This review summarizes recent developments in using bioorthogonal chemistry in prodrug design for the delivery of traditional small molecule- and gasotransmitter-based therapeutics.

Hedgehog (Hh) signaling is an essential pathway in the human body, and plays a major role in embryo development and tissue patterning. Constitutive activation of the Hh signaling pathway through sporadic mutations or other mechanisms is explicitly associated with cancer development and progression in various solid malignancies. Therefore, targeted inhibition of the Hh signaling pathway has emerged as an attractive and validated therapeutic strategy for the treatment of a wide range of cancers. Vismodegib, a first-in-class Hh signaling pathway inhibitor was approved by the US Food and Drug Administration in 2012, and sonidegib, another potent Hh pathway inhibitor, received FDA's approval in 2015 as a new treatment of locally advanced or metastatic basal cell carcinoma. The clinical success of vismodegib and sonidegib provided strong support for the development of Hh signaling pathway inhibitors via targeting the smoothened (Smo) receptor. Moreover, Hh signaling pathway inhibitors aimed to target proteins, which are downstream or upstream of Smo, have also been pursued based on the identification of additional therapeutic benefits. Recently, much progress has been made in Hh singling and inhibitors of this pathway. Herein, medicinal chemistry strategies, especially the structural optimization process of different classes of Hh inhibitors, are comprehensively summarized. Further therapeutic potentials and challenges are also discussed.

Abstract:Hydrogen sulfide (H 2 S), together with nitric oxide (NO) and carbon monoxide (CO), belongs to the gasotransmitter family and plays important roles in mammals as a signaling molecule. Many studies have also shown the various therapeutic effects of H 2 S, which include protection against myocardial ischemia injury, cytoprotection against oxidative stress, mediation of neurotransmission, inhibition of insulin signaling, regulation of inflammation, inhibition of the hypoxia-inducible pathway, and dilation of blood vessels. One major challenge in the development of H 2 S-based therapeutics is its delivery. In this manuscript, we assess the various drug delivery strategies in the context of being used research tools and eventual developability as therapeutic agents.

Nitro reduction-based fluorescent CO probes only sense ruthenium-based CO donors, CORM-2 and CORM-3, not CO in general.