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Reaction of human telomeric unit TTAGGG and a photoactivatable Pt(IV) anticancer prodrug.

Authors :
Lin, Jiafan
Zhang, Jishuai
Ma, Ziqi
Wu, Xiaoqin
Wang, Fuyi
Zhao, Yao
Wu, Kui
Liu, Yi
Source :
Dalton Transactions: An International Journal of Inorganic Chemistry; 9/14/2023, Vol. 52 Issue 34, p12057-12066, 10p
Publication Year :
2023

Abstract

The interaction of a photoactivatable diazidodihydroxido Pt(IV) prodrug, trans,trans,trans-[Pt(N<subscript>3</subscript>)<subscript>2</subscript>(OH)<subscript>2</subscript>(py)<subscript>2</subscript>] (py = pyridine; 1), with a hexamer straight human telomeric DNA unit sequence (5′-T<subscript>1</subscript>T<subscript>2</subscript>A<subscript>3</subscript>G<subscript>4</subscript>G<subscript>5</subscript>G<subscript>6</subscript>-3′, I) upon light irradiation was investigated by electrospray ionization mass spectroscopy (ESI-MS). In the primary mass spectrum, two major mono-platinated I adducts with the bound Pt moieties, trans-[Pt<superscript>II</superscript>(N<subscript>3</subscript>)(py)<subscript>2</subscript>]<superscript>+</superscript> (1′) and trans-[Pt<superscript>II</superscript>(py)<subscript>2</subscript>]<superscript>2+</superscript> (1′′), respectively, were detected. It is rare to observe such high abundance and nearly equal intensity platinated DNA adducts formed by these two Pt<superscript>II</superscript> species because 1′ is usually the only major reduced Pt(II) species produced by the photodecomposition of complex 1 in the presence of DNA while 1′′ was rarely detected as the major reduced Pt<superscript>II</superscript> species reported previously. Subsequent tandem mass spectrometric analysis by collision-induced dissociation (CID) showed that in the former adduct {I + 1′}<superscript>2+</superscript>, G<subscript>6</subscript> and A<subscript>3</subscript> were the platination sites. While in the latter adduct {I + 1′′}<superscript>2+</superscript>, a potential intrastrand crosslink was speculated after G<subscript>4</subscript> and G<subscript>6</subscript> sites were identified. Additionally, other minor platinated adducts like di-platinated I adduct by 1′ with platination sites at G<subscript>4</subscript> and G<subscript>6</subscript> and mono-platinated I adducts containing base oxidation were also detected by mass spectrometry. Due to the rich guanines and their sensitivity to oxidation, the oxidation induced by 1 most probably occurred at guanine. The oxidation adducts were proposed as 8-hydroxyl guanine, spiroiminodihydantoin (Sp), 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyG), 5-guanidinohydantoin (Gh), and/or dehydroguanidinohydantoin (DGh) referring to previous reports. The obtained results provide useful chemical information about the photoreaction between photoactivatable Pt(IV) anticancer prodrugs and human telomeric DNA. Such special damages of Pt(IV) prodrugs on human telomeric DNA implicate its active role in the mechanism of Pt(IV) prodrugs and further support the unique sequence-dependent photointeraction profile of complex 1 reacting with DNA. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
14779226
Volume :
52
Issue :
34
Database :
Complementary Index
Journal :
Dalton Transactions: An International Journal of Inorganic Chemistry
Publication Type :
Academic Journal
Accession number :
170907639
Full Text :
https://doi.org/10.1039/d3dt01643a