Fine-tuning alkyne cycloadditions: Insights into photochemistry responsible for the double-strand DNA cleavage via structural perturbations in diaryl alkyne conjugates

Wang-Yong Yang,Samantha A Marrone,Nalisha Minors,Igor V Alabugin,Diego A R Zorio

doi:10.3762/bjoc.7.93

Abstract

Hybrid molecules combining photoactivated aryl acetylenes and a dicationic lysine moiety cause the most efficient double-strand (ds) DNA cleavage known to date for a small molecule. In order to test the connection between the alkylating ability and the DNA-damaging properties of these compounds, we investigated the photoreactivity of three isomeric aryl–tetrafluoropyridinyl (TFP) alkynes with amide substituents in different positions (o-, m-, and p-) toward a model π-system. Reactions with 1,4-cyclohexadiene (1,4-CHD) were used to probe the alkylating properties of the triplet excited states in these three isomers whilst Stern–Volmer quenching experiments were used to investigate the kinetics of photoinduced electron transfer (PET). The three analogous isomeric lysine conjugates cleaved DNA with different efficiencies (34, 15, and 0% of ds DNA cleavage for p-, m-, and o-substituted lysine conjugates, respectively) consistent with the alkylating ability of the respective acetamides. The significant protecting effect of the hydroxyl radical and singlet oxygen scavengers to DNA cleavage was shown only with m-lysine conjugate. All three isomeric lysine conjugates inhibited human melanoma cell growth under photoactivation: The p-conjugate had the lowest CC50 (50% cell cytotoxicity) value of 1.49 × 10−7 M.

Highlights

Triggering chemical processes with light offers numerous practical advantages
We expanded our studies of alkyne reactivity [12,13,14,15,16,17,18,19,20,21,22,23] to the design of photoactivated DNA cleavers, which combine a DNA-damaging part derived from diaryl alkynes and benzannelated enediynes with a cationic DNA-binding moiety
From the narrowed list of mechanistic scenarios, base alkylation remains a likely origin of the photodamaging ability of such alkynes. Such reactivity is consistent with the abovementioned ability of alkynes to act as electrophilic alkylating agents toward electron-rich π-systems observed in triplet photocycloaddition of TFP-substituted diaryl acetylenes [53]

Summary

Introduction

Triggering chemical processes with light offers numerous practical advantages. does photochemistry open an additional dimension for the control of chemical reactivity by enabling many, otherwise impossible, synthetic transformations, but this mode of activation provides useful spatial and temporal control of chemical processes that are required to Beilstein J. This observation suggests the presence of competitive DNA-cleavage mechanisms, such as guanine alkylation [29,30,31,32,33,34,35], which combine with the oxidative DNA damage to account for the efficient ds cleavage of plasmid DNA. Efficient DNA cleavage by the monoacetylene conjugate 1, which is capable of neither Bergman nor C1–C5 cyclization, suggests that other scenarios are possible and a more detailed understanding of alkyne photochemistry is vital for unraveling the mechanistic scenarios that account for DNA cleavage by these compounds (Figure 3) [25].

Results

Conclusion