Co-reporter:Chen Jin, Shuai Wen, Qiumeng Zhang, Qiwen Zhu, Jiahui Yu, and Wei Lu
ACS Medicinal Chemistry Letters July 13, 2017 Volume 8(Issue 7) pp:762-762
Publication Date(Web):June 27, 2017
DOI:10.1021/acsmedchemlett.7b00189
Due to the low esterase activity in human plasma, many ester and carbonate prodrugs tested in humans may be less effective than that in preclinical animals. In this letter, PTX and SN-38 were attached to the N-1 position of 2-nitroimidazole via a carbonate linker. Presumably, 2-aminoimidazole may help promote the intramolecular hydrolysis of the carbonate bond. The prodrugs exhibited a considerable stability in buffers at different pH values as well as in human plasma. Furthermore, a rapid reduction was exhibited in the presence of nitroreductase. An in vitro cytotoxicity assay demonstrated that hypoxic conditions could increase the toxicity of prodrugs. Potentially, the compound species may form a new class of promising antitumor agents.Keywords: 2-Nitroimidazole; paclitaxel; prodrug; SN-38;
Co-reporter:Chen Jin, Qiumeng Zhang, Wei Lu
European Journal of Medicinal Chemistry 2017 Volume 132(Volume 132) pp:
Publication Date(Web):26 May 2017
DOI:10.1016/j.ejmech.2017.03.040
•We proposed new hypoxia-activated prodrugs that conjugated (1-methyl-2-nitro-1H-imidazol-5-yl)methanol with SN-38.•We improved the synthesis of (1-methyl-2-nitro-1H-imidazol-5-yl)methanol, which increased the yield from 8% to 42%.•Compound IOS was evaluated to be a promising hypoxia-selective antitumor agent.We designed new hypoxia-activated prodrugs by conjugating (1-methyl-2-nitro-1H-imidazol-5-yl)methanol with 7-ethyl-10-hydroxy camptothecin (SN-38). Initially, we improved the method of multi-gram scale synthesis of (1-methyl-2-nitro-1H-imidazol-5-yl)methanol, which increased the yield to 42% compared to 8% by the original synthesis method. The improved method was used to synthesize evofosfamide (TH-302) and hypoxia-activated prodrugs of SN-38. Two different linkages between (1-methyl-2-nitro-1H-imidazol-5-yl)methanol and SN-38 were evaluated that afforded different hypoxia-selectivity and toxicity. Compound 16 (IOS), containing an ether linkage, was considered to be a promising hypoxia-selective antitumor agent.In this study, we proposed a new hypoxia-activated prodrug that conjugated (1-methyl-2-nitro-1H-imidazol-5-yl)methanol with SN-38. Compound IOS containing ether linkage was evaluated as a promising hypoxia-selective antitumor agent.Download high-res image (116KB)Download full-size image
Co-reporter:Rui Che, Qiwen Zhu, Jie Yu, Jiao Li, Jiahui Yu, Wei Lu
Tetrahedron 2017 Volume 73, Issue 43(Issue 43) pp:
Publication Date(Web):26 October 2017
DOI:10.1016/j.tet.2017.09.009
Gram-scale syntheses of two kinds of bleomycin disaccharides are described. l-gulose subunit 12 was accomplished with a novel and short route in six steps and 37% overall yield from 4, which could be easily prepared from the commercially available inexpensive material d-sorbitol, while 6-deoxy-l-gulose subunit was synthesized in 11 steps in 8% yield from d-glucolactone. The disaccharides were then prepared in a previously reported glycosidation coupling of the 3-O-carbamoyl-mannosyl donor with the l-gulopyranoside acceptors. Both disaccharides were finally obtained in gram-scale and the total synthesis of disaccharide 2 was achieved the first time.Download high-res image (158KB)Download full-size image
Co-reporter:Yanfen Fang, Wanli Zhang, Mengli Zhu, Shiguang Chen, Xuan Liu, Wei Lu, Xiongwen Zhang
Journal of Photochemistry and Photobiology B: Biology 2017 Volume 166() pp:264-271
Publication Date(Web):January 2017
DOI:10.1016/j.jphotobiol.2016.11.021
•GLUT-1 was overexpressed in hepatoma HepG2 cells and gastric cancer NCI-N87 cells.•The cellular uptake of N2 was significant higher in cancer cells than normal cells.•d-glucose or GLUT-1 inhibitor effectively inhibited the cellular uptake of N2.•The cellular uptake of N2 was in a concentration- and time-dependent manner.Cancer cells are usually characterized with an increase in glucose uptake when compared with normal cells, which is known as Warburg effect. Near-infrared (NIR) fluorescent glucose analogues have been previously synthesized and been applied in cancer cell imaging. However, most NIR dyes usually have one or more charge in their structures, which may cause low cell membrane permeability and hamper their application in cell imaging. Here we reported a novel glucose analogue N2, which was designed and synthesized based on a new type of NIR dye, DCPO. As expected, higher level of N2 uptake was observed in hepatic carcinoma cells (HepG2) and gastric cancer cells (NCI-N87) than their equivalent cells from normal tissues of the same origin, respectively. The accumulation of N2 in cancer cells was in consistent with the overexpression of glucose transporter GLUT-1 in these cells. The cellular uptake of N2 was then confirmed to be dependent on GLUT-1, which was evidenced by the decreased uptake of N2 in the presence of d-glucose or GLUT-1 inhibitor phloretin. Moreover, uptake of N2 in cancer cells was found to be in a concentration- and time-dependent manner. In all, our study demonstrated that N2, as a novel DCPO-conjugated bioprobe, could be used to monitor cellular glucose consumption, and therefore might be applied in cancer cell bioimaging and bioassay in cancer studies.
Co-reporter:Xikuang Yao;Qiwen Zhu;Cheng Li;Kangjun Yuan;Rui Che;Peng Zhang;Chenchen Yang;Wei Wu;Xiqun Jiang
Journal of Materials Chemistry B 2017 vol. 5(Issue 4) pp:834-848
Publication Date(Web):2017/01/25
DOI:10.1039/C6TB02863B
Conjugation of sugars to antitumor drugs can facilitate drug binding to tumor cells and the saccharide motifs of bleomycins (BLMs) play a crucial role in tumor-seeking. Here, we synthesized BLM monosaccharide, carbamoylmannose, and subsequently prepared carbamoylmannose decorated platinum-incorporating supramolecular nanoparticles formed through the host–guest complexation of poly(N-vinylpyrrolidone) and poly(aspartic acid). The targeting effects of carbamoylmannose decorated supramolecular nanoparticles in various cancer cells and tumor-bearing mice were investigated. It was found that the nanoparticles showed a specific in vitro and in vivo carbamoylmannose-mediated cellular uptake and drug delivery. The cellular uptake of the nanoparticles followed the receptor-mediated endocytosis mechanism in cancer cells but not in healthy cells. In a murine hepatic H22 tumor model, it was demonstrated that the carbamoylmannose moiety increased the plasma concentration, tumor targeting ability and tumor penetration of the nanoparticles, leading to high tumor accumulation and superior antitumor efficacy. This carbamoylmannose molecule may bring an opportunity to design and construct inexpensive but highly efficient drug and gene delivery systems in the future.
Co-reporter:
Chinese Journal of Chemistry 2017 Volume 35(Issue 2) pp:237-241
Publication Date(Web):2017/02/01
DOI:10.1002/cjoc.201600658
AbstractA novel, practical and concise synthesis of 1,3,4,6-tetra-O-acetyl-l-gulose is described, using d-glucuronolactone as the starting material and other inexpensive and readily available agents (22% overall yield in 9 steps). With this method, the synthesis of l-gulose and the tumor-targeting disaccharide of BLMs can be more efficient and convenient.
Co-reporter:Chen Jin;Qiumeng Zhang
RSC Advances (2011-Present) 2017 vol. 7(Issue 30) pp:18217-18223
Publication Date(Web):2017/03/24
DOI:10.1039/C7RA01466J
Hypoxia is a typical feature of solid tumors. To detect hypoxic tumor cells, we designed new selective turn-on probes by conjugating (1-methyl-2-nitro-1H-imidazol-5-yl)methanol to the near-infrared fluorescence probe DCPO through an ether linkage and bis-carbamate linkage specifically. The proposed activation mechanism was demonstrated through the nitroreductase and cytochrome P450 assays in vitro. However, two probes revealed different hypoxia selectivities when evaluated on H460, HeLa and A549 cell lines. The hypoxia selectivity of IOD was higher than that of IND. The probe IOD (containing the ether linkage) was considered to be a promising hypoxia-selective fluorescent probe.
Co-reporter:Qiumeng Zhang;Luyao Zhang;Jie Yu;Heng Li;Shijun He;Wei Tang;Jianping Zuo
RSC Advances (2011-Present) 2017 vol. 7(Issue 42) pp:26060-26069
Publication Date(Web):2017/05/15
DOI:10.1039/C7RA04261B
A series of 4,6-substituted thieno[3,2-d]pyrimidine derivatives as Bruton's tyrosine kinase (BTK) inhibitors are designed, synthesized and evaluated for their enzymatic inhibition and immunosuppressive activities. These derivatives exhibit varying inhibitory activities against BTK in vitro. Compound 8 is a novel potent BTK inhibitor which has an IC50 value of 29.9 nM, exerts excellent immunosuppressive activity by inhibiting the proliferation of B cells (IC50 = 284 nM), and shows low cytotoxicity (CC50 = 53 632 nM) on murine splenocytes. In addition, compound 8 displays considerable selectivity between T cells (IC50 > 10 μM) and B cells. Furthermore, enzymatic assays on more than twenty kinases confirm that compound 8 is more selective than the reference compound Olmutinib. In summary, the results suggest that compound 8 is a potential BTK inhibitor for further evaluation and modification of the C-4 and C-6 position of the thieno[3,2-d]pyrimidine scaffold, which could be considered a new strategy in the development of BTK inhibitors.
Co-reporter:Xuan Zhang, Kaiyong Tang, Hong Wang, Yaqian Liu, Bin Bao, Yanfen Fang, Xiongwen Zhang, and Wei Lu
Bioconjugate Chemistry 2016 Volume 27(Issue 5) pp:1267
Publication Date(Web):April 12, 2016
DOI:10.1021/acs.bioconjchem.6b00099
Traditional antitumor drugs such as camptothecin and paclitaxel derivatives are widely used in cancer chemotherapy. However, the major defects of those agents include severe toxicity and poor water solubility. With these in mind, a novel multifunctional linker was designed and two Cathepsin B (CTB) sensitive CPT conjugates (9a and 9b) were synthesized. Through click chemistry, additional functional group mPEG2000 can be easily introduced into these conjugates. The introduction of mPEG2000 fragment resulted in the formation of nanoparticles 1a and 1b (average particle sizes were 216.9 and 257.9 nm, respectively) with significantly increased water solubility (more than 19 000-fold). The release of therapeutic drug SN-38 in the presence of CTB was confirmed by HPLC and prodrug 1a showed potent in vitro cytotoxicity against all tested cell lines. Impressively, compared with irinotecan, CTB sensitive prodrug 1a displayed similar in vivo efficacy with remarkable decreased in vivo toxicity.
Co-reporter:Lei Wang, Shao Xie, Longjun Ma, Yi Chen, Wei Lu
European Journal of Medicinal Chemistry 2016 Volume 116() pp:84-89
Publication Date(Web):30 June 2016
DOI:10.1016/j.ejmech.2016.03.063
•A boronic acid substituted camptothecin (B1) was synthesized for the first time.•Prodrug B1 selectively activated by cancer cells with elevated levels of H2O2, and displayed potent antitumor activity.•This strategy would be applied to the research and development of natural products.Malignant tumor cells have been found to have high levels of reactive oxygen species such as hydrogen peroxide (H2O2), supporting the hypothesis that a prodrug could be activated by intracellular H2O2 and lead to a potential antitumor therapy. In this study, the 7-ethyl-10-boronic acid camptothecin (B1) was synthesized for the first time as prodrug of SN-38, by linking a cleavable aryl carbon–boron bond to the SN-38. Prodrug B1 selectively activated by H2O2, converted rapidly to the active form SN-38 under favorable oxidative conditions in cancer cells with elevated levels of H2O2. The cell survival assay showed that prodrug B1 was equally or more effective in inhibiting the growth of six different cancer cells, as compared to SN-38. Unexpectedly, prodrug B1 displayed even more potent Topo I inhibitory activity than SN-38, suggesting that it was not only a prodrug of SN-38 but also a typical Topo I inhibitor. Prodrug B1 also demonstrated a significant antitumor activity at 2.0 mg/kg in a xenograft model using human brain star glioblastoma cell lines U87MG.
Co-reporter:Xuan Zhang, Yannan Kong, Jie Zhang, Mingbo Su, Yubo Zhou, Yi Zang, Jia Li, Yi Chen, Yanfen Fang, Xiongwen Zhang, Wei Lu
European Journal of Medicinal Chemistry 2015 Volume 95() pp:127-135
Publication Date(Web):5 May 2015
DOI:10.1016/j.ejmech.2015.03.035
•A new class of colchicine derivatives were designed and synthesized as tubulin–HDAC dual inhibitors.•Compound 6d behaved as potent HDAC–tubulin dual inhibitor and showed comparable cytotoxicity with colchicine.•Hybrid 11a exhibited powerful tubulin inhibitory activity, moderate anti-HDAC activity and the most potent cytotoxicity.A new class of colchicine derivatives were designed and synthesized as tubulin–HDAC dual inhibitors. Biological evaluations of these hybrids included the inhibitory activity of HDAC, tubulin polymerization analysis, in vitro cell cycle analysis in HCT-116 cells and cytotoxicity against different cancer cell lines. Hybrid 6d behaved as potent HDAC–tubulin dual inhibitor and showed comparable cytotoxicity with colchicine. Compound 11a exhibited powerful tubulin inhibitory activity, moderate anti-HDAC activity and the most potent cytotoxicity (IC50 = 2–105 nM).A new class of colchicine derivatives were designed and synthesized as tubulin–HDAC dual inhibitors.
Co-reporter:Lei Wang, Shao Xie, Longjun Ma, Yi Chen, Wei Lu
Bioorganic & Medicinal Chemistry 2015 Volume 23(Issue 9) pp:1950-1962
Publication Date(Web):1 May 2015
DOI:10.1016/j.bmc.2015.03.031
Fifteen novel homocamptothecin derivatives with α-OMe substituted E-rings were designed and synthesized. All of the derivatives exhibited similar or superior cytotoxicities compared with that of SN-38, and they inhibited Topo I activity in a cell-free assay in a manner similar to that of SN-38, confirming that they represent a new class of Topo I inhibitors. Notably, the water soluble compound 36o (1.2 mg/mL) exhibited increased lactone stability, and at 0.5 mg/kg and 3.0 mg/kg, it demonstrated significant antitumor activity in mice bearing a xenograft model using human colon cancer cell line HT-29. On the basis of these positive results, further development of 36o-related compounds as potential anticancer clinical trial candidates is definitely warranted.
Co-reporter:Xuan Zhang, Lun Zhang, Yaqian Liu, Bin Bao, Yi Zang, Jia Li, Wei Lu
Tetrahedron 2015 Volume 71(Issue 29) pp:4842-4845
Publication Date(Web):22 July 2015
DOI:10.1016/j.tet.2015.05.025
A new near-infrared and colorimetric fluorescent molecular probe was developed for rapid detection of H2O2. The near-infrared fluorescence OFF–ON switch is triggered by transformation of phenylboronic acid unit to phenol in the presence of H2O2. No quinone methides are released in this process, which is preferable for in vivo studies. In addition, probe 1 at low concentration exhibits high quality optical imaging during a short period in in vitro cell study.
Co-reporter:Xuan Zhang, Jie Zhang, Mingbo Su, Yubo Zhou, Yi Chen, Jia Li and Wei Lu
RSC Advances 2014 vol. 4(Issue 76) pp:40444-40448
Publication Date(Web):22 Aug 2014
DOI:10.1039/C4RA05508J
A new class of 4′-demethyl-4-deoxypodophyllotoxin derivatives has been designed and synthesized as tubulin–HDAC dual inhibitors. Biological evaluation of these hybrids included the inhibitory activity of HDAC, in vitro cell cycle analysis in HCT-116 cells as well as cytotoxicity against two cancer cell lines (A549 and HCT116). The distance and angle between the HDAC capping group and the zinc binding group were systematically varied. Compounds 14a and 14c showed most potent dual inhibitory activity and powerful antiproliferative activity on HCT116 and A549 cell lines.
Co-reporter:Lei Wang;Wei Yuan;Jie Zhang;Linjiang Tong;Yu Luo;Yi Chen;Qingqing Huang
Chinese Journal of Chemistry 2014 Volume 32( Issue 2) pp:157-162
Publication Date(Web):
DOI:10.1002/cjoc.201300703
Abstract
Camptothecin (CPT) is a natural topoisomerase I inhibitor with powerful antineoplastic activity against colorectal, breast, lung and ovarian cancers. To discover more potent antitumor agents, a series of new CPT derivatives were synthesized utilizing click chemistry. All compounds were assessed for cytotoxicity against A549, HCT-116, HT-29, LoVo, MDA-MB-231 cell lines, and some compounds exhibited good in vitro potency. Furthermore, all compounds kept or enhanced Topo I inhibition.
Co-reporter:Yu Luo;Shanbao Yu;Qingqing Huang
Journal of Heterocyclic Chemistry 2014 Volume 51( Issue 4) pp:1133-1136
Publication Date(Web):
DOI:10.1002/jhet.1549
A facile and eco-friendly approach for synthesizing 9-allyl-10-hydroxycamptothecin (2), a key intermediate for the preparation of camptothecin analogs, is described. The product was obtained in good yield and high purity (≥99% HPLC) under mild Suzuki reaction condition.
Co-reporter:Xuan Zhang, Bin Bao, Xiuhua Yu, Linjiang Tong, Yu Luo, Qingqing Huang, Mingbo Su, Li Sheng, Jia Li, Hong Zhu, Bo Yang, Xiongwen Zhang, Yi Chen, Wei Lu
Bioorganic & Medicinal Chemistry 2013 Volume 21(Issue 22) pp:6981-6995
Publication Date(Web):15 November 2013
DOI:10.1016/j.bmc.2013.09.023
A novel class of podophyllotoxin derivatives have been designed and synthesized based on the synergistic antitumor effects of topoisomerase II and histone deacetylase inhibitors. Their inhibitory activities towards histone deacetylases and Topo II and their cytotoxicities in cancer cell lines were evaluated. The aromatic capping group connection, linker length and zinc-binding group were systematically varied and preliminary conclusions regarding structure–activity relationships are discussed. Among all of the synthesized hybrid compounds, compound 24d showed the most potent HDAC inhibitory activity at a low nanomolar level and exhibited powerful antiproliferative activity towards HCT116 colon carcinoma cells at a low micromolar level. Further exploration of this series led to the discovery of potent dual inhibitor 32, which exhibited the strongest in vitro cytotoxic activity.
Co-reporter:Xuan Zhang, Jie Zhang, Linjiang Tong, Yu Luo, Mingbo Su, Yi Zang, Jia Li, Wei Lu, Yi Chen
Bioorganic & Medicinal Chemistry 2013 Volume 21(Issue 11) pp:3240-3244
Publication Date(Web):1 June 2013
DOI:10.1016/j.bmc.2013.03.049
A novel class of colchicine-SAHA hybrids were designed and synthesised based on the synergistic antitumor effect of tubulin inhibitors and histone deacetylases (HDAC) inhibitors. To the best of our knowledge, this is the first design of molecules that are dual inhibitors of tubulin and HDAC. Biological evaluations of these compounds included the inhibitory activity of HDAC, in vitro cell cycle analysis in BEL-7402 cells as well as cytotoxicity in five cancer cell lines.
Co-reporter:Yu Luo;Haiyan Liu
Journal of Heterocyclic Chemistry 2013 Volume 50( Issue 6) pp:1357-1362
Publication Date(Web):
DOI:10.1002/jhet.1055
A series of thiazolyl moiety-containing pyrimidine derivatives were synthesized and evaluated for their cytotoxicity against chronic myelogenous leukemia cell line K562 and human breast cancer cell line MCF-7. Most compounds showed good antiproliferation activity.
Co-reporter:Taijie Chen;Yu Luo;Li Sheng;Jia Li;Youhong Hu
Molecular Diversity 2013 Volume 17( Issue 3) pp:435-444
Publication Date(Web):2013/08/01
DOI:10.1007/s11030-013-9442-1
A series of novel \(N\)-(3,4,5-trimethoxyphenyl)pyridin-2(\(1H\))-one derivatives were designed, synthesized, and evaluated for their in vitro cytotoxicity against human colon cancer cells HCT-116. The key steps involved consecutive Chan–Lam- and Buchwald–Hartwig couplings. Most of these C-6 substituted pyridone derivatives showed moderate antiproliferative activity. The preliminary SAR indicated that the conformationally restricted pyridones exhibited more potent cytotoxicity than the flexible counterparts. In addition, cell cycle analysis of the selected compounds 4b and e showed a G2/M arrest, suggesting a possible antitubulin mechanism for these novel pyridone derivatives.
Co-reporter:Yu Luo, Shanbao Yu, Linjiang Tong, Qingqing Huang, Wei Lu, Yi Chen
European Journal of Medicinal Chemistry 2012 Volume 54() pp:281-286
Publication Date(Web):August 2012
DOI:10.1016/j.ejmech.2012.05.002
In order to increase the stability of E-ring of homocamptothecins, the electron-withdrawing group –OH or –OAc was induced to α position of ring-E lactone. Ten new homocamptothecin analogs were synthesized. Most compounds showed potent in vitro anticancer activity and potent Topo I inhibition, which was equal or superior to that of CPT, SN-38 and 10-HCPT. The stability studies of this series also displayed significant improvement of the stability.Graphical abstractThe homocamptothecin analogs, with the electron-withdrawing group –OH or –OAc in α position of ring-E lactone, were synthesized. Most compounds showed potent in vitro anticancer activity and potent Topo I inhibition, which was equal or superior to that of CPT, SN-38 and 10-HCPT. The stability studies of this series also displayed significant improvement of the lactone stability.Highlights► New homocamptothecins with the electron-withdrawing group. ► Total synthesis of the homocamptothecins. ► New homocamptothecins show potent anticancer activity and Topo I inhibition. ► New homocamptothecins display good stability of E-ring.
Co-reporter:Xiang-Jun Feng;Xiao-Ying Yang;Yu Luo;Xin Li;Wei Tang;Jian-Ping Zuo
Archiv der Pharmazie 2012 Volume 345( Issue 2) pp:93-100
Publication Date(Web):
DOI:10.1002/ardp.201100092
Abstract
Five new immunomodulators 1a–1e by using a trans-4-alkyl-substituted cyclohexane to replace the flexible C8 alkyl chain of Fingolimod were synthesized. For in-vitro test, the compounds were dissolved in DMSO as a stock solution and diluted to a desired concentration with RPMI 1640 nutrient solution. For in-vivo test, the compounds were prepared in pathogen-free saline containing 0.5% DMSO. These new immunomodulators displayed more potent immunoinhibitory activities in vitro and moderate immunomodulating activities in vivo. They show therapeutic effects on DNFB-induced DTH reaction and inhibitory effects on the antigen-specific T-cell proliferation.
Co-reporter:Lijuan Zhang;Yu Luo;Shanbao Yu
Journal of Heterocyclic Chemistry 2012 Volume 49( Issue 5) pp:1254-1256
Publication Date(Web):
DOI:10.1002/jhet.967
An efficient route for the synthesis of 4-substituted-2-quinolinone-3-carboxylic acid ethyl esters has been developed through Suzuki or Sonogashira reactions. The advantages of the method include high yields, operational simplicity, and suitability for medicinal modification of 4-substituted quinolinones and their derivatives.
Co-reporter:Shanbao Yu, Qing-Qing Huang, Yu Luo, and Wei Lu
The Journal of Organic Chemistry 2012 Volume 77(Issue 1) pp:713-717
Publication Date(Web):December 13, 2011
DOI:10.1021/jo201974f
A new practical and concise total synthesis of enantiopure camptothecin and SN-38 (14% overall yield, 99.9% ee and 99.9% purity) was described, starting from inexpensive and readily available materials. The development of column chromatography-free purification was achieved in all steps, which offers an economic industrial process to the camptothecin-family alkaloids.
Co-reporter:Yu Luo, Feng Xiao, Shijing Qian, Wei Lu, Bo Yang
European Journal of Medicinal Chemistry 2011 Volume 46(Issue 1) pp:417-422
Publication Date(Web):January 2011
DOI:10.1016/j.ejmech.2010.11.014
A novel kind of thiazolylbenzimidazole derivatives were designed and synthesized and evaluated for their antitumor activity against SMMC-7721 and A549 cell lines. Most compounds showed good antitumor activities, and compound 11b displayed remarkable in vitro anticancer activity comparable to taxol. The preliminary structure–activity relationship of these benzimidazole derivatives was discussed based on the experimental data obtained.Synthesis of a series of 2-thiazol-2-yl derivatives and some of them exhibit significant inhibitory activities against SMMC-7721 and A549 cell lines in vitro.Research highlights► Reported thiazolylbenzimidazole-4,7-diones are potentially toxic both to tumor cell lines and to normal counterparts. ► Novel thiazolylbenzimidazole compounds without quinone moiety were designed and synthesized. ► To increase the antitumor activity, efforts were exerted on the structure modification of the thiazole ring. ► Most compounds showed good antitumor activities, and compound 11b displayed remarkable in vitro anticancer activity comparable to taxol.
Co-reporter:Yu Luo, Hao-Min Liu, Ming-Bo Su, Li Sheng, Yu-Bo Zhou, Jia Li, Wei Lu
Bioorganic & Medicinal Chemistry Letters 2011 Volume 21(Issue 16) pp:4844-4846
Publication Date(Web):15 August 2011
DOI:10.1016/j.bmcl.2011.06.046
Two natural piperamides (piperlonguminine and refrofractamide A) and their derivatives were synthesized and evaluated for inhibitory activity against histone deacetylases, as well as the HCT-116 human colon cancer cell line. The preliminary structure activity relationship was discussed. Compounds featuring a hydroxamic acid moiety exhibited moderate HDAC activity and in vitro cytotoxicity.
Co-reporter:Shan Bao Yu, Hao Min Liu, Yu Luo, Wei Lu
Chinese Chemical Letters 2011 Volume 22(Issue 3) pp:264-267
Publication Date(Web):March 2011
DOI:10.1016/j.cclet.2010.10.021
Asymmetric conjugated addition of allylcopper reagents derived from an allyl Grignard reagent and CuBr·Me2S to chiral α,β-unsaturated N-acyl oxazolidinones has been achieved. The synthetic procedure was applied to the preparation of the key intermediate of the novel nonbenzodiazepine hypnotic drug, ramelteon.
Co-reporter:Shan Bao Yu, Li Juan Zhang, Yu Luo, Wei Lu
Chinese Chemical Letters 2011 Volume 22(Issue 1) pp:1-4
Publication Date(Web):January 2011
DOI:10.1016/j.cclet.2010.07.033
This paper described a practical five-step synthetic approach for 2-amino-5-methoxylpropiophenone in 45% overall yield, using 3-chloropropiophenone as the starting material. The advantages of this procedure include short reaction steps, simple operation and good yield.
Co-reporter:Yu Luo, Jia-Ping Yao, Li Yang, Chun-Lan Feng, Wei Tang, Gui-Feng Wang, Jian-Pin Zuo, Wei Lu
Bioorganic & Medicinal Chemistry 2010 Volume 18(Issue 14) pp:5048-5055
Publication Date(Web):15 July 2010
DOI:10.1016/j.bmc.2010.05.076
A series of novel benzimidazole derivatives were synthesized and evaluated for their anti-hepatitis B virus (HBV) activity and cytotoxicity in the HepG2.2.15 cell line. The preliminary SAR was discussed. Compound 12a, with IC50 <0.41 μM and SI >81.2, was the most promising compound and selected as the benchmark compound for further optimization.
Co-reporter:Haiyan Liu;Wenpin Xia;Yu Luo
Monatshefte für Chemie - Chemical Monthly 2010 Volume 141( Issue 8) pp:907-911
Publication Date(Web):2010 August
DOI:10.1007/s00706-010-0334-0
A convenient method has been developed for the synthesis of imatinib and two of its intermediates. N-(2-Methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidinamine, obtained from 2-(methylsulfonyl)-4-(3-pyridyl)pyrimidine via nucleophilic substitution, was reduced by N2H4·H2O/FeCl3·6H2O/C in 92% yield. The resulting amine was condensed with 4-[(4-methylpiperazin-1-yl)methyl]benzoic acid dihydrochloride, which was prepared from 4-(chloromethyl)benzonitrile via substitution and hydrolysis reactions, to provide the final product imatinib in good yield and high purity.
Co-reporter:Shanbao Yu;Yu Luo;Haiyan Liu;Haomin Liu
Monatshefte für Chemie - Chemical Monthly 2010 Volume 141( Issue 2) pp:245-249
Publication Date(Web):2010 February
DOI:10.1007/s00706-009-0245-0
A concise formal synthesis of camptothecin is described. The key pyrido-lactone (DE ring) was prepared effectively starting from 2-chloronicotinic acid via lithiation, reduction, and hydrolysis in 29% overall yield.
Co-reporter:Bo Zhang;Yu Luo;Qinjie Weng;Qiaojun He;Bo Yang
Investigational New Drugs 2008 Volume 26( Issue 6) pp:517-524
Publication Date(Web):2008 December
DOI:10.1007/s10637-008-9120-9
7-[(3-piperidyl)-1-propinyl]-camptothecin (CPT21) is a novel semi-synthetic water-soluble analogue of camptothecin. In this context, we assessed the anti-tumor activity of CPT21 both in vivo and in vitro and explored its molecular mechanism. We found that CPT21 presented a broad anti-tumor spectrum against ten cancer cell lines in vitro, and the IC50 values ranged from 0.1 to 12.0 μM. CPT21 was also capable to interrupt the DNA topoisemerase I activity and caused DNA double strand breaks during DNA replication. Proportion of apoptotic SGC7901 cells induced by CPT21 showed a time- and concentration-dependent increase accompanied with the decrease in mitochondria membrane potential (ΔΨm). We also observed that CPT21 up-regulated the protein expression of p53, phospho-p53, p21, BAX, phospho-c-Jun NH2-terminal protein kinase (JNK), meanwhile down-regulating the protein expression of Bcl-2, procaspase-9, XIAP, and phospho-ERK1/2. In the study of SGC7901 xenograft model, the results suggested that both 5.0 mg/kg and 10.0 mg/kg CPT21 achieved high anti-tumor activity, and the tumor inhibition rates were 42.5% and 75.1% respectively. Taken together, our study demonstrates that CPT21 displays an extensive anti-tumor spectrum and CPT21 can induce the apoptosis of SGC7901 cells via activating the caspases cascade followed by disrupting mitochondrion function.
Co-reporter:Yun-Fei Li, Gui-Feng Wang, Yu Luo, Wei-Gang Huang, Wei Tang, Chun-Lan Feng, Li-Ping Shi, Yu-Dan Ren, Jian-Ping Zuo, Wei Lu
European Journal of Medicinal Chemistry 2007 Volume 42(11–12) pp:1358-1364
Publication Date(Web):November–December 2007
DOI:10.1016/j.ejmech.2007.03.005
A series of 1-isopropylsulfonyl-2-amine benzimidazole derivatives were synthesized and evaluated for their anti-hepatitis B virus (HBV) activity and cytotoxicity in the HepG2.2.15 cell line. In general, these derivatives are potent HBV inhibitors (IC50 < 4 μM) with high selectivity indices (SIs > 40). Compounds 5b–e, g, j, and 9a were among the most prominent compounds, with IC50s of 0.70–2.0 μM and SIs of 41–274. The potent anti-HBV activity and safety profiles of the most promising compounds 5d and j (IC50s = 0.70 μM, SIs > 120) demonstrate the potential of this series of benzimidazoles for the development of new anti-HBV drugs.Synthesis of a series of 1-isopropylsulfonyl-2-amine benzimidazoles and their significant inhibitory activities against hepatitis B virus in vitro is presented.
Co-reporter:Weigang Huang, Jingya Li, Wei Zhang, Yueyang Zhou, Chuanming Xie, Yu Luo, Yunfei Li, Jingli Wang, Jia Li, Wei Lu
Bioorganic & Medicinal Chemistry Letters 2006 Volume 16(Issue 7) pp:1905-1908
Publication Date(Web):1 April 2006
DOI:10.1016/j.bmcl.2005.12.080
Miltirone analogues were synthesized and evaluated for inhibitory activity against Cdc25 and PTP1B. Most of the compounds demonstrated potent Cdc25 inhibitory activity, and several exhibited higher selectivity for Cdc25 than for PTP1B. In a cytotoxic assay, most of the compounds displayed cytotoxicity against the tumor cell lines A549 and HCT-116, producing IC50 values in the micromolar range.
Co-reporter:Yi-Bin Xu, Li Yang, Gui-Feng Wang, Xian-Kun Tong, Ya-Juan Wang, Ye Yu, Jing-Feng Jing, Chun-Lan Feng, Pei-Lan He, Wei Lu, Wei Tang, Jian-Ping Zuo
Antiviral Research (July 2014) Volume 107() pp:6-15
Publication Date(Web):July 2014
DOI:10.1016/j.antiviral.2014.04.002
Co-reporter:Xikuang Yao, Qiwen Zhu, Cheng Li, Kangjun Yuan, Rui Che, Peng Zhang, Chenchen Yang, Wei Lu, Wei Wu and Xiqun Jiang
Journal of Materials Chemistry A 2017 - vol. 5(Issue 4) pp:NaN848-848
Publication Date(Web):2016/12/22
DOI:10.1039/C6TB02863B
Conjugation of sugars to antitumor drugs can facilitate drug binding to tumor cells and the saccharide motifs of bleomycins (BLMs) play a crucial role in tumor-seeking. Here, we synthesized BLM monosaccharide, carbamoylmannose, and subsequently prepared carbamoylmannose decorated platinum-incorporating supramolecular nanoparticles formed through the host–guest complexation of poly(N-vinylpyrrolidone) and poly(aspartic acid). The targeting effects of carbamoylmannose decorated supramolecular nanoparticles in various cancer cells and tumor-bearing mice were investigated. It was found that the nanoparticles showed a specific in vitro and in vivo carbamoylmannose-mediated cellular uptake and drug delivery. The cellular uptake of the nanoparticles followed the receptor-mediated endocytosis mechanism in cancer cells but not in healthy cells. In a murine hepatic H22 tumor model, it was demonstrated that the carbamoylmannose moiety increased the plasma concentration, tumor targeting ability and tumor penetration of the nanoparticles, leading to high tumor accumulation and superior antitumor efficacy. This carbamoylmannose molecule may bring an opportunity to design and construct inexpensive but highly efficient drug and gene delivery systems in the future.
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