The Search of DNA-Intercalators as Antitumoral Drugs: What it Worked and What did not Work

Abstract

The discovery of new compounds with antitumoral activity has become one of the most important goals in medicinal chemistry. One interesting group of chemotherapeutic agents used in cancer therapy comprises molecules that interact with DNA. Research in this area has revealed a range of DNA recognizing molecules that act as antitumoral agents, including groove binders, alkylating and intercalator compounds. DNA intercalators (molecules that intercalate between DNA base pairs) have attracted particular attention due to their antitumoral activity. For example, a number of acridine and anthracycline derivatives are excellent DNA intercalators that are now on the market as chemotherapeutic agents. Commercially available acridine and anthracycline derivatives have been widely studied from a variety of viewpoints, such as physicochemical properties, structural requirements, synthesis and biological activity. However, the clinical application of these and other compounds of the same class has encountered problems such as multidrug resistance (MRD), and secondary and/or collateral effects. These shortcomings have motivated the search for new compounds to be used either in place of, or in conjunction with, the existing compounds. Unfortunately, the results of this search have not met expectations. The vast majority of candidate intercalator compounds tested for use as anticancer agents have shown little or no biological activity. Research in this area has not been without benefits, however, for it has produced much information on the synthesis and antitumoral properties of hundreds of compounds, which have been tested on diverse tumoral cell lines. This review considers the structural and biological considerations relevant to the use of DNA intercalators and bis-intercalators as antitumoral agents, with an emphasis on the relationship between structure and activity, produced in last decade.

Antineoplastic DNA-Binding Compounds: Intercalating and Minor Groove Binding Drugs

“…The only recognised forces that maintain the stability of the complex, even more than DNA alone, are van der Waals, hydrogen bonding, hydrophobic effects, and/or charge transfer forces (19). Classical intercalators have a straight, heteroaromatic ring which comes in between two neighbouring base pairs.…”

“…They are direct participants in the recognition of DNA and the fundamental steps of cellular growth when DNA replication is active, as well as in the S phase of the cell cycle in which topology of DNA plays a signifi cant role. Topoisomerases infl uence chromatin arrangement in the M phase of the cell cycle indicating that they can be poisoned not only in the S but also in the M phase (19). Topoisomerases can be grouped into two main classes: topoisomerase I (topo I), which breaks only one strand of DNA and topo II, which breaks both strands of the duplex (19).…”

“…Topoisomerases infl uence chromatin arrangement in the M phase of the cell cycle indicating that they can be poisoned not only in the S but also in the M phase (19). Topoisomerases can be grouped into two main classes: topoisomerase I (topo I), which breaks only one strand of DNA and topo II, which breaks both strands of the duplex (19). Alterations in DNA topo II have been identifi ed in tumour cell lines selected for resistance to natural products, including etoposide and doxorubicin (18).…”

Tetraaza[14]macrocyclic Transition Metal Complexes as DNA Intercalators

“…[1] Their ability to inhibit the synthesis of nucleic acids in living organisms, and thus the potential to act as anticancer agents, is one of the most important reasons why they have lately attracted much attention from researchers. [2,3] A vast majority of intercalator molecules contain aromatic multi-ring π-acceptor components (e.g. dipyridophenazine, [4] phenanthrolino [5,6-b]hexaazatriphenylene [5] and pyrene [6] derivatives) able to π-stack between the base-pairs.…”

Synthesis and characterisation of platinum (II) salphen complex and its interaction with calf thymus DNA

“…However, metal complex intercalators had been a particular interest in research field because it is widely used in biomedical applications especially for mutagens, antibiotics, antibacterials and antitumor agents [3].…”