Advances in heterocycles as DNA intercalating cancer drugs

The insertion of a molecule between the bases of DNA is known as intercalation. A molecule is able to interact with DNA in different ways. DNA intercalators are generally aromatic, planar, and polycyclic. In chemotherapeutic treatment, to suppress DNA replication in cancer cells, intercalators are used. In this article, we discuss the anticancer activity of 10 intensively studied DNA intercalators as drugs. The list includes proflavine, ethidium bromide, doxorubicin, dactinomycin, bleomycin, epirubicin, mitoxantrone, ellipticine, elinafide, and echinomycin. Considerable structural diversities are seen in these molecules. Besides, some examples of the metallo-intercalators are presented at the end of the chapter. These molecules have other crucial properties that are also useful in the treatment of cancers. The successes and limitations of these molecules are also presented.

DNA Intercalators Inhibit Eukaryotic Ribosomal RNA Synthesis by Impairing the Initiation of Transcription

In eukaryotes, ribosome biogenesis is driven by the synthesis of the ribosomal RNA (rRNA) by RNA polymerase I (Pol-I) and is tightly linked to cell growth and proliferation. The 3D-structure of the rDNA promoter plays an important, yet not fully understood role in regulating rRNA synthesis. We hypothesized that DNA intercalators/groove binders could affect this structure and disrupt rRNA transcription. To test this hypothesis, we investigated the effect of a number of compounds on Pol-I transcription in vitro and in cells. We find that intercalators/groove binders are potent inhibitors of Pol-I specific transcription both in vitro and in cells, regardless of their specificity and the strength of its interaction with DNA. Importantly, the synthetic ability of Pol-I is unaffected, suggesting that these compounds are not targeting post-initiating events. Notably, the tested compounds have limited effect on transcription by Pol-II and III, demonstrating the hypersensitivity of Pol-I transcription. We propose that stability of pre-initiation complex and initiation are affected as result of altered 3D architecture of the rDNA promoter, which is well in line with the recently reported importance of biophysical rDNA promoter properties on initiation complex formation in the yeast system.

Programming ultrasensitive threshold response through chemomechanical instability

The ultrasensitive threshold response is ubiquitous in biochemical systems. In contrast, achieving ultrasensitivity in synthetic molecular structures in a controllable way is challenging. Here, we propose a chemomechanical approach inspired by Michell’s instability to realize it. A sudden reconfiguration of topologically constrained rings results when the torsional stress inside reaches a critical value. We use DNA origami to construct molecular rings and then DNA intercalators to induce torsional stress. Michell’s instability is achieved successfully when the critical concentration of intercalators is applied. Both the critical point and sensitivity of this ultrasensitive threshold reconfiguration can be controlled by rationally designing the cross-sectional shape and mechanical properties of DNA rings.

Photoinduced DNA Cleavage and Photocytotoxic of Phenanthroline-Based Ligand Ruthenium Compounds

The photophysical and biological properties of two new phenanthroline-based ligand ruthenium complexes were investigated in detail. Their DNA interaction modes were determined to be the intercalation mode using spectra titration and viscosity measurements. Under irradiation, obvious photo-reduced DNA cleavages were observed in the two complexes via singlet oxygen generation. Furthermore, complex 2 showed higher DNA affinity, photocleavage activity, and singlet oxygen quantum yields than complex 1. The two complexes showed no toxicity towards tumor cells (HeLa, A549, and A375) in the dark. However, obvious photocytotoxicities were observed in the two complexes. Complex 2 exhibited large PIs (phototherapeutic indices) (ca. 400) towards HeLa cells. The study suggests that these complexes may act as DNA intercalators, DNA photocleavers, and photocytotoxic agents.

Synthesis and Photochromic Properties of a Novel Chromene Derivative

A convenient synthetic approach to a novel 2,2-diphenyl-2H-chromene derivative is developed starting from vanillin or acetovanillone. The photochromic properties of the resulting chromene are studied. The kinetic characteristics of this compound show its potential for the design of new efficient DNA intercalators.

Synthesis of new quinolizinium-based fluorescent compounds and application studies on photocatalysis

Quinoliziniums, cationic aromatic heterocycles bearing a quaternary bridgehead nitrogen, have been widely applied to research areas, such as fluorescent dyes, DNA intercalators and ionic liquids. A library of new quinolizinium...