title: Engineering pH-gated transitions for selective and efficient double-strand DNA photocleavage in hypoxic tumors.
abstract: 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.
authors: Department of Chemistry and Biochemistry, Florida State University, Tallahassee, Florida 32306-4390, United States.
authors: Wang-Yong
authors: WY
authors: Yang
authors: Saumya
authors: S
authors: Roy
authors: Boondaniwon
authors: B
authors: Phrathep
authors: Zach
authors: Z
authors: Rengert
authors: Rachael
authors: R
authors: Kenworthy
authors: Diego A R
authors: DA
authors: Zorio
authors: Igor V
authors: IV
authors: Alabugin
mesh_terms: D000480:Alkynes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D053903:DNA Breaks, Double-Stranded; D053904:DNA Breaks, Single-Stranded; D053837:DNA Cleavage / Q000528:radiation effects*; D004277:DNA, Single-Stranded / Q000528:radiation effects; D004278:DNA, Superhelical / Q000528:radiation effects*; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008027:Light; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000480:Alkynes; D004277:DNA, Single-Stranded; D004278:DNA, Superhelical; D004151:Dipeptides; C024575:lysyllysine