Title:Noncovalent Binding to DNA: Still a Target in Developing Anticancer Agents
Volume: 23
Issue: 36
Author(s): José Portugal and Francisca Barceló
Affiliation:
Keywords:
Antitumor chemotherapy, DNA-binding drugs, DNA recognition, Drug discovery, Mechanism of action,
Sequence specificity.
Abstract: DNA-binding compounds are of extraordinary importance in medicine, accounting
for a substantial portion of antitumor drugs in clinical usage. However, their mechanisms
of action remain sometimes incompletely understood. This review critically examines two
broad classes of molecules that bind noncovalently to DNA: intercalators and groove binders.
Intercalators bind to DNA by inserting their chromophore moiety between two consecutive
base pairs, whereas groove binders fit into the grooves of DNA. Noncovalent DNAinteractive
drugs can recognize certain supramolecular DNA structures such as the Gquadruplexes
found in telomeres and in numerous gene promoters, and they can act as topoisomerase
I and II poisons. We discuss how DNA-binding compounds affect transcription and
compete with protein factors for binding to consensus binding sites in gene promoters both in
vitro and in cultured cancer cells. Moreover, we comment on the design of molecules that
can tightly and specifically bind to any desired target DNA, such as various hairpin polyamides
which efficacy as chemotherapeutic agents is being evaluated. At present, genome-wide
studies, which provide details of events that may influence both cancer progression and
therapeutic outcome, are a common way used to analyze the effects of DNA-binding compounds.
A conclusive feature that emerges from reviewing the information on DNA-binding
compounds is that both natural sources and chemical approaches can be productively used to
obtain drugs to manipulate gene expression in cancer cells.