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1.
Mengjiao Huang Juanjuan Yang Teng Wang Jia Song Jinglu Xia Lingling Wu Wei Wang Qiaoyi Wu Zhi Zhu Yanling Song Chaoyong Yang 《Angewandte Chemie (International ed. in English)》2020,59(12):4800-4805
Immunotherapy has revolutionized cancer treatment, but its efficacy is severely hindered by the lack of effective predictors. Herein, we developed a homogeneous, low‐volume, efficient, and sensitive exosomal programmed death‐ligand 1 (PD‐L1, a type of transmembrane protein) quantitation method for cancer diagnosis and immunotherapy response prediction (HOLMES‐ExoPD‐L1). The method combines a newly evolved aptamer that efficiently binds to PD‐L1 with less hindrance by antigen glycosylation than antibody, and homogeneous thermophoresis with a rapid binding kinetic. As a result, HOLMES‐ExoPD‐L1 is higher in sensitivity, more rapid in reaction time, and easier to operate than existing enzyme‐linked immunosorbent assay (ELISA)‐based methods. As a consequence of an outstanding improvement of sensitivity, the level of circulating exosomal PD‐L1 detected by HOLMES‐ExoPD‐L1 can effectively distinguish cancer patients from healthy volunteers, and for the first time was found to correlate positively with the metastasis of adenocarcinoma. Overall, HOLMES‐ExoPD‐L1 brings a fresh approach to exosomal PD‐L1 quantitation, offering unprecedented potential for early cancer diagnosis and immunotherapy response prediction. 相似文献
2.
Jrhau Lung Ming-Szu Hung Yu-Ching Lin Chien-Hui Hung Chih-Cheng Chen Kuan-Der Lee Ying Huang Tsai 《Molecules (Basel, Switzerland)》2020,25(22)
Genetic mutations accumulated overtime could generate many growth and survival advantages for cancer cells, but these mutations also mark cancer cells as targets to be eliminated by the immune system. To evade immune surveillance, cancer cells adopted different intrinsic molecules to suppress immune response. PD-L1 is frequently overexpressed in many cancer cells, and its engagement with PD-1 on T cells diminishes the extent of cytotoxicity from the immune system. To resume immunity for fighting cancer, several therapeutic antibodies disrupting the PD-1/PD-L1 interaction have been introduced in clinical practice. However, their immunogenicity, low tissue penetrance, and high production costs rendered these antibodies beneficial to only a limited number of patients. PD-L1 dimer formation shields the interaction interface for PD-1 binding; hence, screening for small molecule compounds stabilizing the PD-L1 dimer may make immune therapy more effective and widely affordable. In the current study, 111 candidates were selected from over 180,000 natural compound structures through virtual screening, contact fingerprint analysis, and pharmacological property prediction. Twenty-two representative candidates were further evaluated in vitro. Two compounds were found capable of inhibiting the PD-1/PD-L1 interaction and promoting PD-L1 dimer formation. Further structure optimization and clinical development of these lead inhibitors will eventually lead to more effective and affordable immunotherapeutic drugs for cancer patients. 相似文献
3.
Yacong An Xundou Li Fengjiao Yao Jinhong Duan Xian-Da Yang 《Molecules (Basel, Switzerland)》2022,27(5)
The PD-1/PD-L1 pathway blockade can generate a good clinical response by reducing immunosuppression and provoking durable antitumor immunity. In addition to antibodies, aptamers can also block the interaction between PD-1 and PD-L1. For the in vivo application, however, free aptamers are usually too small in size and quickly removed from blood via glomerular filtration. To avoid renal clearance of aptamer, we conjugated the PD-L1 aptamer to albumin to form a larger complex (BSA-Apt) and evaluated whether BSA-Apt would enhance the in vivo antitumor efficacy. The PD-L1 aptamer was thiol-modified and conjugated to the amino group of BSA via a SMCC linker. The average size of BSA-Apt was 11.65 nm, which was above the threshold for renal clearance. Functionally, BSA-Apt retained the capability of the PD-L1 aptamer to bind with PDL1-expressing tumor cells. Moreover, both the free aptamer and BSA-Apt augmented the PBMC-induced antitumor cytotoxicity in vitro. Furthermore, BSA-Apt generated a significantly stronger antitumor efficacy than the free PD-L1 aptamer in vivo without raising systemic toxicity. The results indicate that conjugating the PD-L1 aptamer to albumin may serve as a promising strategy to improve the in vivo functionality of the aptamer and that BSA-Apt may have application potential in cancer immunotherapy. 相似文献
4.
Dr. Wen Su Dr. Mixiao Tan Zhihang Wang Jie Zhang Wenping Huang Haohao Song Xinye Wang Prof. Haitao Ran Prof. Yanfeng Gao Prof. Guangjun Nie Prof. Hai Wang 《Angewandte Chemie (International ed. in English)》2023,62(11):e202218128
Proteolysis targeting chimeras (PROTACs) technology is an emerging approach to degrade disease-associated proteins. Here, we report carbon-dot (CD)-based PROTACs (CDTACs) that degrade membrane proteins via the ubiquitin-proteasome system. CDTACs can bind to programmed cell death ligand 1 (PD-L1), recruit cereblon (CRBN) to induce PD-L1 ubiquitination, and degrade them with proteasomes. Fasting-mimicking diet (FMD) is also used to enhance the cellular uptake and proteasome activity. More than 99 % or 90 % of PD-L1 in CT26 or B16-F10 tumor cells can be degraded by CDTACs, respectively. Furthermore, CDTACs can activate the stimulator of interferon genes (STING) pathway to trigger immune responses. Thus, CDTACs with FMD treatment effectively inhibit the growth of CT26 and B16-F10 tumors. Compared with small-molecule-based PROTACs, CDTACs offer several advantages, such as efficient membrane protein degradation, targeted tumor accumulation, immune system activation, and in vivo detection. 相似文献
5.
Natascha Leleu-Chavain Romain Regnault Hania Ahouari Raphaël Le Biannic Mostafa Kouach Frdrique Klupsch Romain Magnez Herv Vezin Xavier Thuru Christian Bailly Jean-Franois Goossens Rgis Millet 《Molecules (Basel, Switzerland)》2022,27(10)
Small molecules targeting the PD-1/PD-L1 checkpoint are actively searched to complement the anticancer arsenal. Different molecular scaffolds have been reported, including phenyl-pyrazolone derivatives which potently inhibit binding of PD-L1 to PD-1. These molecules are structurally close to antioxidant drug edaravone (EDA) used to treat amyotrophic lateral sclerosis. For this reason, we investigated the capacity of five PD-L1-binding phenyl-pyrazolone compounds (1–5) to scavenge the formation of oxygen free radicals using electron spin resonance spectroscopy with DPPH/DMPO probes. In addition, the reactivity of the compounds toward the oxidized base 5-formyluracil (5fU) was assessed using chromatography coupled to mass spectrometry and photodiode array detectors. The data revealed that the phenyl-pyrazolone derivatives display antioxidant properties and exhibit a variable reactivity toward 5fU. Compound 2 with a N-dichlorophenyl-pyrazolone moiety cumulates the three properties, being a potent PD-L1 binder, a robust antioxidant and an aldehyde-reactive compound. On the opposite, the adamantane derivative 5 is a potent PD-L1 binding with a reduced antioxidant potential and no aldehyde reactivity. The nature of the substituent on the phenyl-pyrazolone core modulates the antioxidant capacity and reactivity toward aromatic aldehydes. The molecular signature of the compound can be adapted at will, to confer additional properties to these PD-L1 binders. 相似文献
6.
Jiajun Dong Jinmin Miao Yiming Miao Zihan Qu Sheng Zhang Peipei Zhu Florian Wiede Brenson A. Jassim Yunpeng Bai Quyen Nguyen Jianping Lin Lan Chen Tony Tiganis W. Andy Tao Zhong-Yin Zhang 《Angewandte Chemie (International ed. in English)》2023,62(22):e202303818
Protein tyrosine phosphatase 1B (PTP1B) and T-cell protein tyrosine phosphatase (TC-PTP) play non-redundant negative regulatory roles in T-cell activation, tumor antigen presentation, insulin and leptin signaling, and are potential targets for several therapeutic applications. Here, we report the development of a highly potent and selective small molecule degrader DU-14 for both PTP1B and TC-PTP. DU-14 mediated PTP1B and TC-PTP degradation requires both target protein(s) and VHL E3 ligase engagement and is also ubiquitination- and proteasome-dependent. DU-14 enhances IFN-γ induced JAK1/2-STAT1 pathway activation and promotes MHC-I expression in tumor cells. DU-14 also activates CD8+ T-cells and augments STAT1 and STAT5 phosphorylation. Importantly, DU-14 induces PTP1B and TC-PTP degradation in vivo and suppresses MC38 syngeneic tumor growth. The results indicate that DU-14, as the first PTP1B and TC-PTP dual degrader, merits further development for treating cancer and other indications. 相似文献
7.
Jie Sun Yan Liang Lin Xie An Kang Yuan Xie Wei-Dong Chen Hua Lv Guang-Ji Wang 《Chromatographia》2007,66(1-2):49-54
Olprinone is a phosphodiesterase (PDE)-3 inhibitor. This paper describes a simple, selective and sensitive method for the
quantification of olprinone in rat plasma using a liquid–liquid extraction procedure followed by liquid chromatography mass
spectrometric (LC–MS) analysis. The method had an advantage of high sensitivity. Analyses were conducted at a flow rate of
0.25 mL min−1 by a gradient elution. The detection utilized selected ion monitoring in the positive ion mode at m/z 251.0 and 344.0 for the protonated molecular ions of olprinone and the internal standard, respectively. The quantitation
limit for olprinone in rat plasma was 0.5 ng mL−1. The linearity was also excellent over the concentration range of 0.5–100 ng mL−1 of olprinone. The intra- and inter-day precision (relative standard deviation (RSD) %) was lower than 10%, and accuracy ranged
from 90 to 110%. This developed method was successfully applied to analysis of olprinone in biological fluids. 相似文献
8.
Vijayavitthal T. Mathad Gorakshanath B. Shinde Sharad S. Ippar Navnath C. Niphade Raghavendra K. Panchangam Pravinchandra J. Vankawala 《合成通讯》2013,43(3):341-346
An efficient synthesis of 1-(naphthalen-1-yl)ethanamine ( RS -2) and its practical resolution to optically pure (1R)-(naphthalen-1-yl)ethanamine ( R -(+)-2), a key intermediate in the synthesis of cinacalcet hydrochloride (1), is described. The resolution of RS -2 using R-(?)-mandelic acid as a resolving agent in ethanol was established on an industrial scale to give pure R -(+)-2 with >99.8% ee after liberation of the amine from its mandelate salt. An efficient process for the racemization of undesired isomer S -(?)-2 is also provided to maximize the yield of desired enantiomer. 相似文献
9.
10.
M. B. Madhusudana Reddy 《合成通讯》2013,43(14):2081-2085
An easy access to various 5-aryl-1H-tetrazoles by a one-pot direct conversion of aldehydes to tetrazoles without the isolation of the intermediate nitriles using commercially available iodine as a catalyst is described. The protocol offers advantages in terms of good yields, mild reaction conditions, short reaction times, and use of readily available environmentally compatible catalyst. 相似文献
11.
Jia Rong LI Shu Ling MA 《中国化学快报》2005,16(11):1424-1426
2H-3, 1-Benzoxazine heterocyclic compounds are a series of potent nonsteroidal pro- gesterone receptor agonists1-3 and have many other applications such as carbonaceous electrode, plant growth regulating and anti-stress activities4-6, etc.. Comparing to other benzoxazine series, such as 1, 4-benzoxazine, 2H-1, 3-benzoxazine, etc., little attentions have been paid for this series of compounds. There is only one method for the preparation of 2H-3, 1-benzoxazine, e.g. cyclocondensation of o-amin… 相似文献
12.
Sensitive and selective magnetoimmunosensing platform for determination of the food allergen Ara h 1
V. Ruiz-Valdepeñas Montiel S. Campuzano A. Pellicanò R.M. Torrente-Rodríguez A.J. Reviejo M.S. Cosio J.M. Pingarrón 《Analytica chimica acta》2015
A highly sensitive disposable amperometric immunosensor based on the use of magnetic beads (MBs) is described for determination of Ara h 1, the major peanut allergen, in only 2 h. The approach uses a sandwich configuration involving selective capture and biotinylated detector antibodies and carboxylic acid-modified MBs (HOOC-MBs). The MBs bearing the immunoconjugates are captured by a magnet placed under the surface of a disposable screen-printed carbon electrode (SPCE) and the affinity reactions are monitored amperometrically at −0.20 V (vs a Ag pseudo-reference electrode) in the presence of hydroquinone (HQ) as electron transfer mediator and upon addition of H2O2 as the enzyme substrate. The developed immunosensor exhibits a wide range of linearity between 20.8 and 1000.0 ng mL−1 Ara h 1, a detection limit of 6.3 ng mL−1, a great selectivity, a good reproducibility with a RSD of 6.3% for six different immunosensors and a useful lifetime of 25 days. The usefulness of the immunosensor was demonstrated by determining Ara h 1 in different matrices (food extracts and saliva). The results correlated properly with those provided by a commercial ELISA method offering a reliable and promising analytical screening tool in the development of user-friendly devices for on-site determination of Ara h 1. 相似文献
13.
《Analytical letters》2012,45(10):2251-2268
Abstract The interaction of 1-naphthol and 2-naphthol with several quaternary ammonium salts was studied. Spectrofluorimetric methods were developed for the determination of both naphthols in hexadecyltrimethylammonium bromide micellar medium. The detection limits are 1.4 and 10.2 ng/ml for 1-naphthol, and 6.2 and 5.1 ng/ml for 2-naphthol employing the conventional and synchronous spectrofluorimetric methods, respectively. The use of the first-derivative spectrum allows for the simultaneous determination of both naphthols. The recoveries of 1-naphthol and 2-naphthol in natural waters are acceptable. 相似文献
14.
An efficient methodology for the synthesis of acridinedione derivatives 4a–o has been achieved by one-pot, multicomponent condensation of dimedone 1, various amines 2a–d, and substitute aromatic aldehydes 3a–k, in the presence of the easily available, inexpensive, and nontoxic catalyst vitamin B1 (VB1) as a versatile biodegradable. Synthesis of acridine-type compounds was performed in good yields in water as green solvent. Its high-yield efficiency; clean, ecofriendly, simple workup procedure; and easy purification are regarded as the main advantages of this method besides its green solvent. The synthesized compounds are characterized using spectroscopic analyses (FTIR, 1H NMR, 13C NMR, and high-resolution mass spectrometry) techniques. 相似文献
15.
An efficient HPTLC method for the analysis of umbelliferone, carvone and myristicin in Anethum graveolens and Carum carvi seed was developed. The method employed HPTLC plates precoated with silica gel 60 F254 as the stationary phase. Methanol extracts of seeds from three different sources were used. The calibration plot for umbelliferone,
carvone and myristicin were linear with the correlation coefficient of 0.997 ± 0.016, 0.999 ± 0.009 and 0.999 ± 0.013, respectively,
which were indicative of good linear dependence of peak area on concentration. The method permits reliable quantification
of umbelliferone, carvone and myristicin and showed good resolution and separation. The method was validated as per ICH guidelines.
To study the accuracy of the method, recovery studies were performed by the method of standard addition at three different
levels and the average percentage recovery was found to be 99.05% for umbelliferone, 100.28% for carvone and 99.8% for myristicin.
The proposed HPTLC method for quantitative monitoring of umbelliferone, carvone and myristicin in A. graveolens and C. carvi seed can be used for routine quality testing of these extracts. 相似文献
16.
Li-Lin Jiang Sen-Jie Hu Dr. Qing Xu Dr. Hongxing Zheng Dr. Wen-Ting Wei 《化学:亚洲杂志》2021,16(20):3068-3081
2-Pyrrolidones have aroused enormous interest as a useful structural moiety in drug discovery; however, not only does their syntheses suffer from low selectivity and yield, but also it requires high catalyst loadings. The radical cyclization of 1,n-enynes and 1,n-dienes has demonstrated to be an attractive method for the synthesis of 2-pyrrolidones due to its mild reaction conditions, fewer steps, higher atom economy, excellent functional group compatibility, and high regioselectivity. Furthermore, radical receptors with unsaturated bonds (i. e. 1,n-enynes and 1,n-dienes) play a crucial role in realizing radical cyclization because of the ability to selectively introduce one or more radical sources. In this review, we discuss representative examples of methods involving the radical cyclization of 1,n-enynes and 1,n-dienes published in the last five years and discuss each prominent reaction design and mechanism, providing favorable tools for the synthesis of valuable 2-pyrrolidone for a variety of applications. 相似文献
17.
DanMeiDAI YouChengLIU JingLI PeiWANG XuDongCHEN ThomasC.W.MAK 《中国化学快报》2004,15(3):353-356
1,1-Di-p-methoxyphenyl-2, 2-dinitroethylene reacts with 1-benzyl-1, 4-dihydronicotinamide (BNAH) in deaerated acetonitrile to give 1,1-di-p-methoxyphenyl-2, 2-dinitroethane,while 1,1-di-O-methoxyphenyl-2, 2-dinitroethylene fails to react with BNAH under the same conditions, which provides evidence for a concerted electron-hydrogen atom transfer mechanism. 相似文献
18.
《Analytical letters》2012,45(5):871-889
Abstract A new sensitive, selective, rapid, and reproducible method is presented for the analysis of trace amounts of molybdenum (VI) (Mo(VI)). The method is based on the reaction of molybdenum (VI) with a new analytical reagent, 6‐(5‐Chloro‐2‐hydroxy‐4‐sulfophenylazo)‐5‐hydroxy‐1‐naphthalenesulfonic acid, disodium salt. Under optimum reaction conditions, molybdenum (VI) forms a red complex with a maximum absorption peak at 589 nm. The color reaction is rapidly completed at room temperature. The apparent molar absorption coefficient and Sandell sensitivity were 1.13×104 L · mol?1 · cm?1 and 0.0084 µg · cm?2, respectively. Beer's law was obeyed up to 8.5 µg · mL?1. Methods for the determination of Mo(VI) by first‐derivative spectrophtometry have also been proposed at 547 and 625 nm. The proposed methods offer the advantages of sensitivity, rapidity, selectivity, and simplicity without any prior separation or extraction. The methods have been applied to the determination of Mo(VI) in various environmental samples and some alloys; satisfactory results have been obtained. 相似文献
19.
Petra R. Varga Alexandra Belovics Pter Bagi Szilrd Tth Gergely Szakcs Szilvia Bsze Rita Szab Lszl Drahos Gyrgy Keglevich 《Molecules (Basel, Switzerland)》2022,27(7)
An efficient method applying acyl chlorides as reagents was developed for the acylation of the hindered hydroxy group of dialkyl α-hydroxy-benzylphosphonates. The procedure did not require any catalyst. A few acylations were also performed with the SC-enantiomer of dimethyl α-hydroxy-benzylphosphonate, and the optical purity was retained. A part of the acyloxyphosphonates was tested against eight tumor cell lines of different tissue origin at c = 50 μM concentration. The compounds elicited moderate cytostatic effect against breast, skin, prostate, colon, and lung carcinomas; a melanoma cell line; and against Kaposi’s sarcoma cell lines. Then, dose-dependent cytotoxicity was assayed, and benzoylation of the α-hydroxy group was identified as a moiety that increases anticancer cytotoxicity across all cell lines. Surprisingly, a few analogues were more toxic to multidrug resistant cancer cell lines, thus evading P-glycoprotein mediated drug extrusion. 相似文献
20.
《Analytical letters》2012,45(16):1343-1354
Abstract Electrochemical monitoring of 1, 4-dihydroxy-5, 8-bis-[2-(2-hydroxyethy1) aminoethy amino]-9, 10-anthracenedione was employed for the quantitation of this cancer chemotherapy drug following high performance liquid chromatography. Detection was performed by oxidation of the compound at a glassy carbon electrode at +0.80 V vs. SCE. A rapid and convenient sample treatment procedure was developed which is suitable for determination involving physiological samples. A detection limit of 2 ng injected was obtained for urine samples. 相似文献