Study of the Mode and Efficiency of DNA Binding in the Damage Induced by Photoactivated Water Soluble Porphyrins

Abstract

We have investigated the DNA binding interactions and in vitro photoactivated DNA damage induced by a neutral water soluble porphyrin derivative 5,10,15,20-tetrakis(2,4,6-trihydroxyphenyl)porphyrin (TTHPP) and its zinc derivative 5,10,15,20-tetrakis(2,4,6-trihydroxyphenyl)porphyrinato zinc(II) (Zn-TTHPP) upon visible light irradiation through various spectroscopic techniques and employing repair endonucleases. These porphyrin derivatives exhibited high affinity toward DNA through groove binding interactions as evidenced through the UV-vis absorption, emission, circular dichroism spectral and viscosity changes. Interestingly, the free base porphyrin derivative, TTHPP generated efficient singlet oxygen mediated DNA damage sensitive to formamidopyrimidine-DNA glycosylase (Fpg protein), when compared with its metal derivative and to the well-known photosensitizer, hematoporphyrin. These results provide direct evidence for the role of DNA binding mode as well as extent of interactions with DNA in the efficiency of photoactivated DNA damage induced by the neutral porphyrins, which are believed to be the ideal candidates for photodynamic therapeutic applications.

Naphthalene Imide Conjugates: Formation of Supramolecular Assemblies, and the Encapsulation and Release of Dyes through DNA‐Mediated Disassembly

“…The K DNA value between conjugate 2 and DNA was 5.56 AE 0.1 10 4 m À1 ,d etermined by half-reciprocal analysis. [12] The K DNA value of bolaamphiphilic conjugate 1 was about 1.6-fold highert han that of conjugate 2.T his is due to the presence of two cationic charges in the former versus as ingle cationic chargeinthe latter.…”

“…D is the concentration of ct-DNA base pairs, De ap = [e a Àe F ], De = [e b Àe F ], [12] e a is the apparent extinction coefficient (A max[observed] /[conjugate]), e b is the extinction coefficient of the bound form of the conjugate and e F is the extinction coefficient of the free conjugate. e b was determined from the gradient (1/De)a nd K DNA was obtained from the ratio of the slope to the y-intercept [1/(DeK DNA )].…”

Comparative in vitro Studies of the Topoisomerase I Inhibition and Anticancer Activities of Metallated N‐Confused Porphyrins and Metallated Porphyrins

“…One such multi target ligands are synthetic or unnatural porphyrins (Figure B) which have been anticipated to act as remarkably promising chemotype for development of anticancer agents and photodynamic therapy which includes FDA‐approved and clinically used sensitizer Photofrin. [13,14] Porphyrin derivatives have diverse pharmaceutical properties and wide range of biological activities such as selective modes of DNA binding, mimicking photosynthetic centers, vitamin B12 and P‐450 . Recently, we reported the design and synthesis of a new class of neutral porphyrin derivative 5,10‐bis(4‐carboxyphenyl)‐15, 20‐bis(4‐dimethylaminophenyl)‐ porphyrin (Figure B) as a potent catalytic inhibitor of human Top1 .…”

“…[13,14] Porphyrin derivatives have diverse pharmaceutical properties and wide range of biological activities such as selective modes of DNA binding, mimicking photosynthetic centers, vitamin B12 and P-450. [15][16][17][18] Recently, we reported the design and synthesis of a new class of neutral porphyrin derivative 5,10-bis(4-carboxyphenyl)-15, 20-bis(4-dimethylaminophenyl)-porphyrin ( Figure 2B) as a potent catalytic inhibitor of human Top1. [19] In contrast to CPT (Camptothecin (CPT) selectively traps topoisomerase 1-DNA cleavable complexes (Top1cc) to promote anticancer activity), porphyrin (Figure2B) was found to reversibly bind with the free enzyme and inhibits the formation of Top1cc and promotes reversal of the preformed Top1cc with CPT.…”

Neutral Porphyrin Derivative Exerts Anticancer Activity by Targeting Cellular Topoisomerase I (Top1) and Promotes Apoptotic Cell Death without Stabilizing Top1-DNA Cleavage Complexes

“… 3 , 4 Porphyrins are a remarkably promising chemotype for development of anticancer agents and photodynamic therapy, which include FDA-approved and clinically used sensitizer Photofrin. 19 , 20 Porphyrin derivatives have wide pharmaceutical properties and broad range of biological activities that constitute selective modes of DNA binding, mimicking photosynthetic centers, vitamin B12, and P-450; 19 , 21 − 24 nevertheless, the cellular target of the compounds is still unclear.…”