- Simple alkanoyl acylating agents for reversible RNA functionalization and control CHEMICAL COMMUNICATIONS 2019; 55 (35): 5135–38
Simple alkanoyl acylating agents for reversible RNA functionalization and control.
Chemical communications (Cambridge, England)
We describe the synthesis and RNA acylation activity of a series of minimalist azidoalkanoyl imidazole reagents, with the aim of functionalizing RNA at 2'-hydroxyl groups at stoichiometric to superstoichiometric levels. We find marked effects of small structural changes on their ability to acylate and be reductively removed, and identify reagents and methods that enable efficient RNA functionalization and control.
View details for PubMedID 30977472
- Exceptionally rapid oxime and hydrazone formation promoted by catalytic amine buffers with low toxicity CHEMICAL SCIENCE 2018; 9 (23): 5252–59
Aldehyde dehydrogenase 3A1 activation prevents radiation-induced xerostomia by protecting salivary stem cells from toxic aldehydes.
Proceedings of the National Academy of Sciences of the United States of America
Xerostomia (dry mouth) is the most common side effect of radiation therapy in patients with head and neck cancer and causes difficulty speaking and swallowing. Since aldehyde dehydrogenase 3A1 (ALDH3A1) is highly expressed in mouse salivary stem/progenitor cells (SSPCs), we sought to determine the role of ALDH3A1 in SSPCs using genetic loss-of-function and pharmacologic gain-of-function studies. Using DarkZone dye to measure intracellular aldehydes, we observed higher aldehyde accumulation in irradiated Aldh3a1-/- adult murine salisphere cells and in situ in whole murine embryonic salivary glands enriched in SSPCs compared with wild-type glands. To identify a safe ALDH3A1 activator for potential clinical testing, we screened a traditional Chinese medicine library and isolated d-limonene, commonly used as a food-flavoring agent, as a single constituent activator. ALDH3A1 activation by d-limonene significantly reduced aldehyde accumulation in SSPCs and whole embryonic glands, increased sphere-forming ability, decreased apoptosis, and improved submandibular gland structure and function in vivo after radiation. A phase 0 study in patients with salivary gland tumors showed effective delivery of d-limonene into human salivary glands following daily oral dosing. Given its safety and bioavailability, d-limonene may be a good clinical candidate for mitigating xerostomia in patients with head and neck cancer receiving radiation therapy.
View details for PubMedID 29794221
Exceptionally rapid oxime and hydrazone formation promoted by catalytic amine buffers with low toxicity.
2018; 9 (23): 5252–59
Hydrazone and oxime bond formation between α-nucleophiles (e.g. hydrazines, alkoxy-amines) and carbonyl compounds (aldehydes and ketones) is convenient and is widely applied in multiple fields of research. While the reactants are simple, a substantial drawback is the relatively slow reaction at neutral pH. Here we describe a novel molecular strategy for accelerating these reactions, using bifunctional buffer compounds that not only control pH but also catalyze the reaction. The buffers can be employed at pH 5-9 (5-50 mM) and accelerate reactions by several orders of magnitude, yielding second-order rate constants of >10 M-1 s-1. Effective bifunctional amines include 2-(aminomethyl)imidazoles and N,N-dimethylethylenediamine. Unlike previous diaminobenzene catalysts, the new buffer amines are found to have low toxicity to human cells, and can be used to promote reactions in cellular applications.
View details for PubMedID 29997880
Dark Hydrazone Fluorescence Labeling Agents Enable Imaging of Cellular Aldehydic Load.
ACS chemical biology
2016; 11 (8): 2312-2319
Aldehydes are key intermediates in many cellular processes, from endogenous metabolic pathways like glycolysis to undesired exogenously induced processes such as lipid peroxidation and DNA interstrand cross-linking. Alkyl aldehydes are well documented to be cytotoxic, affecting the functions of DNA and protein, and their levels are tightly regulated by the oxidative enzyme ALDH2. Mutations in this enzyme are associated with cardiac damage, diseases such as Fanconi anemia (FA), and cancer. Many attempts have been made to identify and quantify the overall level of these alkyl aldehydes inside cells, yet there are few practical methods available to detect and monitor these volatile aldehydes in real time. Here, we describe a multicolor fluorogenic hydrazone transfer ("DarkZone") system to label alkyl aldehydes, yielding up to 30-fold light-up response in vitro. A cell-permeant DarkZone dye design was applied to detect small-molecule aldehydes in the cellular environment. The new dye design also enabled the monitoring of cellular acetaldehyde production from ethanol over time by flow cytometry, demonstrating the utility of the DarkZone dyes for measuring and imaging the aldehydic load related to human disease.
View details for DOI 10.1021/acschembio.6b00269
View details for PubMedID 27326450