Engineering pH-Gated Transitions for Selective and Efficient Double-Strand DNA Photocleavage in Hypoxic Tumors

We describe a family of hybrid compounds for the most efficient light-activated double-strand (ds) DNA cleavage known to date. This family represents the second generation of “switchable” molecular systems for pH-gated ds DNA-cleavage which combine a potent DNA-photocleaver and a pH-regulated part d...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2011-12, Vol.54 (24), p.8501-8516
Main Authors: Yang, Wang-Yong, Roy, Saumya, Phrathep, Boondaniwon, Rengert, Zach, Kenworthy, Rachael, Zorio, Diego A. R, Alabugin, Igor V
Format: Article
Language:English
Subjects:
Alkynes - chemical synthesis
Alkynes - chemistry
Alkynes - pharmacology
Cell Hypoxia
Cell Line, Tumor
Cell Proliferation - drug effects
Dipeptides - chemical synthesis
Dipeptides - chemistry
Dipeptides - pharmacology
DNA Breaks, Double-Stranded
DNA Breaks, Single-Stranded
DNA Cleavage - radiation effects
DNA, Single-Stranded - radiation effects
DNA, Superhelical - radiation effects
Drug Screening Assays, Antitumor
Humans
Hydrogen-Ion Concentration
Light
Neoplasms - genetics
Neoplasms - pathology
Stereoisomerism
Structure-Activity Relationship
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Summary:We describe a family of hybrid compounds for the most efficient light-activated double-strand (ds) DNA cleavage known to date. This family represents the second generation of “switchable” molecular systems for pH-gated ds DNA-cleavage which combine a potent DNA-photocleaver and a pH-regulated part derived from a dipeptide. Design of the pH-switchable part utilizes amino groups of different basicity. Whereas the basic amino groups are protonated throughout the biologically relevant pH range, the pH-gating amines undergo protonation at the pH threshold which separates cancer and normal cells. Control over the reactivity and selectivity is achieved via transformation of the initial protonation state (a monocation or a dication) into a trication at the acidic pH. This change leads to an extraordinary increase in the efficiency of ds DNA cleavage leading to the ds:ss ratios comparable with the most efficient nonenzymatic ds DNA cleavers. Statistical analysis reveals that these high ds:ss ratios result from the combination of several factors: (a) true double-stranded cleavage, and (b) conversion of single-stranded (ss)-scission into ds cleavage. Considerable part of ds cleavage is also produced via the combination of ss cleavage events.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm2010282