Prodrug strategies for targeted therapy triggered by reactive oxygen species

Abstract

A comprehensive review of ROS-activated produg strategies for targeted therapy, including state-of-the-art and future perspectives.

Oxidative Cyclization‐Induced Activation of a Phosphoinositide 3‐Kinase Inhibitor for Enhanced Selectivity of Cancer Chemotherapeutics

“…Thus, the phenol of Pi103 was chosen as the point for attachment to the self-cyclizing portion of the molecule to make a ROS-sensitive PI3K prodrug. Detailed synthetic procedures, yields, and spectroscopic data including 1 H-NMR, 13 C-NMR, and highresolution MS are provided in Supplementary Information. Reaction of 1 with ROS is expected to release Pi103 and form a non-cytotoxic aromatic system (black, Figure 2C).…”

“…Compound 1 was synthesized in three steps, starting from commercially available Pi103, in an overall yield of 60 % (Scheme 1). Detailed synthetic procedures, yields, and spectroscopic data including 1 H-NMR, 13 C-NMR, and highresolution MS are provided in Supplementary Information.…”

“…[12,13] We have designed a prodrug strategy, called selfcyclizing prodrugs, that undergo unique reactions when oxidized specifically in cancer cells, which have high levels of reactive oxygen species (ROS), to produce non-toxic byproducts and release an inhibitor [14][15] (Figure 1). [12,13] We have designed a prodrug strategy, called selfcyclizing prodrugs, that undergo unique reactions when oxidized specifically in cancer cells, which have high levels of reactive oxygen species (ROS), to produce non-toxic byproducts and release an inhibitor [14][15] (Figure 1).…”

“…Cancer cells have important phenotypic differences compared to normal cells that are exploitable as a prodrug strategy. [12,13] We have designed a prodrug strategy, called selfcyclizing prodrugs, that undergo unique reactions when oxidized specifically in cancer cells, which have high levels of reactive oxygen species (ROS), to produce non-toxic byproducts and release an inhibitor [14][15] (Figure 1). At the biochemical level, ROS are not only deleterious byproducts of metabolism but also serve as signaling molecules.…”

“…mg, 0.15 mmol) in DMSO (2 mL), K 2 CO 3 (30 mg, 0.2 mmol) was added, followed by addition of 2-fluoro-5-nitrobenzenamine (50 mg, 0.3 mmol). H NMR (400 MHz, Chloroform-d) δ 8.62 (dd, J = 4.9, 1.8 Hz, 1H), 8.58 (dd, J = 7.7, 1.8 Hz, 1H), 8.32 (d, J = 7.8, 1H), 8.28(s,1H), 7.72 (d, J = 2.7 Hz, 1H), 7.58-7.52 (m, 2H), 7.43 (dd, J = 7.7, 4.8 Hz, 1H), 7.13-7.06 (m, 1H), 6.81 (d, J = 8.9 Hz, 1H), 4.27 (s, 2H), 4.22 (t, J = 4.8 Hz, 4H), 9.92 (t, J = 4.8 Hz, 4H) 13. After overnight incubation, the reaction mixture was diluted with 25 mL H 2 O and extracted with ethyl acetate and washed with brine.…”