Carbon monoxide has shown promise as a therapeutic agent against cancers. Reactive oxygen species (ROS)-activated CO prodrugs are highly demanded for targeted cancer treatment but remain sporadic. In addition, little attention is on how the release rate affects CO's biological effects. Herein, we describe a new type of ROS-activated metal-free CO prodrug, which releases CO with tunable release rates in response to multiple ROS and exhibits very pronounced tumor suppression effects in a mouse 4t1 breast tumor model. Importantly, for the first time, we observe both in vitro and in vivo that CO release rate has a direct impact on its antiproliferative potency and a correlation between release rate and antiproliferative activity is observed. In aggregates, our results not only deliver ROS-sensitive CO prodrugs for cancer treatment but also represent a promising starting point for further in-depth studies of how CO release kinetics affect anticancer activity.
A mild and practical protocol is developed for the synthesis of functionalized 4-(arylamino)butanenitriles via selective C–C bond cleavage and subsequent C(sp3)–N coupling.
Time- and space-resolved drug delivery is highly demanded for cancer treatment, which, however, can barely be achieved with a traditional prodrug strategy. In recent years, the prodrug strategy based on a bioorthogonal bond cleavage chemistry has emerged with the advantages of high temporospatial resolution over drug activation and homogeneous activation irrespective of individual heterogeneity. In the past five years, tremendous progress has been witnessed in this field with one such bioorthogonal prodrug entering Phase II clinical trials. This Perspective aims to highlight these new advances (2019–2023) and critically discuss their pros and cons. In addition, the remaining challenges and potential strategic directions for future progress will also be included.
A mild and practical protocol is developed for the synthesis of distal azido and thiocyanato alkylamines via N-directed remote C(sp3)–H functionalization.
Abstract Photolysis‐based prodrug strategy can address some critical drug delivery issues, which otherwise are very challenging to tackle with traditional prodrug strategy. However, the need for external light irradiation significantly hampers its in vivo application due to the poor light accessibility of deep tissue. Herein, we propose a new strategy of chemiexcitation‐triggered prodrug activation, wherein a photoresponsive prodrug is excited for drug payload release by chemiexcitation instead of photoirradiation. As such, the bond‐cleavage power of photolysis can be employed to address some critical drug delivery issues while obviating the need for external light irradiation. We have established the proof of concept by the successful development of a chemiexcitation responsive carbon monoxide delivery platform, which exhibited specific CO release at the tumor site and pronounced tumor suppression effects. We anticipate that such a concept of chemiexcitation‐triggered prodrug activation can be leveraged for the targeted delivery of other small molecule‐based drug payloads.
Photolysis-based prodrug strategy can address some critical drug delivery issues, which otherwise are very challenging to tackle with traditional prodrug strategy. However, the need for external light irradiation significantly hampers its in vivo application due to the poor light accessibility of deep tissue. Herein, we propose a new strategy of chemiexcitation-triggered prodrug activation, wherein a photoresponsive prodrug is excited for drug payload release by chemiexcitation instead of photoirradiation. As such, the bond-cleavage power of photolysis can be employed to address some critical drug delivery issues while obviating the need for external light irradiation. We have established the proof of concept by the successful development of a chemiexcitation responsive carbon monoxide delivery platform, which exhibited specific CO release at the tumor site and pronounced tumor suppression effects. We anticipate that such a concept of chemiexcitation-triggered prodrug activation can be leveraged for the targeted delivery of other small molecule-based drug payloads.
A metal-free, mild, and simple protocol is developed for the synthesis of tertiary alcohols bearing tri-/difluoromethyl groups upon visible-light irradiation.
A redox-neutral, transition-metal-free and photocatalytic protocol is developed for the synthesis of functionalized phenols from para-quinone methides.
Herein, we demonstrate that dichloromethanol but not difluoromethanol is a viable surrogate of carbon monoxide for prodrug design. A proof of concept was established by the successful development of a ROS-responsive carbon monoxide prodrug, presenting specific CO release in response to endogenous ROS in cells.
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