JOURNAL OF MEDICINAL CHEMISTRY
·
2025
·
IF 6.8
Tianyu Zhu,Jipeng Ding,Fan Zheng,Yanpeng Fang,Wenzhi Huang,Ying Yin,Wenbin Zeng
Nitrogen mustard, a widely used chemotherapeutic agent for more than 70 years, exhibits significant efficacy. However, its clinical applications are severely limited by poor tumor selectivity and severe side effects on normal tissues. To address these limitations, we developed a near-infrared (NIR)-activatable nitrogen mustard prodrug, MBNM. Upon NIR irradiation, the controlled cleavage of the urea bond within MBNM facilitates the simultaneous release of nitrogen mustard and methylene blue (MB), enabling a synergistic approach combining chemotherapy and photodynamic therapy (PDT) for effective tumor suppression. Moreover, the release of MB upon activation enables real-time monitoring of prodrug activation. Notably, MBNM demonstrated significantly improved biosafety compared to free nitrogen mustard. These findings suggest that the photocleavable prodrug MBNM offers a promising strategy for safe and effective combination cancer therapy.
研究领域:
肿瘤学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Omega
·
2024
·
IF 3.7
Jin Long Zhang,Xiao Wei Zhang,Bing Yuan,Heng Zhang,Xing Zhi Wang,Hao Wang,Hong Wei Zhao
Advances in chemotherapeutic strategies are urgently required to improve antitumor efficiency. Herein, a carboxylated pillar[6]arene (CP6A) was employed to load chemotherapy medication, nitrogen mustard (NM), via forming a direct host–guest complex, as this helps to decrease the cytotoxicity of NM on normal mammary epithelial cells. Attributed to the stronger complexation ability of CP6A for endogenous spermine (SPM) than for NM, the complexed NM could be competitively released from the CP6A cavity via replacement with SPM. This chemotherapy strategy performed well in vitro and in vivo for SPM-overexpressed cancers. In comparison with free NM, antitumor efficiency of NM/CP6A was significantly enhanced, which originated from the synergistic effect of competitive release of NM and simultaneous trapping of SPM. This strategy might guide expansion to other first-line antitumor agents to improve therapeutic efficacy and decrease side effects, thereby replenishing the possibilities of supramolecular chemotherapy.
研究领域:
药学
·
肿瘤学
·
超分子化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF THE CHINESE CHEMICAL SOCIETY
·
2019
·Vol. 67
·期 4
·646-651
·
IF 1.188
Chun-Mei Liu,Xiao-Yan Tian,Chun-Hua Su,Jia-Yan Huang,Xiang-Wu Chu,Sheng-Ping Deng,Ke-Guang Cheng
To discover novel nitrogen mustards, the reported mustard pharmacophore was combined with natural pentacyclic triterpenes, which are characterized with pharmacological and structural diversity. Thus, six conjugates were synthesized with 1,2,3-triazole linking N , N -bis (2-chloroethyl)-1,4-phenylenediamine and oleanolic acid, ursolic acid, or glycyrrhetinic acid, and their biological activity was evaluated against tumor cell lines HeLa, BGC-823, BEL-7404, and NCI-H460 using the MTT assay. As a result, these conjugates showed some selective cytotoxicity to NCI-H460, though all their activity potency was moderate or weak in the four cell lines.
研究领域:
药物化学
·
肿瘤学
·
有机合成
✓ 已验证
DOI
高影响因子
ANALYTICAL CHEMISTRY
·
2022
·
IF 8.008
Xiangui Ma,Mengmeng Lv,Fangxin Du,Cunqi Wu,Baohua Lou,Abdallah M. Zeid,Guobao Xu
Some mustard compounds (mustards) are highly toxic chemical warfare agents. Some are explored as new anticancer drugs. Therefore, the fast, selective, and sensitive detection of mustards is extremely important for public security and cancer therapy. Mustards mostly target the N7 position on the guanine bases of DNA. The guanine-rich G-quadruplex DNA (G4) has been widely studied in the sensing area, and it was found that dimeric G4 (D-G4) could dramatically light up the fluorescence intensity of thioflavin T (ThT). Based on this, we used for the first time the D-G4 DNA as a selective probe for ultrasensitive fluorescence detection of nitrogen mustard (NM). When NM occupies the N7 on guanine, it can block the formation of the D-G4 structure due to the steric hindrance, and hence, it inhibits the combination of D-G4 with ThT, leading to a sharp decrease of fluorescence intensity. The proposed reaction mechanism is proved using ultraviolet–visible (UV–Vis) spectra, circular dichroism (CD) spectra, and polyacrylamide gel electrophoresis. Herein, the concentration of D-G4/ThT used is as low as 50 nM due to its highly fluorescent performance, enabling both high sensitivity and low cost. NM can be detected with a wide linear range from 10 to 2000 nM. The detection limit of NM reaches a surprisingly low concentration of 6 nM, which is 2 or 3 orders of magnitude lower than that of previously developed fluorescence methods for mustards and simulants.
研究领域:
生物化学
·
医学检测
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
MEDICINAL CHEMISTRY RESEARCH
·
2021
·Vol. 30
·期 10
·1856-1867
·
IF 1.965
Yin Yu-dong,Liu Jing-jing,Liao Wen-fei,Guo Xian-kun,Zhang Li-shan,Mo Wei-bin,Cheng Ke-guang
As 17 β -estradiol and its derivatives have good affinity with estrogen receptors and have unique antitumor properties, O 1 -propargyl- N 4 , N 4 -bis(2-chloroethyl)-4-aminophenol and N 4 , N 4 -dipropargyl- N 1 , N 1 -bis(2-chloroethyl)-1,4-phenylenediamine were respectively combined with 17 β -estradiol through linkers of different lengths. These targeted novel nitrogen mustard 17 β -estradiol derivatives were tested antiproliferative activity using the MTT assay. The results illustrated that these compounds were less toxicity to HL-7702 (human liver cells) and SKOV-3, though all their activity potency was moderate or weak aganist the MDA-MB-231, MCF-7 and BEL-7404 cell lines. The inhibitory activity of the O 1 -propargyl- N 4 , N 4 -bis (2-chloroethyl)-4-aminophenol derivatives (compounds III-1~6 and VII-1~4 ) were obviously better than the N 4 -dipropargyl- N 1 , N 1 -bis (2-chloroethyl) -1,4-phenylenediamine derivatives (compounds IV-1~6 and VIII-1~4 ) against tested tumor cell lines. And three hybrids (compounds III-2 , III-6 , and VII-3 ) exhibited good inhibitory activity against BEL-7404 cell line (IC 50 = 13.5, 15.3 and 13.9 μM, respectively). After that, we performed KEGG pathway analysis on compound III-6 , and the results showed that III-6 mainly induced breast cancer cell apoptosis by regulating the expression of the proteins in NF-κ B pathway.
研究领域:
药理学
·
肿瘤学
·
分子生物学
✓ 已验证
DOI
高影响因子
RESEARCH ON CHEMICAL INTERMEDIATES
·
2012
·Vol. 39
·期 5
·1949-1956
·
IF 0.697
Li Shan,Li He-ping,Qin Long
To improve the specificity of nitrogen mustards towards tumor cells, glucose-nitrogen mustard, fructose-nitrogen mustard, and lactose-nitrogen mustard were prepared as three novel glycosylated nitrogen mustard derivatives by esterification of bis(2-chloroethyl)carbamic chloride (BCC) with glucose, fructose, and lactose, respectively. BCC was synthesized from bis(2-chloroethyl)amine hydrochloride and triphosgene. The topic products were characterized by infrared (IR) and mass spectrometry (MS), and their interaction with bovine serum albumin was investigated by measuring fluorescence spectra in tris(hydroxymethyl)aminomethane hydrochloride (Tris–HCl) buffer solution at physiological conditions.
研究领域:
药理学
·
生物化学
✓ 已验证
产品关联
DOI
高影响因子
CHEMISTRY OF NATURAL COMPOUNDS
·
2018
·Vol. 54
·期 1
·106-111
·
IF 0.45
Huang Jia-yan,Yang Lin-dong,Su Chun-hua,Chu Xiang-wu,Zhang Jiang-yu,Deng Sheng-ping,Cheng Ke-guang
Using a reported pharmacophore, 4-[N,N-bis(2-chloroethyl)-amino]phenol, and pentacyclic triterpenes, pharmacologically and structurally diverse components of natural products, six pentacyclic triterpene-4-[N,N-bis(2-chloroethyl)-amino]phenol conjugates were synthesized by click chemistry. Their cytotoxicities against the BEL-7404 and NCI-H460 tumor cell lines were evaluated by the MTT assay. The in vitro results from the cytotoxicity assay indicated that at a compound concentration of 20 μM, these conjugates showed low toxicity (< 16%) toward the tested tumor cells in culture.
研究领域:
药理学
·
肿瘤学
·
有机化学
✓ 已验证
DOI
高影响因子
ACS Applied Materials & Interfaces
·
2019
·
IF 8.456
Tingting Luan,Lulu Cheng,Ju Cheng,Xiaoyun Zhang,Yufei Cao,Xiangdong Zhang,Haiyan Cui,Guanghui Zhao
The reactive oxygen species (ROS)-responsive intelligent drug delivery system has developed rapidly in recent years. However, because of the low concentration of ROS in most types of tumor cells, it is not possible to rapidly and effectively stimulate the drug delivery system to release the active drug. Here, we introduced “sequential induced activation processes” for efficient tumor therapy by designing a new ROS-responsive drug release platform. β-Lapachone, a positively charged nitrogen mustard (NM) prodrug, and two diblock molecules (mPEG-AcMH and PAsp-AcMH) are self-assembled to form prodrug primary micelles, which are further aggregated into nanoparticles that facilitate drug codelivery. When administered by intravenous injection, the nanoparticles reach the tumor site and enter the tumor cells by endocytosis. The β-lapachone released in the tumor cells induces a large amount of H2O2, and the ROS-responsive NM prodrug is activated to form activated NM, quinone methide, and boric acid under the induction of H2O2. The activated NM leads to tumor cell apoptosis.
研究领域:
生物医学工程
·
肿瘤学
·
药剂学
✓ 已验证
DOI
PubMed
高影响因子
MOLECULAR PHARMACEUTICS
·
2019
·
IF 4.396
Mengting Lin,Wangwei Guo,Zhentao Zhang,Yi Zhou,Jiejian Chen,Tiantian Wang,Xincheng Zhong,Yiying Lu,Qiyao Yang,Qichun Wei,Min Han,Donghang Xu,Jianqing Gao
Nitrogen mustard (NM) is among the earliest drugs used to treat malignant tumors and it kills tumor cells by cross-linking DNA. Unfortunately, because of the short half-life and unfavorable selectivity, NM causes significant damage to normal tissues. As NM can increase the levels of reactive oxygen species (ROS) in tumor cells, a ROS-activated nitrogen mustard prodrug (NM-Pro) was synthesized and mixed with NM at a specific ratio to obtain an “NM-ROS-NM-Pro-NM” positive feedback system, which ultimately achieves a specific lethal effect on hematological neoplasms. The further encapsulation of NM/NM-Pro in liposomes allows the sustained release of the drug and prolongs the residence time in vivo. Here, we prepared stable liposomes with a uniform particle size of 170.6 ± 2.2 nm. The optimal ratio of NM to NM-Pro in this study was 2:1. The active drug NM in the NM/NM-Pro system continuously stimulated ROS production by the cells, which in turn further activated the NM-Pro to continuously generate NM. The positive feedback pathway between the NM and NM-Pro resulted in the specific death of tumor cells. Furthermore, the K562 hematological neoplasm model was utilized to evaluate the therapeutic effect of NM/NM-Pro liposomes in vivo. After encapsulation in liposomes, the targeting of tumor cells was increased approximately two times compared with that of normal cells, and NM/NM-Pro liposomes exhibited reduced toxicity, without an increase in drug activity compared to the NM/NM-Pro combination. The NM/NM-Pro delivery system exerts a positive feedback effect on ROS production in tumor cells and displays good potential for the specific killing of hematoma cells.
研究领域:
肿瘤学
·
药理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2023
·
IF 5.8
Wendi Liang,Yingzhen Fan,Yinghui Liu,Ting Fang,Jian Zhang,Yuyi Xu,Ji Li,Dongkai Wang
The high level of reactive oxygen species (ROS) at the tumor site has been widely used in the tumor targeted delivery. However, the ROS stimulus-responsive vector itself is also a ROS consumer, and the consumption of endogenous ROS may not be sufficient to maintain sustained drug release. In this study, we designed and synthesized ROS/pH dual-sensitive polymer micelles for the co-delivery of emodin (EMD) and chlorambucil (CLB). The release of quinone methides (QM) can consume GSH, on the one hand, it can enhance the chemotoxicity of phenylbutyrate nitrogen mustard, on the other hand, emodin can induce oxidative damage of tumor cells and maintain the sustained targeted release of drugs.
研究领域:
药学
·
癌症研究
·
纳米技术
·
药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
RSC Advances
·
2023
·Vol. 13
·期 39
·27535-27548
·
IF 3.9
Fang-chao Yang,Yang Yang,Long Yan,Feng-yun Wang,Lei Wu,Ming-zhu Xia,Xiao-Sen Li
Methyl-diethanolamine (CAS: 105-59-9), ethyl-diethanolamine (CAS: 139-87-7), and triethanolamine (CAS: 102-71-6) were identified as the degradation products and bio-markers of nitrogen mustard exposure. Sensitive and convenient detection methods for amino alcohol are of great importance to identify nitrogen mustard exposure in forensic analysis. Herein, analytical methods including gas chromatography-tandem mass spectrometry combined with heptafluorobutyryl derivatization and solid phase extraction were established for retrospective detection of the biomarkers in human plasma and urine samples. The efficiency of the method was improved by optimizing the conditions for sample preparation and the GC-MS/MS method. The optimization included the derivatization temperature, reaction time, reagent dosage and solid phase extraction cartridges, eluent and pH of the loading sample. The results indicated that the SCX cartridge resulted in better enrichment and purification effects, and the best recovery could be obtained with pH = 3–4 for the loading samples and an eluent of 2 mL 10% NH4OH/MeOH. The GC-MS/MS parameters were also optimized for better specificity and sensitivity. The established method was fully validated for each analyte both in plasma and urine matrixes. The linear range of analytes in plasma was 1.0–1000 ng mL−1 with a correlation parameter (R2) of ≥0.994, intra-day/inter-day accuracy of 93.7–117%, and relative standard deviation (RSD) of ≤6.5%. Meanwhile the results in urine were 1.0–1000 ng mL−1 with R2 of ≥0.996, intra-day/inter-day accuracy of 94.3–122%, and RSD of ≤6.6%. The detection limit of the analytes was 1.0 ng mL−1. The method was applied for the detection and identification of trace amino alcohols present in urine samples dispatched by the Organization for the Prohibition of Chemical Weapons (OPCW) and the results were confirmed to be correct.
研究领域:
分析化学
·
毒理学
·
法医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2022
·Vol. 9
·期 23
·2201271
·
IF 17.521
Yihang Gong,Wenjie Chen,Xiuxing Chen,Yizhan He,Hua Jiang,Xijian Zhang,Lijie Pan,Beibei Ni,Fan Yang,Yan Xu,Qi Zhang,Lei Zhou,Yusheng Cheng
Triple-negative breast cancer (TNBC) exhibits resistance to conventional treatments due to the presence of cancer stem cells (CSCs), causing postsurgical relapse and a dismal prognosis. Umbilical cord blood natural killer (UCB-NK) cell-based immunotherapy represents a promising strategy for cancer treatment. However, its therapeutic efficacy is greatly restrained by downregulation of the NK cell activation ligand MHC class I-related chain A/B (MICA/B) and autophagy-mediated degradation of NK cell-derived granzyme B (GZMB) in CSCs. Herein, it is demonstrated that suberoylanilide hydroxamic acid (SAHA) epigenetically downregulates let-7e-5p and miR-615-3p to increase MICA/B expression and that 3-methyl adenine (3MA) inhibits autophagy-mediated GZMB degradation, thereby sensitizing breast CSCs to UCB-NK cells. Then, an injectable hydrogel is designed to codeliver SAHA and 3MA to enhance UCB-NK cell infusion efficacy in TNBC. The hydrogel precursors can be smoothly injected into the tumor resection bed and form a stable gel in situ, allowing for a pH-sensitive sustained release of SAHA and 3MA. Moreover, UCB-NK cell infusion in combination with the hydrogel efficiently controls postsurgical relapse of TNBC. In addition, the hydrogel exhibits good hemostasis and wound-healing functions. Therefore, the work provides proof of concept that an injectable epigenetic autophagic modulatory hydrogel augments UCB-NK cell therapy to combat postsurgical relapse of TNBC.
研究领域:
肿瘤学
·
免疫治疗
·
药学
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）