Interaction of G-Quadruplexes with Nonintercalating Duplex-DNA Minor Groove Binding Ligands Akash K. Jain ‡ and Santanu Bhattacharya* ,‡,† ‡ Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India † Chemical Biology Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore 560 012, India ABSTRACT: The enzyme telomerase synthesizes the G-rich DNA strands of the telomere and its activity is often associated with cancer. The telomerase may be therefore responsible for the ability of a cancer cell to escape apoptosis. The G-rich DNA sequences often adopt tetra-stranded structure, known as the G-quadruplex DNA (G4-DNA). The stabilization of the telomeric DNA into the G4-DNA structures by small molecules has been the focus of many researchers for the design and development of new anticancer agents. The compounds which stabilize the G-quadruplex in the telomere inhibit the telomerase activity. Besides telomeres, the G4-DNA forming sequences are present in the genomic regions of biological significance including the transcriptional regulatory and promoter regions of several oncogenes. Inducing a G-quadruplex structure within the G-rich promoter sequences is a potential way of achieving selective gene regulation. Several G-quadruplex stabilizing ligands are known. Minor groove binding ligands (MGBLs) interact with the double-helical DNA through the minor grooves sequence-specifically and interfere with several DNA associated processes. These MGBLs when suitably modified switch their preference sometimes from the duplex DNA to G4-DNA and stabilize the G4-DNA as well. Herein, we focus on the recent advances in understanding the G- quadruplex structures, particularly made by the human telomeric ends, and review the results of various investigations of the interaction of designed organic ligands with the G-quadruplex DNA while highlighting the importance of MGBL-G-quadruplex interactions. ■ INTRODUCTION At the ends of the chromosomes, i.e., the telomeres, DNA does not consist of a complex protein-coding sequence. Instead, these are made of a simple sequence such as TTGGGG in the ciliate Tetrahymena 1 or TTAGGG in humans, 2 which are repeated a few hundred times in humans and fewer times in ciliates. The bulk of telomeric DNA adopts a double-helical conformation keeping the GT-rich sequence paired with its CA-rich complement. However, the 3′-end of such DNA protrudes as a single-stranded overhang in all the eukaryotes studied. 2-5 This DNA sequence binds to specific proteins, which cap the chromosome ends either directly or by inducing a particular DNA structure. 5 DNA in the cell nucleus is copied and transcribed by enzymes such as DNA and RNA polymerases. DNA synthesis is catalyzed by DNA polymerase, an enzyme which has crucial role in the DNA replication. A DNA polymerase elongates the new DNA strand from 5′ to 3′ direction, by adding a free nucleotide onto the growing 3′-end of the new strand. It never begins the synthesis of a new chain, and therefore, it needs a primer to add the first nucleotide at the 3′-OH group of the primer. The first two bases of the primer are always the RNA bases, while other bases may be either DNA or RNA. Primers are synthesized by an enzyme, primase. Conversion of the duplex DNA into a single-stranded DNA, with the help of an enzyme, called helicase, facilitates the replication of each strand. Complete replication of the overhanging end of the chromosome cannot be accomplished by conventional DNA polymerases. 4 In almost all eukaryotes, the chromosomal end- replication problem is solved by the enzyme telomerase, a ribo- nucleoprotein. 5 A portion of the RNA subunit of telomerase provides the nucleic acid template that the DNA cannot provide for itself. 6,7 The enzyme telomerase is upregulated in nearly 80-90% of the cancer cells, leading to an abnormal growth of cells. 7 Telomerase inhibition therefore comprises a key strategy for the development of anticancer agents. This is because studies so far have shown that the telomerase inhibitors can stop the proliferation of the cancer cells or cause apoptosis of the cancer cells, while they have no effect on most of the normal cells. 8 The telomere cap is composed of telomerase (having the components hTERT, hTERC, Hsp90, Tp1, and so forth), telomere-associated proteins (like TRF1, TRF2, Tankyrase, TIN2, POT1, Dykserin, and so forth), and telomeric DNA repair proteins (for instance, MRE11, RAD50, KU70, XRCC5/ KU80, and H2AX, etc.). This machinery maintains the length of Received: May 30, 2011 Revised: September 14, 2011 Published: November 10, 2011 Review pubs.acs.org/bc © 2011 American Chemical Society 2355 dx.doi.org/10.1021/bc200268a | Bioconjugate Chem. 2011, 22, 2355-2368