Synthesis and Biological Evaluation of New Asymmetrical Bisintercalators as Potential Antitumor Drugs

Abstract

The good results obtained in the past decade with various types of potential bisintercalating agents, e.g., LU 79553, DMP 840, BisBFI, MCI3335, WMC-26, BisAC, BisPA, and the asymmetrical derivative WMC-79 (Chart 1), prompted us to investigate a new series of asymmetrical bisintercalators, compounds 1a-t (Chart 2), which can combine the potentiality of bisintercalation with a possible different mechanism of action due to two diverse chromophores. The DNA-binding properties of these compounds have been examined using fluorometric techniques: target compounds are excellent DNA ligands, with a clear preference for binding to AT-rich duplexes. In vitro cytotoxicity of these derivatives toward human hormone-refractory prostate adenocarcinoma cell line (PC-3) is described. Apoptosis assays of four selected compounds are also reported. Very potent cytotoxic compounds, some of them capable of inducing early apoptosis, have been identified.

Design, synthesis, and biological evaluation of a novel series of bisintercalating DNA-binding piperazine-linked bisanthrapyrazole compounds as anticancer agents

“…6 In principle, bisintercalating molecules should be able to interact more strongly with DNA and thus should have a prolonged residence time on DNA allowing them to interfere with DNA processing enzymes. 7-10 Bisintercalators should also, in principle, have enhanced DNA sequence specificity compared to monointercalators or minor groove binders. However, because intercalators typically only have a slight preference for GC base-pairs, sequence specificity may not necessarily be achieved.…”

“…Bisintercalating compounds, as exemplified by echinomycin, occur naturally and it and several purely synthetic compounds have progressed into clinical trials as antitumor agents. 7,9-12 …”

The structure-based design, synthesis, and biological evaluation of DNA-binding amide linked bisintercalating bisanthrapyrazole anticancer compounds

“…Bisintercalating compounds, as exemplified by echinomycin, occur naturally and it and several purely synthetic compounds have progressed into clinical trials as antitumor agents. 5,7,8 In order to direct the synthesis of new bisanthrapyrazoles, molecular modeling and DNA docking studies were carried out on the amide-linked bisanthrapyrazoles containing different numbers of methylene linkers. Compound 6 ( Fig.…”

Recognition of Single Stranded and Double Stranded DNA/RNA Sequences in Aqueous Medium by Small Bis-Aromatic Derivatives

“…[27] ( ) n ( ) n ref. [24] acridine, antracene ref. [ homo-dimers consisting of well known phenanthridinium and acridinium derivatives linked by various (more or less inert) spacers were studied in detail, including their interactions with DNA and screening of biological activity [11].…”

“…For instance, some derivatives within series of bis-intercalating acridine-consisting heterodimeric bisaromatics Fig. (2) [24] revealed remarkable preference to AT-rich duplexes. Bis-intercalators based on the bisimidazoacridone and indolo[2, 3-b]quinoxaline linked by simple aminoalkyl linkers Fig.…”