Optimizing Protonation States for Selective Double-Strand DNA Photocleavage in Hypoxic Tumors: pH-Gated Transitions of Lysine Dipeptides

Abstract

We report pH-switching properties of the new family of dipeptide-acetylene conjugates where pH-gated light-activated double-strand (ds) DNA cleavage is controlled by variations in electronic and geometric parameters. The conjugates have higher activities at the slightly acidic pH values that separate normal and cancerous tissue (pH < 7). This favorable pH dependence originates from several elements of structural design. Basicities of the two amines determine the threshold pH range where the changes in binding and reactivity are observed, whereas the distance between the two amino groups and the hydrophobic aryl alkyne moiety can further modulate DNA binding. The changes of the protonation state from a neutral molecule to a dication results in dramatically increased efficiency of ds DNA photocleavage, the most therapeutically valuable type of DNA cleavage.

Electrochemical behavior of N‐oxyphthalimides: Cascades initiating self‐sustaining catalytic reductive N―O bond cleavage

“…In addition to organic synthesis, understanding the processes of the formation and decomposition of PI‐OR RAs gains increasing importance for medicinal chemistry. In this field, there is a need for new structural units capable of releasing active functional groups or generating reactive free radicals directly in living tissues, eg, via photoinduced electron transfer . Compounds having such properties can be particularly useful for the development of approaches to the therapy of hypoxic tumors, which are difficult to treat with cytotoxic drugs with other mechanisms of action .…”

Photochemical Activation of Enediyne Warheads: A Potential Tool for Targeted Antitumor Therapy

“…We will show below that this feature bestows upon it the ability to distinguish between the cancerous and healthy tissues. 78 Thus, the presence of the free α-amine is particularly important for the design of pH-controlled DNA cleavers. Furthermore, the dicationic conjugate acid of the Cconjugate is expected to have greater DNA binding capability.…”

“…It was experimentally found (via NMR and fluorescence quenching) that the α-amine has the considerably lower p K a among the two. We will show below that this feature bestows upon it the ability to distinguish between the cancerous and healthy tissues . Thus, the presence of the free α-amine is particularly important for the design of pH-controlled DNA cleavers.…”

“…Regarding the modification of the DNA binding part, a third generation of lysine hybrids comprising a further variation in the binding part was reported in 2016, where two α-amino groups were grafted into the hybrid enyne (Figure ).…”

“…Figure15. Structures of dipeptide acetylene conjugates with two α-NH 2 groups with varying bridge lengths (Kaya) 78. …”