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1.
J Med Chem ; 66(5): 3250-3261, 2023 03 09.
Article in English | MEDLINE | ID: mdl-36855911

ABSTRACT

Overexpression of the selenoprotein thioredoxin reductase (TrxR) has been documented in malignant tissues and is of pathological significance for many types of tumors. The antibiotic puromycin (Puro) is a protein synthesis inhibitor causing premature polypeptide chain termination during translation. The well-defined action mechanism of Puro makes it a useful tool in biomedical studies. However, the nonselective cytotoxicity of Puro limits its therapeutic applications. We report herein the construction and evaluation of two Puro prodrugs, that is, S1-Puro with a five-membered cyclic disulfide trigger and S2-Puro with a linear disulfide trigger. S1-Puro is selectively activated by TrxR and shows the TrxR-dependent cytotoxicity to cancer cells, while S2-Puro is readily activated by thiols. Furthermore, S1-Puro displays higher stability in plasma than S2-Puro. We expect that this prodrug strategy may promote the further development of Puro as a therapeutic agent.


Subject(s)
Prodrugs , Thioredoxin-Disulfide Reductase , Thioredoxin-Disulfide Reductase/metabolism , Prodrugs/pharmacology , Puromycin/pharmacology
2.
Bioorg Med Chem ; 79: 117169, 2023 02 01.
Article in English | MEDLINE | ID: mdl-36657375

ABSTRACT

The selenoprotein thioredoxin reductase (TrxR) is of paramount importance in maintaining cellular redox homeostasis, and aberrant upregulation of TrxR is frequently observed in various cancers due to their elevated oxidative stress in cells. Thus, it seems promising and feasible to target the ablation of intracellular TrxR for the treatment of cancers. We report herein the design and synthesis of a series of Baylis-Hillman adducts, and identified a typical adduct that possesses the superior cytotoxicity against HepG2 cells over other types of cancer cells. The biological investigation shows the selected typical adduct selectively targets TrxR in HepG2 cells, which thereafter results in the collapse of intracellular redox homeostasis. Further mechanistic studies reveal that the selected typical adduct arrests the cell cycle in G1/G0 phase. Importantly, the malignant metastasis of HepG2 cells is significantly restrained by the selected typical adduct. With well-defined molecular target and mechanism of action, the selected typical adduct, even other Baylis-Hillman skeleton-bearing compounds, merits further development as candidate or ancillary agent for the treatment of various cancers.


Subject(s)
Neoplasms , Thioredoxin-Disulfide Reductase , Humans , Thioredoxin-Disulfide Reductase/metabolism , Oxidative Stress , Neoplasms/drug therapy , Oxidation-Reduction
3.
Med Res Rev ; 42(5): 1930-1977, 2022 09.
Article in English | MEDLINE | ID: mdl-35657029

ABSTRACT

Following the discovery of nitric oxide (NO) and carbon monoxide (CO), hydrogen sulfide (H2 S) has been identified as the third gasotransmitter in humans. Increasing evidence have shown that H2 S is of preventive or therapeutic effects on diverse pathological complications. As a consequence, it is of great significance to develop suitable approaches of H2 S-based therapeutics for biomedical applications. H2 S-releasing agents (H2 S donors) play important roles in exploring and understanding the physiological functions of H2 S. More importantly, accumulating studies have validated the theranostic potential of H2 S donors in extensive repertoires of in vitro and in vivo disease models. Thus, it is imperative to summarize and update the literatures in this field. In this review, first, the background of H2 S on its chemical and biological aspects is concisely introduced. Second, the studies regarding the H2 S-releasing compounds are categorized and described, and accordingly, their H2 S-donating mechanisms, biological applications, and therapeutic values are also comprehensively delineated and discussed. Necessary comparisons between related H2 S donors are presented, and the drawbacks of many typical H2 S donors are analyzed and revealed. Finally, several critical challenges encountered in the development of multifunctional H2 S donors are discussed, and the direction of their future development as well as their biomedical applications is proposed. We expect that this review will reach extensive audiences across multiple disciplines and promote the innovation of H2 S biomedicine.


Subject(s)
Hydrogen Sulfide , Humans , Hydrogen Sulfide/pharmacology
4.
J Med Chem ; 65(8): 6056-6069, 2022 04 28.
Article in English | MEDLINE | ID: mdl-35427109

ABSTRACT

The controlled release of a molecule of interest (MOI) is useful in probe design, prodrug construction, and drug delivery. We report herein a versatile thiol-triggered fluorogenic release system using the Baylis-Hillman (BH) adducts as a module. Common functional groups (e.g., amino, hydroxyl, carboxylic, and sulfhydryl groups) in a MOI are readily integrated into the module. The MOI release is fast (∼10 min) with a nearly quantitative yield and a >250-fold fluorescence increment. We further prepared two prodrugs to release camptothecin and nitric oxide (NO) using the two-photon excitable template, and the activation of prodrugs was visualized in live cells and mouse tissues. The therapeutic potential of the NO prodrug was also validated in a stroke model. This BH adduct-based fluorogenic release features multiple advantages, such as easy preparation, compatibility of various functional groups, fast response, high release yield, and tunable emission spectra, and is expected to have broad applications.


Subject(s)
Prodrugs , Animals , Camptothecin , Fluorescence , Mice , Sulfhydryl Compounds
5.
Chem Commun (Camb) ; 56(19): 2857-2860, 2020 Mar 05.
Article in English | MEDLINE | ID: mdl-32031544

ABSTRACT

The first ß-allyl carbamate fluorescent probe, AC-green, was reported for specifically imaging vicinal dithiol proteins (VDPs) in living systems. The probe displays low toxicity and features high sensitivity and fast response towards VDPs. A drastic loss of VDPs in a Parkinson's model was disclosed by AC-green, linking the fluctuation of VDP levels to Parkinson's disease for the first time. The structural novelty and favorable properties of AC-green will advance the development of novel VDP probes.


Subject(s)
Carbamates/chemistry , Fluorescent Dyes/chemistry , Proteins/analysis , Sulfhydryl Compounds/chemistry , Humans , Parkinson Disease/metabolism , Proteins/chemistry , Proteins/metabolism
6.
J Pharm Biomed Anal ; 141: 192-199, 2017 Jul 15.
Article in English | MEDLINE | ID: mdl-28448888

ABSTRACT

Eight impurities ranging from 0.03 to 0.97% in anidulafungin bulk drug were detected by HPLC. Four impurities (Imp-I, Imp-II, Imp-III and Imp-VIII) among impurities were isolated from the self-prepared or marketed samples of anidulafungin bulk drug by means of preparative HPLC. A thorough study was undertaken to characterize these impurities and based on 1D (1H, 13C, H-D, DEPT 90 and 135) and 2D (COSY, TOCSY, HSQC, HMBC) NMR and ESI-MS spectral data. Based on the characterization data, Imp-I was found to be known open-chain hydrolysis product formed during the synthesis and degradation. Imp-II and Imp-III was lacked a methyl group at the C-4 and C-8 in anidulafungin, respectively, whereas Imp-VIII contained a methoxy group at the C-23. The latter three new impurities were identified as process-related substances.


Subject(s)
Echinocandins/analysis , Anidulafungin , Chromatography, High Pressure Liquid , Drug Contamination , Magnetic Resonance Spectroscopy
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