Photosensitizers Based on G-Quadruplex Ligand for Cancer Photodynamic Therapy

Abstract

G-quadruplex (G4) is the non-canonical secondary structure of DNA and RNA formed by guanine-rich sequences. G4-forming sequences are abundantly located in telomeric regions and in the promoter and untranslated regions (UTR) of cancer-related genes, such as RAS and MYC. Extensive research has suggested that G4 is a potential molecular target for cancer therapy. Here, we reviewed G4 ligands as photosensitizers for cancer photodynamic therapy (PDT), which is a minimally invasive therapeutic approach. The photosensitizers, such as porphyrins, were found to be highly toxic against cancer cells via the generation of reactive oxidative species (ROS) upon photo-irradiation. Several porphyrin derivatives and analogs, such as phthalocyanines, which can generate ROS upon photo-irradiation, have been reported to act as G4 ligands. Therefore, they have been implicated as promising photosensitizers that can selectively break down cancer-related DNA and RNA forming G4. In this review, we majorly focused on the potential application of G4 ligands as photosensitizers, which would provide a novel strategy for PDT, especially molecularly targeted PDT (mtPDT).

Keywords: G-quadruplex; RAS; cancer; photodynamic therapy; photosensitizer; telomeres.

Figure 1

The schematic illustration of photochemical reactions in photodynamic therapy (PDT), and schematic model depicting the PDT strategy. ROS: reactive oxidative species.

Figure 2

(A) Schematic DNA structures; duplex (upper), triplex (middle), and tetraplexes (lower). Tetraplexes including G-quadruplex and I-motif. (B) Chemical structure of G-quartets along with the cation coordinates of O6 sites corresponding to four guanines. The sphere with M⁺ in the center of G-quartet represents a central cation. (C) Schematic structure depicting the G-quadruplex (G4) folding conformation: parallel (left), antiparallel (middle), and hybrid (right). Green and black arrowheads indicate the loop and guanine region, respectively. (D) Typical CD spectra of the parallel, antiparallel, and hybrid conformations. Left: CD spectrum of NRAS DNA, d(GGGAGGGGCGGGTCTGGG), forming parallel G4 in a buffer containing 100 mM K⁺. Middle: CD spectrum of telomeric DNA, dA(GGGTTA)₃GGG, forming antiparallel G4 in a buffer containing 100 mM Na⁺. Right: CD spectrum of telomeric DNA of, dA(GGGTTA)₃GGG, forming hybrid G4 in a buffer containing 100 mM Na⁺ (right). Red arrows indicate the representative peaks of each G4 conformation.

Figure 3

Chemical structures of telomestatin (A), tetra-meso (N-methyl-4-pyridyl) (TMPyP4) (B), and graphene oxide (GO) complex (TMPyP@GO) (C).

Figure 4

Chemical structures of tetrakis-(diisopropyl-guanidine) phthalocyanine (Zn-DIGP) (A), anthrafurandiones (ATFD) (B), and anthrathiophenediones (ATPD) (C).

Figure 5

Chemical structures of 5,10,15,20-tetra-{4-[2-(1-methyl-1-piperidinyl)ethoxy]phenyl} porphyrin (TMPipEOPP) (A), Zn(II)-5,10,15,20-tetrakis(N-carboxymethyl-4-pyridinium)porphyrin (ZnPI) (B), and tri-meso(N-methyl-4-pyridyl)-meso(N-tetradecyl-4-pyridyl (TMPyP4-C14) (C).

Figure 6

Chemical structure of zinc(II) phthalocyanine 3,4″,4″,4′″-tetrasulfonic acid, tetrasodium salt (ZnAPC).