Highly Selective Suppression of Melanoma Cells by Inducible DNA Cross-Linking Agents: Bis(catechol) Derivatives

Abstract

A series of bis(catechol) quaternary ammonium derivatives were designed and synthesized. We investigated their ability to cross-link DNA induced by tyrosinase and found that the o-quinone is key intermediate in the process by using the nucleophile 3-methyl-2-benzothiazolinone hydrazone (MBTH) in the tyrosinase assay. Their cytotoxicities to B16F1, Hela, and CHO cells were tested by MTT assays. The specific and potent abilities to kill the tyrosinase-efficient melanoma cells kindled our interest in exploring the relationship between their abilities of cross-linking DNA and their selective cytotoxicities to cells. Through an integrated approach including intracellular imaging for detection of the dihydroxyphenyl groups, alkaline comet assays, and γ-H2AX immunofluorescence assays, the speculation was confirmed. The bis(catechol) quaternary ammonium derivatives showed notable cell selectivity because they displayed cytotoxicities after being oxidized by tyrosinase, and they were able to target the DNA efficiently in the tyrosinase-efficient melanoma cells, forming both alkylated and cross-linked species.

Synthesis and antioxidant activity of hydroxylated phenanthrenes as cis-restricted resveratrol analogues

“…Taken together, these results imply that ortho-quinone plays an important role in not only antioxidant, but also prooxidant action, of catechol type compounds. From an antioxidant point of view, this prooxidant action is a drawback, but the prooxidant-induced DNA strand breakage is believed to be a promising strategy for killing cancer cells (Bai et al, 2010;Fan et al, 2009). Zhou and co-workers have recently reported that bis(catechol) derivatives could selectively suppress melanoma cells by inducing DNA cross-link via an ortho-quinone intermediate (Bai et al, 2010).…”

Existence of G-quadruplex structures in promoter region of oncogenes confirmed by G-quadruplex DNA cross-linking strategy

“…Due to frangibility, reactions of nucleic acids were required to be very mild, selective and readily controllable. o -Quinone intermediate, an actively potent DNA cross-linking unit resulted from a catechol precursor upon oxidation, has been proved to possess good cross-linking activity toward duplex DNAs without resulting in G-quadruplex cross-linked25. A superiority of the o -quinone mediated DNA cross-linking was that it could be readily stimulated by tyrosinase, which is highly expressed in some malignant tumors26272829, thus bringing in good cell selectivity.…”

“…Taken together, the catechol moiety was an ideal scaffold that could fit multifaceted requirements. We previously reported N,N′-(3,4-Dihydroxylbenzyl)-N,N,N′,N′–tetramethyl-4,4′-biphenyldiamine dibromide as double strand DNA cross-linking agent25. In these studies, for purpose of demonstration of G-quadruplex's existence in vivo , we designed a new series of Schiff-base catechol derivatives as G-quadruplex cross-linking candidates.…”

Oxidatively Activated DNA‐Modifying Agents for Selective Cytotoxicity

“…Catechol was recently used in the selective modification of DNA in cancer cells. [29] Catechol, with a 1,2-diol, also shows a decreased IC 50 value of 71 mm. We synthesized a derivative that is not prone to oxidation: An-Hq-CH 3 .…”