Developing Novel G-Quadruplex Ligands: from Interaction with Nucleic Acids to Interfering with Nucleic Acid⁻Protein Interaction

Abstract

G-quadruplex is a special secondary structure of nucleic acids in guanine-rich sequences of genome. G-quadruplexes have been proved to be involved in the regulation of replication, DNA damage repair, and transcription and translation of oncogenes or other cancer-related genes. Therefore, targeting G-quadruplexes has become a novel promising anti-tumor strategy. Different kinds of small molecules targeting the G-quadruplexes have been designed, synthesized, and identified as potential anti-tumor agents, including molecules directly bind to the G-quadruplex and molecules interfering with the binding between the G-quadruplex structures and related binding proteins. This review will explore the feasibility of G-quadruplex ligands acting as anti-tumor drugs, from basis to application. Meanwhile, since helicase is the most well-defined G-quadruplex-related protein, the most extensive research on the relationship between helicase and G-quadruplexes, and its meaning in drug design, is emphasized.

Keywords: G-quadruplex; G-quadruplex ligand; G-quadruplex-related proteins; anti-tumor; helicase.

Figure 1

The structure of the G-quadruplex. Four guanines construct a G-quartet via Hoogsteen hydrogen bonds. Two or three G-quartets stack to form a G-quadruplex structure. Univalent metal cations (Na⁺ or K⁺) locate in the central channel of the G-quartet to stabilize the structure.

Figure 2

Structural diversity of G-quadruplexes. G-quadruplexes structures may form intramolecular G-quadruplex or intermolecular G-quadruplex structures (PDB: 6A7Y [46], 6MC4 [47], and 6AU4 [48]). Moreover, the G-quadruplex structures divide into different conformations, including parallel (PDB: 5I2V [49]), antiparallel (PDB: 2MBJ [50]), hybrid (PDB: 6H1K [51], 5ZEV [52], and 5MBR [53]) conformations.

Figure 3

Schematic diagram of the possible role of G-quadruplexes in several cellular events. (a) G-quadruplexes block the replication process, and G4 helicase could withstand this inhibition. (b) G-quadruplexes forming in the promoter regions could interfere with the DNA damage response. (c) G-quadruplexes upstream of the TSS could inhibit the transcription process. (d) G-quadruplexes could also interfere with the ribosome scanning process and thus inhibit protein translation.

Figure 4

Structures of typical G-quadruplex ligands in this review, including BRACO-19, TMPyP4, Telomestatin, CX3543, CX5461, and pyridostatin (PDS).

Figure 5

Structures of compounds inhibiting G-quadruplex-related proteins, including N-methyl mesoporphyrin IX (NMM), PIPER, isaindigotone derivative 37, NSC 19630, ML216, and bismuth porphyrin complex.