JOURNAL OF MOLECULAR STRUCTURE
·
2024
·
IF 4
Lei Chen,Yang Song,Lian Deng,Jianpeng Liu,Jiabao Liu,Daobing Jiang,Xiaoshuang Dai,Ke Mei,Junda Liu,Neng Qiu
Podophyllotoxin (PPT) has excellent antitumor activity. However, poor water solubility and severe adverse effects hinder its extensive clinical applications. To effectively utilize PPT to fight against cancer, PPT was conjugated with adamantanamine (Ad) via glutathione (GSH) response disulfide bond and the resulting PPT-SS-AD was incorporated in β-cyclodextrin (β-CD) and hydroxypropyl-β-cyclodextrin (HP-β-CD) to generate high-affinity PPT-SS-AD/β-CD and PPT-SS-AD/HP-β-CD inclusion complexes. By conjugating with AD, the stability constants ( K s ) of PPT-SS-AD/β-CDs were notably higher than that of PPT/β-CDs. In addition, the water solubility of PPT-SS-AD/β-CD and PPT-SS-AD/HP-β-CD increased 5.1-fold and 8.71-fold compared to free PPT, respectively. Both PPT-SS-AD/β-CD and PPT-SS-AD/HP-β-CD inclusion complexes exhibited accelerated release in the presence of DTT and at acidic condition. The inclusion complex with hydrophilic CD and hydrophobic PPT could self-assemble into nanosized particles with spherical shape. Cell uptake studies showed that uptake of PPT-SS-AD/β-CD NPs was 2.12-fold greater than that of PPT. Moreover, the in vitro studies showed that the cytotoxic effects of PPT-SS-AD/β-CD and PPT-SS-AD/HP-β-CD inclusion complexes were also enhanced compared to free PPT and the most significant cell growth inhibition was observed in Hela cells. Our study demonstrates the potential of utilizing adamantanamine modification to enhance the complexation of anticancer drugs with cyclodextrins and subsequently boosting the anticancer efficacy.
研究领域:
药学
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肿瘤学
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产品关联
DOI
高影响因子
BMC MICROBIOLOGY
·
2026
·
IF 5.4
Ru Yi,Yu Ying,Liu Chuanxin,Liu Yunge,Liu Dongxia,Chen Ruyan,Chen Xiaowan,Bai Xiaoyang,Jiang Tao,Duan Jiajia
Podophyllotoxin (PPT) is a naturally occurring plant-derived insecticide, yet its potent cytotoxicity raises concerns regarding potential neurobehavioral toxicity in non-target organisms. However, the underlying mechanisms remain largely unclear. This study aims to investigate the neurotoxic effects of PPT in zebrafish. Three-day post-fertilization wild-type AB strain zebrafish were exposed to six concentration gradients of PPT (0.997–31.2 µg/mL). Based on the determined LC10 and MNLC values, four concentrations including 0.140, 0.420, 1.26, and 1.57 µg/mL were selected for intestinal-brain toxicity assessments and color preference tests were conducted. Histopathological damage in brain and intestinal tissues were evaluated through hematoxylin-eosin and acridine orange staining techniques. Subsequently, based on the maximum non-lethal concentration of 1.26 µg/mL, the mechanisms were further investigated using 16S rRNA sequencing, HM700 targeted metabolomics, and bulk RNA-seq, with key genes being validated via quantitative PCR. Correlation analysis was employed to elucidate the relationships among gut microbiota, differential metabolites, and gene expression. Our results showed that zebrafish exposed to various concentrations of PPT for 2 days exhibited significant intestinal and neurotoxic effects, including alterations in color preference behavior and structural damage in both the brain and intestinal tissues. 16S rRNA sequencing revealed reduced gut microbial diversity and increased levels of Acinetobacter and Perlucidibaca . Metabolomic profiling revealed that PPT disrupts purine metabolism, significantly reducing neuroprotective metabolites like adenosine and inosine, while increasing neurotoxic compounds such as quinolinic and oxalic acids. Transcriptomic analysis showed that genes associated with neuronal damage and inflammation were affected. qPCR confirmed that PPT exposure suppresses genes crucial for synaptic function (gad1b, drd2b) and upregulates genes related to the complement pathway (c3a.1, c1qc) and pro-inflammatory cytokines (IL-6, IL-1β, TNF-α). Correlation analysis linked changes in gut bacteria, Acinetobacter and Perlucidibaca , to altered purine metabolism and genes involved in synaptic and inflammatory pathways. These findings suggest that PPT-induced neurotoxicity is associated with alterations in gut microbial composition, dysregulation of purine metabolism, and changes in neuroinflammatory and synaptic-related pathways. This study highlights the potential association between microbiota-gut-brain axis disturbances and PPT-induced neurotoxicity and provides new insights for evaluating its environmental health risks. Graphical The alternative text for this image may have been generated using AI.
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DOI
PubMed
高影响因子
ANALYTICA CHIMICA ACTA
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2011
·
IF 4.311
Ya Yuan,Yuzhi Wang,Meidong Huang,Ran Xu,Huan Zeng,Chan Nie,Jinhuan Kong
In the present work, microwave heating initiated precipitation polymerization was developed to prepare podophyllotoxin (PPT) molecularly imprinted polymers (MIPs), resulting in much shorter polymerization time and better particle morphology. Prior to the polymerization, ultraviolet and FTIR spectroscopy were used to study the interactions between PPT and the functional monomers . The synthesized parameters were respectively optimized and the optimal conditions for the efficient adsorption property were template: PPT, 1 mmol; functional monomer: acrylamide , 6 mmol; bi-crosslinker: ethylene glycol dimethacrylate , 20 mmol and divinylbenzene, 20 mmol; porogen : acetonitrile , 40 mL; initiator: azobisisobutyronitrile, 0.01 mol L −1 ; polymerization temperature: 60 °C. FTIR spectroscopy, SEM and thermal analysis were used to characterize the MIPs. The results of the equilibrium rebinding experiments and the competitive adsorption experiments showed that these imprinted polymers exhibited good adsorption ability for the PPT. Scatchard analysis illustrated that two and one types of binding sites were generated in the MIPs and non-imprinted polymers (NIPs), respectively. Using the prepared MIPs as the solid phase extraction (SPE) sorbent , PPT was extracted selectively and efficiently from Dysosma versipellis , Sinopodophyllum hexandrum and Diphylleia sinensis . The regression equation was y = 5.873 × 10 6 x + 17075.659 with the correlation coefficient of 0.9994 in the concentration range of 0.005–0.4 mg mL −1 . After washing and eluting the SPE column with methanol and MeOH/acetic acid solution (v/v, 9:1), the limits of detection were 0.12–0.18 μg mL −1 and their recoveries were in the range of 89.5–91.1% with all RSDs lower than 3.7.
研究领域:
药学
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分析化学
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DOI
高影响因子
JOURNAL OF LIPOSOME RESEARCH
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2019
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IF 2.507
Zeyu Wu,Tingting Wang,Yonghong Song,Yang Lu,Tianyun Chen,Pengpeng Chen,Ailing Hui,Yan Chen,Haixiang Wang,Wencheng Zhang
The purpose of this study was to optimize the preparation conditions of podophyllotoxin liposomes (PPT-Lips), and to investigate their effects on PC3 cells. PPT-Lips were prepared by using a thin-film dispersion method. In order to achieve maximum drug encapsulation efficiency (EE), the process and formulation variables were optimized by response surface methodology (RSM). The optimum preparation conditions were cholesterol to lecithin ratio of 3.6:40 (w/w), lipid to drug ratio of 15.8:1 (w/w), and the ultrasonic intensity of 35% (total power of 400 W). The experimental EE of PPT-Lips was 90.425%, which was consistent with the theoretically predicted value. The characterization studies showed that PPT-Lips were well-dispersible spherical particles with an average size of 106 nm and a zeta potential of –10.1 mV. A gradual and time-dependent pattern of PPT from liposomes was found in in vitro drug release with a cumulative release amount up to 70.3% in 24 h. Results of cell viability experiments on PC3 cells demonstrated that PPT-Lips exhibited more effective anticancer activity in comparison with free PPT. Therefore, PPT-Lips represent an efficient and promising drug delivery system for PPT.
研究领域:
药剂学
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肿瘤学
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药物递送
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF CHROMATOGRAPHY A
·
2023
·
IF 4.1
Lidong Cheng,Zhiqing Mo,Qiongzhi Zhang,Man Yang,Xianglin Liao,Liyu Qiu,Shizhong Wang,Xixiang Yang,Xiaogang Hu
A novel hydroxylpropyl cellulose (HPC) modified graphene oxide (GO)-based molecularly imprinted polymers (HPC-GO-MIP) have been developed as a solid phase extraction (SPE) material for the selective separation and extraction of podophyllotoxin. In this strategy, the cellulose with rich hydroxyl groups was introduced to form bi-functional monomers with methacrylic acid to provide more recognition sites for the improving of extraction efficiency, then GO was added as a two-dimensional substrate for MIP to improve the material morphology and surface area. The extraction performances of obtained HPC-GO-MIP material were tested, and the results prove its high efficiency and selectivity for podophyllotoxin extraction. The saturated adsorption capacity reached 23.1 μg/mg, and high enrichment efiiciency of 463.8 folds was realized under the premise of ensuring the recovery rate. The selective imprinting factor was much higher than those of kaempferol and quercetin, which were the main compounds in podophyllum fruit. Under the optimized SPE conditions, the HPC-GO-MIP based SPE-HPLC method showed the detection limit of 14.2 ng/mL for podophyllotoxin assay. When applied to podophyllum fruit samples, the material showed excellent ability of selective separation and enrichment of podophyllotoxin, and the relative standard deviations (RSD) of intra and inter batches were less than 8.1 % and 5.7 % in real samples detection. The HPC-GO-MIP SPE method broadened the application for high multiple extraction in trace analyte samples and provided a valuable solution to improve the selective separation and detection.
研究领域:
分析化学
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材料科学
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药学
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产品关联
DOI
PubMed
高影响因子
TOXICOLOGY
·
2025
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IF 4.6
Yanli Lu,Yunge Liu,Xiaoyang Bai,Tao Jiang,Xiaowan Chen,Yanqiu Wang,Peipei Du,Yuhan Sun,Chuanxin Liu,Jiajia Duan
Podophyllotoxin (PPT), a lignan extracted from the roots and stems of Podophyllum species, exhibits significant enterotoxicity that limits its clinical application. However, its underlying mechanisms remain unclear. This study aimed to elucidate the mechanisms underlying PPT-induced enterotoxicity. Changes in body weight, fecal morphology, toxic phenotypes, and histopathological features were evaluated. 3D reconstruction, 16S rRNA sequencing, targeted short-chain fatty acids (SCFAs) analysis, and inflammatory cytokine assays were performed. The findings demonstrated that PPT induced pathological changes in rats, including weight loss, diarrhea, and colonic damage. PPT administration significantly reduced beneficial bacteria such as Lactobacillus , while increasing harmful bacteria such as Escherichia-Shigella . The predicted pathways of bacterial invasion of epithelial cells and lipopolysaccharide biosynthesis were significantly upregulated. Levels of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), were also increased. Additionally, the expression of undecaprenyl-diphosphate synthase (UPPS) and SCFAs production was reduced. These findings indicate that PPT may alter gut microbial composition, increase Escherichia-Shigella invasion in the intestinal epithelial cells, promote lipopolysaccharide production, enhance the release of pro-inflammatory cytokines, including TNF-α and IL-6, and inhibit UPPS expression and SCFAs generation, collectively contributing to enterotoxicity. This study provides novel insights into the mechanisms behind PPT-induced enterotoxicity, which is essential for preventing and treating PPT toxicity.
研究领域:
药理学
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毒理学
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微生物学
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免疫学
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生物信息学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Acta Biomaterialia
·
2018
·
IF 6.383
Huicong Zhou,Shixian Lv,Dawei Zhang,Mingxiao Deng,Xuefei Zhang,Zhaohui Tang,Xuesi Chen
Podophyllotoxin (PPT) is a chemotherapeutic agent which has shown significant activity against P-glycoprotein (P-gp) mediated multi drug resistant cancer cells. However, because of the poor aqueous solubility and high toxicity, PPT cannot be used in clinical cancer therapy. In order to enhance the efficiency and reduce side effect of PPT, a polypeptide based PPT conjugate PLG- g -mPEG-PPT was developed and used for the treatment of multi drug resistant breast cancer. The PLG- g -mPEG-PPT was prepared by conjugating PPT to poly( l -glutamic acid)- g -methoxy poly(ethylene glycol) (PLG- g -mPEG) via ester bonds. The PPT conjugates self-assembled into nanoparticles with average sizes about 100 nm in aqueous solution. Western blotting assay showed that the PLG- g -mPEG-PPT could effectively inhibit the expression of P-gp in the multiple drug resistant MCF-7/ADR cells. In vitro cytotoxicity assay indicated that the resistance index (RI) values of PLG- g -mPEG-PPT on different drug-resistant cancer cell lines exhibited 57–270 folds reduction than of traditional microtubule inhibitor chemotherapeutic drug PTX or DTX. Hemolysis assay demonstrated that the conjugation greatly decreased the hemolytic activity of free PPT. Maximum tolerated dose (MTD) of PLG- g -mPEG-PPT increased greatly (13.3 folds) as compared to that of free PPT. In vivo study showed that the PLG- g -mPEG-PPT conjugate remarkably enhanced the antitumor efficacy against MCF-7/ADR xenograft tumors with a tumor suppression rate (TSR) of 82.5%, displayed significantly improved anticancer efficacy as compared to free PPT (TSR = 37.1%) with minimal toxicity when both of the two formulations were used in MTD. Statement of Significance The development of multiple drug resistance (MDR) of cancer cells is the main cause of chemotherapy failure. The over-expression of P-glycoprotein (P-gp) has been recognized to be the most important cause of MDR in cancer. Podophyllotoxin (PPT) is a chemotherapeutic agent which has shown strong activity against P-gp mediated multidrug resistant cancer cells by simultaneously inhibiting the over-expression of P-gp and the growth of cancer cells. However, PPT can not be used in clinical cancer treatment due to its poor aqueous solubility and high toxicity. Herein, we developed a polypeptide based PPT conjugate PLG- g -mPEG-PPT by conjugating PPT to poly( l -glutamic acid)- g -methoxy poly(ethylene glycol). The PLG- g -mPEG-PPT shows significantly decreased hemolytic activity, greatly improved maximum tolerated dose and remarkably enhanced antitumor efficacy against MCF-7/ADR xenograft tumors as compared to free PPT.
研究领域:
药学
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肿瘤学
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药物递送系统
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癌症治疗
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DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2025
·
IF 13.2
Chaozheng Zhang,Yao Chen,Yi Zuo,Maolin Wang,Hongyu Chen,Chuanqi Wang,Yuening Cao,Yingjie Zeng,Ying Chen,Tingting Zhang,Xian Ge,Xiujun Cao,Yilan Liu,Hongbin Cheng,Yun Deng,Jun Lu
Ligand-receptor recognition-based nanodrug delivery systems incorporate stimulus-responsive functionality to proactively transport chemotherapeutics to lesional tissues and intelligently release drugs in response to stimulation, thereby augmenting drug accumulation at target sites, boosting drug bioavailability, and avoiding systemic toxicity, which reveals a promising potential in malignant tumor therapy. Herein, we designed and prepared a dual-targeted nanomedicine, FA-HA-SS-PPT, utilizing microwave-assisted quantitative conjugating of podophyllotoxin (PPT) to folic acid (FA) and hyaluronic acid (HA) carriers via short-chain PEG bearing the tumor microenvironment-sensitive disulfide bond. The FA-HA-SS-PPT nanoparticles developed by self-assembly exploited the peculiarity of specifically binding to the folate receptor (FR) and CD44 receptor, initiated targeting to translocate the drug into the tumor cells and released the PPT by self-cyclization in high intracellular GSH concentration. Furthermore, this nanomedicine demonstrated superior tumor cytotoxicity and proliferation inhibition in vitro by triggering the mitochondrial apoptotic pathway and suppressing the microtubule protein formation. Notably, quantitative disulfide bond conjugation and nanomedicine formation endowed FA-HA-SS-PPT nanoparticles with astonishing in vivo circulatory stability and tumor microenvironmental responsiveness, further reinforcing drug security and anti-tumor capability. Therefore, quantitatively conjugating drugs provide a promising safe and efficient means to treat multi-receptor overexpressing tumors with multi-targeted nanomedicines.
研究领域:
药剂学
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肿瘤学
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生物化学
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DOI
高影响因子
JOURNAL OF ELECTROANALYTICAL CHEMISTRY
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2020
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IF 3.807
Yansheng Li,Si Zhang,Na Li,Jin Wang,Chaofan Jin,Liyan Zheng,Qiue Cao
To obtain an electrochemical sensor with high sensitivity and good selectivity for determination of podophyllotoxin (PPT), a kind of graphene composite (rGO@TiO 2 ) with multi-layer structure and excellent conductivity was prepared by hydrothermal treatment of reduced graphene oxide (rGO) and TiO 2 nanoparticles . The composite was characterized by transmission electron microscope (TEM), scanning electron microscope (SEM), X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS), and a sensor using rGO@TiO 2 as a signal amplification element was fabricated by in-situ polymerization of PPT imprinted membrane (PPT-MIM) on the rGO@TiO 2 modified glassy carbon electrode (PPT-MIM/rGO@TiO 2 /GCE). The structure and electrochemical performance of PPT-MIM/rGO@TiO 2 /GCE as well as the mechanism with superior conductivity of rGO@TiO 2 exceeding the ones of the mixture of TiO 2 and rGO (TiO 2 -rGO) or the pure TiO 2 and rGO were explained with different technologies. Under the optimal conditions, the present sensor showed a linear response for the determination of PPT by differential pulse voltammetry (DPV) in the range of 1.0 × 10 −9 − 1.0 × 10 −7 mol L −1 (R 2 = 0.9980) and 1.0 × 10 −7 − 3.0 × 10 −4 mol L −1 (R 2 = 0.9991) with the limit of quantification is 1.0 × 10 −9 mol L −1 and the limit of detection of 3.0 × 10 −10 mol L −1 . The sensor not only possesses high sensitivity and good selectivity, but also exhibits excellent repeatability and stability. It has been used to detect PPT in real samples (including Podophyllum hexandrum , human urine and human whole blood) with satisfied recoveries of 92.0%–102.3%.
研究领域:
分析化学
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药物分析
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纳米材料科学
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产品关联
DOI
高影响因子
Chemical Biology & Drug Design
·
2022
·Vol. 99
·期 6
·828-838
·
IF 2.873
Yan Zhao,Danyao Li,Yun Han,Haohao Wang,Rui Du,Zhaowei Yan
Infantile hemangioma (IH) is a common benign endothelial cell tumor in infants and young children, sometimes accompanied by potential complications, and may develop into malignant tumors. Hemangioma endothelial cells (HemECs) are one of the main components of IH. Podophyllotoxin (PPT) has been reported to have many pharmacological activities, especially anti-tumor, but its high toxicity, poor water solubility, and serious gastrointestinal side effects limit its clinical application. In this study, we have designed and synthesized 20 ester derivatives by introducing Boc-amino acids or organic acids at the C-4 position of podophyllotoxin through esterification reactions. The cytotoxicity of these compounds was evaluated on HemECs. Changes in cell proliferation and apoptotic signaling pathways were studied by DAPI staining, colony formation assay, migration assay, measurement of reactive oxygen species (ROS) levels flow cytometry, and Western blot analysis. We found that eight of the compounds were more potent than PPT. Of these, compound V-31 was the most active (IC 50 = 0.079 ± 0.0049 µM). Further research indicated that compound V-31 inhibited its proliferation and migration, increased the level of ROS in cells, and induced apoptosis by downregulating p-PI3K, p-Akt, and Bcl-2, and upregulating cleaved caspase-3 and Bax. Our research provides the first insight into the application of PPT derivatives in HemECs, may provide an effective medicine for IH treatment.
研究领域:
药理学
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肿瘤学
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细胞生物学
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药物设计
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产品关联
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2024
·
IF 6.2
Chuanxin Liu,Xiaobin Huang,Jiao Kong,Xuejiao Li,Yuming Wang,Fangfang Zhang,Jiajia Duan
Background Podophyllotoxin (PPT), a highly active compound extracted from the rhizome of Dysosma versipellis (DV), has been used as an effective anti-cancer drug clinically since the 1950s. It possesses various biological activities, including antiviral and antitumor effects. However, its clinical application is severely limited due to its hepatotoxicity, and the underlying mechanisms remain unclear. This study aims to elucidate the mechanisms of PPT-induced hepatotoxicity using tandem quality tag (TMT) based quantitative proteomics and phosphoproteomics, providing potential targets and directions for developing new therapeutic strategies to facilitate the safe and rational use of podophyllotoxin in clinical settings. Methods We employed a comprehensive assessment of PPT-induced hepatotoxicity based on the Toxicology Evidence Chain (TEC) concept, originally proposed by our research group in 2018. This approach involves a tiered search for evidence of Harmful Ingredients Evidence (HIE), Injury Phenotype Evidence (IPE), Adverse Outcomes Evidence (AOE), and Toxic Events Evidence (TEE) during the development of PPT-induced hepatotoxicity, thereby constructing a guiding toxicology evidence chain. Sprague-Dawley (SD) rats were administered 20 mg/kg PPT for 4 consecutive days (HIE). Indicators such as hepatic function, oxidative stress, inflammatory factors, as well as the histopathology of liver tissue were evaluated to assess liver damage and synthetic function (AOE). Proteomics and phosphoproteomics were conducted to systematically assess PPT-induced hepatotoxicity at the level of modified proteins and verify the molecular mechanisms of key molecular pathways (TEE1). Furthermore, in vitro THLE-2 cell models were used in conjunction with CCK8, immunofluorescence, and ELISA assays to validate cytotoxicity and its underlying mechanisms (TEE2). Results Our results showed that after 4 days of PPT administration at 20 mg/kg (HIE), serum levels of AST/ALT, TBA, TP, and ALB in SD rats were significantly increased ( P < 0.05), indicating severe liver damage. SOD and T-AOC levels were significantly decreased ( P < 0.05), suggesting an oxidative stress state. TNF-α levels were significantly elevated, while IL-10 and IL-3 levels were significantly reduced ( P < 0.05), indicating strong activation of the inflammatory response in the liver. Histopathological examination revealed liver sinusoidal congestion in the liver tissue (AOE). Omics analysis revealed that hepatotoxicity primarily affected the complement-pyroptosis and cGMP-PKG-autophagy pathways. Western blot (WB) and RT-qPCR results showed significant upregulation of complement-pyroptosis pathway proteins (C5a, C5aR, NLRP3) and cGMP-PKG-autophagy pathway proteins (PKG, mTOR) in the PPT group ( P < 0.05) (TEE1). In vitro cell experiments showed that PPT significantly reduced cell viability ( P < 0.05) and increased the expression of proteins associated with pyroptosis and autophagy pathways, including ROS, NLRP3, PKG, and mTOR ( P < 0.05) (TEE2). Conclusion PPT activates the complement system through the C5a/C5aR/ROS/NLRP3 pathway and induces the formation of inflammasomes, promoting pyroptosis. Simultaneously, PPT activates the cGMP-PKG pathway, inhibiting autophagy and further accelerating pyroptosis, ultimately leading to hepatotoxicity. In conclusion, this study comprehensively revealed the underlying mechanisms of PPT-induced hepatotoxicity using the TEC concept. This approach transforms fragmented toxicity indicators into systematic evidence of toxicity, presenting a hierarchical progression of toxicity evidence and avoiding data accumulation in natural drug toxicology. Our findings represent a significant breakthrough in the elucidation of the mechanisms of hepatotoxicity induced by podophyllotoxin.
研究领域:
药理学
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毒理学
·
分子生物学
·
蛋白质组学
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DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
·
2019
·
IF 4.833
Wei Zhao,Long He,Tian-Le Xiang,Ya-Jie Tang
The colchicine binding site of tubulin is an attractive molecular target domain for cancer therapies. However, there was no FDA approved drug for targeting colchicine domain. Our previous crystallography discovered that a potential binding site of αT5 loop-αH7 nearby colchicine domain was beneficial for introducing affinity fragment. In this work, benzo heterocycles (i.e., indole , indazole and quinoline) with the high affinity ability of αT5 loop-αH7 were chosen as affinity fragment to modify the molecule structure of podophyllotoxin for improving the tubulin binding affinity . 4β- NH -(benzo heterocycles)-4-desoxy-podophyllotoxin were synchronously located at α/β interface of tubulin through providing affinity fragment to αT5 loop-αH7 (i.e., α178Ser, α182Val, α241Phe) and colchicine domain (i.e., β241Cys, β124ASP). 4β- NH -(6″-aminoindole)-4-desoxy-podophyllotoxin not only exhibited nanomolar antitumor potency in vitro but also destroyed solid tumor growth without lethal toxicity in vivo . The correctness of rational drug design was strictly demonstrated by bioactivity test.
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DOI
PubMed
高影响因子
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