotonin and dopamine receptor sites. [5][6][7] They also exhibit a vast diversity of biological activities, very often significant antitumor action, 8 by DNA intercalation, [9][10][11] DNA binding, 12,13 or DNA synthesis inhibition 14 among others. Very recently, tetrahydro-b-carboline derivatives demonstrated antileishmanial activity against the transgenic infrared fluorescent Leishmania infantum strain.…”

DNA-binding studies of the natural β-carboline eudistomin U

“…The known intercalators harman and norharman displayed similar spectral changes in neutral phosphate buffer (see Supporting Information). 16 Finally, since eudistomin U possesses a basic amine functional group, we investigated the pH-dependence of this binding through changes in the UV-Vis spectrum. Similar hyperchromicity at 257 nm and red-shifting above 400 nm were observed in both basic and acidic buffer.…”