A Versatile Water-Soluble Ball-Type Phthalocyanine as Potential Antiproliferative Drug: The Interaction with G- Quadruplex Formed From Tel 21 and cMYC

Abstract

G-quadruplexes are biologically important DNA conformations exist generally in guanine-rich segments of DNA, such as telomere and proto-oncogene. The formation of these secondary structures is thought to inhibit the expression of certain genes, such as the inhibition of telomerase. The inhibition of telomerase and suppression of a specific gene expression are important approaches for interruption of cancer cell's proliferation. In the present study, the effect of a versatile water soluble ball-type phthalocyanine (BtPc) on G-quadruplex formation and stabilization was investigated to demonstrate its potential usage in cancer chemotherapy. Two important guanine rich oligomers, cMYC and Tel 21 were used as G-quadruplex former sequence. To the best of our knowledge, this is the first study about the interaction of a BtPc with G-quadruplex structures. The interactions of the compound with G-quadruplex molecules were monitored spectrophotometrically. The binding constants were calculated from BenesiHildebrand equation and the highest binding constant (0.1114 µM-1) was found for Tel 21 in the presence of KCl. The structural differentiations of G-quadruplex after binding were investigated with circular dichroism spectrophotometry. The CD spectra were demonstrated the stabilization of both parallel and anti-parallel Tel 21 G-quadruplex in the presence of KCl and stabilization of anti-parallel form in the absence of KCl. The stability of the parallel structure was achieved for cMYC in the absence of KCl up to 4.10 µM of Pc. The disruption of staking of parallel form was achieved for cMYC in the presence of KCl. The replacement ability of the molecule with a known DNA binding molecule, ethidium bromide, was clarified fluorometrically. The Stern-Volmer studies were conducted for determination of the quenching mechanism. The strong interaction of the molecules (BtPc with oligomer) showed us the potential usage of these drug conjugates for targeted photodynamic therapy in the future

G-quadruplexes are biologically important DNA conformations exist generally in guanine-rich segments of DNA, such as telomere and proto-oncogene. The formation of these secondary structures is thought to inhibit the expression of certain genes, such as the inhibition of telomerase. The inhibition of telomerase and suppression of a specific gene expression are important approaches for interruption of cancer cell's proliferation. In the present study, the effect of a versatile water soluble ball-type phthalocyanine (BtPc) on G-quadruplex formation and stabilization was investigated to demonstrate its potential usage in cancer chemotherapy. Two important guanine rich oligomers, cMYC and Tel 21 were used as G-quadruplex former sequence. To the best of our knowledge, this is the first study about the interaction of a BtPc with G-quadruplex structures. The interactions of the compound with G-quadruplex molecules were monitored spectrophotometrically. The binding constants were calculated from BenesiHildebrand equation and the highest binding constant (0.1114 µM-1) was found for Tel 21 in the presence of KCl. The structural differentiations of G-quadruplex after binding were investigated with circular dichroism spectrophotometry. The CD spectra were demonstrated the stabilization of both parallel and anti-parallel Tel 21 G-quadruplex in the presence of KCl and stabilization of anti-parallel form in the absence of KCl. The stability of the parallel structure was achieved for cMYC in the absence of KCl up to 4.10 µM of Pc. The disruption of staking of parallel form was achieved for cMYC in the presence of KCl. The replacement ability of the molecule with a known DNA binding molecule, ethidium bromide, was clarified fluorometrically. The Stern-Volmer studies were conducted for determination of the quenching mechanism. The strong interaction of the molecules (BtPc with oligomer) showed us the potential usage of these drug conjugates for targeted photodynamic therapy in the future