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Yichao Wan Tingting Liu Xiaoxian Li Chen Chen Hao Fang 《Bioorganic & medicinal chemistry》2017,25(1):138-152
As an important member of anti-apoptotic Bcl-2 protein, myeloid cell leukemia sequence 1 (Mcl-1) protein is an attractive target for cancer therapy. In this study, a new series of pyrrolidine derivatives as Mcl-1 inhibitors were developed by mainly modifying the amino acid side chain of compound 1. Among them, compound 18 (Ki = 0.077 μM) exhibited better potent inhibitory activities towards Mcl-1 protein compared to positive control Gossypol (Ki = 0.18 μM). In addition, compound 40 possessed good antiproliferative activities against PC-3 cells (Ki = 8.45 μM), which was the same as positive control Gossypol (Ki = 7.54 μM). 相似文献
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Fa-Qian Shen Zhong-Chang Wang Song-Yu Wu Shen-Zhen Ren Ruo-Jun Man Bao-Zhong Wang Hai-Liang Zhu 《Bioorganic & medicinal chemistry letters》2017,27(16):3653-3660
In our previous study, we designed a series of pyrazole derivatives as novel COX-2 inhibitors. In order to obtain novel dual inhibitors of COX-2 and 5-LOX, herein we designed and synthesized 20 compounds by hybridizing pyrazole with substituted coumarin who was reported to exhibit 5-LOX inhibition to select potent compounds using adequate biological trials sequentially including selective inhibition of COX-2 and 5-LOX, anti-proliferation in vitro, cells apoptosis and cell cycle. Among them, the most potent compound 11g (IC50 = 0.23 ± 0.16 μM for COX-2, IC50 = 0.87 ± 0.07 μM for 5-LOX, IC50 = 4.48 ± 0.57 μM against A549) showed preliminary superiority compared with the positive controls Celecoxib (IC50 = 0.41 ± 0.28 μM for COX-2, IC50 = 7.68 ± 0.55 μM against A549) and Zileuton (IC50 = 1.35 ± 0.24 μM for 5-LOX). Further investigation confirmed that 11g could induce human non-small cell lung cancer A549 cells apoptosis and arrest the cell cycle at G2 phase in a dose-dependent manner. Our study might contribute to COX-2, 5-LOX dual inhibitors thus exploit promising novel cancer prevention agents. 相似文献
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J. Thomas Sanderson Hélène Clabault Cody Patton Grégoire Lassalle-Claux Jacques Jean-François Aurélie F. Paré Martin J.G. Hébert Marc E. Surette Mohamed Touaibia 《Bioorganic & medicinal chemistry》2013,21(22):7182-7193
Caffeic acid and its naturally occurring derivative caffeic acid phenethyl ester (CAPE) have antiproliferative and cytotoxic properties in a variety of cancer cell lines without displaying significant toxicity toward healthy cells, and are considered to be potential anticancer agents. However, little is known about their effects on prostate cancer cells. We synthesized and evaluated the effects of caffeic acid, CAPE (2) and 18 synthetic derivatives on cell viability and androgen-dependent cell proliferation, subcellular localisation and expression of androgen receptor (AR) and secretion of prostate-specific antigen (PSA) in LNCaP human hormone-dependent prostate cancer cells. Several synthetic derivatives of CAPE were strong, concentration-dependent cytotoxic agents in LNCaP cells with IC50 values in the 6.8–26.6 μM range, potencies that were up to five-fold greater than that of CAPE (33.7 ± 4.0 μM). A number of caffeic acid derivatives were inhibitors of androgen-stimulated LNCaP cell proliferation with concomitant inhibition of DHT-stimulated PSA secretion. Compound 24 was the most cytotoxic and antiproliferative caffeic acid derivative (IC50 values of 6.8 ± 0.3 and 2.4 ± 0.8 μM, respectively) inhibiting DHT-stimulated cell proliferation and PSA secretion statistically significantly at concentrations as low as 0.3 μM. Exposure to DHT increased cytoplasmic and nuclear AR levels and co-treatment with increasing concentrations of compound 24 or CAPE (2), notably, further increased these levels. In conclusion, a number of synthetic derivatives of caffeic acid are potent inhibitors of androgen-dependent prostate cancer cell proliferation and viability, acting, at least in part, via an antiandrogenic mechanism that involves increased nuclear accumulation of (presumably inactive) AR. 相似文献
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Qing-Kun Shen Chuan-Feng Liu Hong-Jian Zhang Yu-Shun Tian Zhe-Shan Quan 《Bioorganic & medicinal chemistry letters》2017,27(21):4871-4875
Two series of xanthotoxin-triazole derivatives were designed, synthesized, and studied for their antiproliferative properties. The in vitro cytotoxicity of the compounds in the AGS cancer cell line and the L02 normal cell line was evaluated via MTT assay. Among the synthesized compounds, 9-((1-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)methoxy)-7H-furo[3,2-g]chromen-7-one (6p) was found to have the greatest antiproliferative activity against AGS cells (IC50 = 7.5 μM) and showed better activity than the lead compound (xanthotoxin, IC50 > 100 μM) and the reference drug (5-fluorouracil, IC50 = 29.6 μM) did. The IC50 value of 6p in L02 cells was 13.3 times higher than that in the AGS cells. Therefore, the compound exhibited better therapeutic activity and specificity compared with the positive control 5-fluorouracil. Cell cycle analysis revealed that compound 6p inhibited cell growth via the induction of S/G2 phase arrest in AGS cells. Compound 6p was identified as a promising lead compound for the further development and identification of 1,2,3-triazole-based anticancer agents. 相似文献
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Zhiyuan Shao Pan Xu Wen Xu Linjuan Li Shien Liu Rukang Zhang Yu-Chih Liu Chenhua Zhang Shijie Chen Cheng Luo 《Bioorganic & medicinal chemistry letters》2017,27(2):342-346
DNA methyltransferases are involved in diverse biological processes and abnormal methylation patterns play essential roles in cancer initiation and progression. DNA methyltransferase 3A (DNMT3A) acting as a de novo DNA methyltransferase, has gained widespread attention especially in haematological diseases. To date, large numbers of DNMTs inhibitors have been discovered, however, the small molecular inhibitors targeting DNMT3A are still in its infancy. In this study, structure-based virtual screening in combination with biological assays was performed to discovery potent novel DNMT3A inhibitors. Compound 40 and 40_3 displayed comparable in vitro inhibitory activity against DNMT3A with IC50 values of 46.5 μM and 41 μM, respectively. Further binding mode analysis suggested these molecules inhibit DNMT3A activity through binding the S-adenosyl-l-methionine (SAM) pocket. Overall, 40 and 40_3 may serve as novel scaffolds for further optimization and small molecular probes for investigating DNMT3A function. 相似文献
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《Bioorganic & medicinal chemistry letters》2014,24(21):4948-4953
A versatile and high yielding synthesis of novel androgen receptor (AR) antagonists is presented. Using this methodology, six 1,4-substituted-1,2,3-triazole derived bicalutamide mimics were synthesised in five steps and in isolated overall yields from 41% to 85%. Evaluation of these compounds for their anti-proliferative properties against androgen dependent (LNCaP) and independent (PC-3) cells showed promising IC50 values of 34–45 μM and 29–151 μM, respectively. The data suggest that the latter compounds may be an excellent starting point for the development of prostate cancer therapeutics for both androgen dependent and independent forms of this disease. Docking of these compounds (each enantiomer) in silico into the T877A mutated androgen receptor, as possessed by LNCaP cells, was also undertaken. 相似文献
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Jinlei Bian Tinghan Li Tianwei Weng Jubo Wang Yu Chen Zhiyu Li 《Bioorganic & medicinal chemistry letters》2017,27(4):1012-1016
A novel series of 49 wogonin derivatives were synthesized by introducing group at 7-, 8- or B ring of wogonin. The cytotoxic activities against HepG2, A549 and BCG-823 cancer cell lines were also investigated in vitro. Several of them showed obvious cytotoxic activities and compound 3h possessed the highest potency against HepG2, A549, and BCG-823 with IC50 values of 1.07 μM, 1.74 μM and 0.98 μM, respectively. A quantitative structure-activity relationship (QSAR) study of these synthetic derivatives as well as wogonin indicated that high solubility and low octanol/water partition coefficient are favorable, and excessive electrostatic properties and refractivity are unfavorable for the cytotoxic activities of these wogonin derivatives. These findings and results provide a base for further investigations. 相似文献
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A series of novel salicyl-hydrazone analogues were synthesized and evaluated for their in vitro cytotoxic activities in five human cancer cell lines, namely, lung cancer (A549), ovarian cancer (SK-OV-3), skin cancer (SK-MEL-2), colon cancer (HCT15) and pancreatic cancer (MIA-PaCa-2) cells, and for their in vitro tropomyosin receptor kinase A (TrkA) inhibitory activities. Each of the compounds showed significant cytotoxicity against all cancer cells. Compound 3i was found to be most potent against all cancer cell lines with IC50 values of 2.46 (A549), 0.87 (SK-OV-3), 1.43 (SK-MEL-2), 0.89 (HCT15), and 0.48 μM (MIA-PaCa-2), followed by compound 3l. Cytotoxicity of 3i was similar to that of doxorubicin (0.87 μM) against HCT15 cells. Compounds 3i and 3l also showed highest TrkA inhibitory activities with IC50 values of 0.231 and 0.380 μM, respectively. A SAR study of the series revealed that compounds with hydroxyl groups showed better cytotoxicity and TrkA inhibitory potency (in the following order 2,4-OH > 2,3,4-OH > 3,4-OH > 4-OH) than compounds possessing electron donating or withdrawing groups on the benzylidenephenyl ring. Docking studies of compounds 3i and 3l conducted on the crystal structure of TrkA receptor (a promising target for anticancer agents) showed both had a high docking score and similar order of experimental TrkA inhibitory activities. The formation of several hydrogen bonds involving N and O containing moieties contributed most significantly to ligand binding and stabilization at the active site of the receptor. In addition, ligand-receptor complexes were further stabilized by π-cation, π-anion, amide-π stacked, and van der Waal’s interactions. Conformational analyses showed ligand molecules adopted similar conformations at the receptor active site during interactions, but that the low energy optimized conformations of compounds 3i and 3l differed. 相似文献
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Jun Chen Zhangzhe Peng Miaomiao Lu Xuan Xiong Zhuo Chen Qianbin Li Zeneng Cheng Dejian Jiang Lijian Tao Gaoyun Hu 《Bioorganic & medicinal chemistry letters》2018,28(2):222-229
Oxidative stress, inflammation and fibrosis can cause irreversible damage on cell structure and function of kidney and are key pathological factors in Diabetic Nephropathy (DN). Therefore, multi-target agents are urgently need for the clinical treatment of DN. Using Pirfenidone as a lead compound and based on the previous research, two novel series (5-trifluoromethyl)-2(1H)-pyridone analogs were designed and synthesized. SAR of (5-trifluoromethyl)-2(1H)-pyridone derivatives containing nitrogen heterocyclic ring have been established for in vitro potency. In addition, compound 8, a novel agent that act on multiple targets of anti-DN with IC50 of 90 μM in NIH3T3 cell lines, t1/2 of 4.89 ± 1.33 h in male rats and LD50 > 2000 mg/kg in mice, has been advanced to preclinical studies as an oral treatment for DN. 相似文献
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Carole-Anne Lefebvre Elsa Forcellini Sophie Boutin Marie-France Côté René C.-Gaudreault Patrick Mathieu Patrick Lagüe Jean-François Paquin 《Bioorganic & medicinal chemistry letters》2017,27(2):299-302
The synthesis of two series of novel substituted pyrimidine derivatives bearing a sulfamide group have been described and their in vitro cancer growth inhibition activities have been evaluated against three human tumour cell lines (HT-29, M21, and MCF7). In general, growth inhibition activity has been enhanced by the introduction of a bulky substituent on the aromatic ring with the best compound having GI50 < 6 μM for all the human tumour cell lines. The MCF7 selective compounds were evaluated on four additional human invasive breast ductal carcinoma cell lines (MDA-MB-231, MDA-MB-468, SKBR3, and T47D) and were selective against T47D cell line in all cases except one, suggesting a potential antiestrogen activity. 相似文献
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Cinzia Tavani Lara Bianchi Annalisa De Palma Giovanna Ilaria Passeri Giuseppe Punzi Ciro Leonardo Pierri Angelo Lovece Maria Maddalena Cavalluzzi Carlo Franchini Giovanni Lentini Giovanni Petrillo 《Bioorganic & medicinal chemistry letters》2017,27(17):3980-3986
A series of 1-[(methylsulfonyl)methyl]-2-nitro-5,6,7,8-tetrahydroindolizines and homologs were designed, prepared, and evaluated as non-sugar-type α-glucosidase inhibitors. The inhibitory activity appeared to be related to cyclo homologation with the best congeners being tetrahydroindolizines. The introduction of a methoxycarbonyl group as an additional hydrogen bond acceptor into the exocyclic methylene group was beneficial affording the most potent congener 3e (half maximal inhibitory concentration, IC50 = 8.0 ± 0.1 μM) which displayed 25-fold higher inhibitory activity than 1-deoxynojirimycin (2, IC50 = 203 ± 9 μM)—the reference compound. Kinetic analysis indicated that compound 3e is a mixed inhibitor with preference for the free enzyme over the α-glucosidase–substrate complex (Ki,free = 3.6 μM; Ki,bound = 7.6 μM). Molecular docking experiments were in agreement with kinetic results indicating reliable interactions with both the catalytic cleft and other sites. Circular dichroism spectroscopy studies suggested that the inhibition exerted by 3e may involve changes in the secondary structure of the enzyme. Considering the relatively low molecular weight of 3e together with its high fraction of sp3 hybridized carbon atoms, this nitro-substituted tetrahydroindolizine may be considered as a good starting point towards new leads in the area of α-glucosidase inhibitors. 相似文献
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Fang-Jun Cao Li-Fei Zhu Qian Kuang Xing-Qiang Li Bo-Hang Zhou Xin-Juan Yang Le Zhou 《Bioorganic & medicinal chemistry letters》2017,27(1):55-60
As our continuing research, a series of 2-aryl-8-OR-3,4-dihydroisoquinolin-2-ium bromides were evaluated for cytotoxic activity on cancer cells and apoptosis induction in the present study. SAR was derived also. Among them, 23 compounds showed the higher cytotoxicity on MKN-45 cells with IC50 values of 1.99–11.3 μM than a standard anticancer drug cis-platinum (IC50 = 11.4 μM) or their natural model compound chelerythrine (IC50 = 12.7 μM); 16 compounds possessed the medium to high activity on NB4 cells with IC50 values of 1.67–4.62 μM. SAR analysis showed that both substitution patterns of the N-aromatic ring and the type of 8-OR significantly impact the activity. AO/EB staining and flow cytometry analysis with Annexin V/PI double staining showed that the compounds were able to induce apoptosis in a concentration-dependent manner. The results above suggested that the title compounds are a class of promising compounds for the development of new anti-cancer drugs. 相似文献
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Wenlin Xie Huilin Zhang Jingjing He Jingai Zhang Qiuyan Yu Chunxiang Luo Shangru Li 《Bioorganic & medicinal chemistry letters》2017,27(3):530-532
Two series of novel kojic acid analogues (4a–j) and (5a–d) were designed and synthesized, and their mushroom tyrosinase inhibitory activities was evaluated. The result indicated that all the synthesized derivatives exhibited excellent tyrosinase inhibitory properties having IC50 values in the range of 1.35 ± 2.15–17.50 ± 2.75 μM, whereas standard inhibitor kojic acid have IC50 values 20.00 ± 1.08 μM. Specifically, 5-phenyl-3-[5-hydroxy-4-pyrone-2-yl-methylmercap-to]-4-(2,4-dihydroxyl-benzylamino)-1,2,4-triazole (4f) exhibited the most potent tyrosinase inhibitory activity with IC50 value of 1.35 ± 2.15 μM. The kinetic studies of the compound (4f) demonstrated that the inhibitory effects of the compound on the tyrosinase were belonging to competitive inhibitors. Meanwhile, the structure-activity relationship was discussed. 相似文献
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Jia-Li Song Juan Zhang Chang-Liang Liu Chao Liu Kong-Kai Zhu Fei-Fei Yang Xi-Gong Liu João Paulo Figueiró Longo Luis Alexandre Muehlmann Ricardo Bentes Azevedo Yu-Ying Zhang Yue-Wei Guo Cheng-Shi Jiang Hua Zhang 《Bioorganic & medicinal chemistry letters》2017,27(20):4682-4686
Twenty-five novel pregnenolone/2-cyanoacryloyl conjugates (6–30) were designed and prepared, with the aim of developing novel anticancer drugs with dual NF-κB inhibitory and anti-proliferative activities. Compounds 22 and 27–30 showed inhibition against TNF-α-induced NF-κB activation in luciferase assay, which was confirmed by Western blotting. Among them, compound 30 showed potent NF-κB inhibitory activity (IC50 = 2.5 μM) and anti-proliferative against MCF-7, A549, H157, and HL-60 cell lines (IC50 = 6.5–36.2 μM). The present study indicated that pregnenolone/2-cyanoacryloyl conjugate I can server as a novel scaffold for developing NF-κB inhibitors and anti-proliferative agents in cancer chemotherapy. 相似文献
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Yunyun Wang Wen Gu Yu Shan Fei Liu Xu Xu Yiqin Yang Qiangjian Zhang Yan Zhang Hongbo Kuang Zhonglong Wang Shifa Wang 《Bioorganic & medicinal chemistry letters》2017,27(11):2360-2363
A series of new nopinone-based thiosemicarbazone derivatives were designed and synthesized as potent anticancer agents. All these compounds were identified by 1H NMR, 13C NMR, HR-MS spectra analyses. In the in vitro anticancer activity, most derivatives showed considerable cytotoxic activity against three human cancer cell lines (MDA-MB-231, SMMC-7721 and Hela). Among them, compound 4i exhibited most potent antitumor activity against three cancer cell lines with the IC50 values of 2.79 ± 0.38, 2.64 ± 0.17 and 3.64 ± 0.13 μM, respectively. Furthermore, the cell cycle analysis indicated that compound 4i caused cell cycle arrest of MDA-MB-231 cells at G2/M phase. The Annexin V-FITC/7-AAD dual staining assay also revealed that compound 4i induced the early apoptosis of MDA-MB-231 cells. 相似文献
17.
Wei Shi Jinglin Hu Na Bao Dongang Li Li Chen Jianbo Sun 《Bioorganic & medicinal chemistry letters》2017,27(2):147-151
12 novel scopoletin-isoxazole and scopoletin-pyrazole hybrids were designed, synthesized and their chemical structures were confirmed by HR-MS, IR, 1H NMR and 13C NMR spectra. The anticancer activities of the newly synthesized compounds were evaluated in vitro against three human cancer cell lines including HCT-116, Hun7 and SW620 by MTT assay. The screening results showed that six compounds (9a, 9c, 9d, 12a, 18b and 18d) exhibited potent cytotoxic activities with IC50 values below 20 μM. Besides, we have further evaluated the growth inhibitory activities of six compounds against the human normal tissue cell lines HFL-1. Especially, compound 9d displayed significant anti-proliferative activity with IC50 values ranging from 8.76 μM to 9.83 μM and weak cytotoxicity with IC50 value of 90.9 μM on normal cells HFL-1, which suggested that isoxazole-based hybrids of scopoletin were an effective chemical modification to improve the anticancer activity of scopoletin. 相似文献
18.
Guangcheng Wang Ming Chen Jing Wang Yaping Peng Luyao Li ZhenZhen Xie Bing Deng Shan Chen Wenbiao Li 《Bioorganic & medicinal chemistry letters》2017,27(13):2957-2961
A series of chromone hydrazone derivatives 4a–4p have been synthesized, characterized by 1H NMR and 13C NMR and evaluated for their in vitro α-glucosidase inhibitory activity. Out of these tested compounds, six (4a, 4b, 4d, 4j, 4o and 4p) displayed potent α-glucosidase inhibitory activity with IC50 values in the range of 20.1 ± 0.19 μM to 45.7 ± 0.23 μM, as compared to the standard drug acarbose (IC50 = 817.38 ± 6.27 μM). Among this series, compound 4d (IC50 = 20.1 ± 0.19 μM) with 4-sulfonamide substitution at phenyl part of hydrazide was found to be the most active compound. Lineweaver-Burk plot analysis indicated that compound 4d is a non-competitive inhibitor of α-glucosidase. The binding interactions of the most active analogs were confirmed through molecular docking studies. Docking studies showed 4d are interacting with the residues Glu-276, Asp-214, Asp-349 and Arg-439 through hydrogen bonds, arene-anion and arene-cation interactions. In summary, our studies shown that these chromone hydrazone derivatives are a new class of α-glucosidase inhibitors. 相似文献
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Guangcheng Wang Xin Li Jing Wang Zhenzhen Xie Luyao Li Ming Chen Shan Chen Yaping Peng 《Bioorganic & medicinal chemistry letters》2017,27(5):1115-1118
A novel series of 2-((5,6-diphenyl-1,2,4-triazin-3-yl)thio)-N-arylacetamides 5a–5q have been synthesized and evaluated for their α-glucosidase inhibitory activity. All newly synthesized compounds exhibited potent α-glucosidase inhibitory activity in the range of IC50 = 12.46 ± 0.13–72.68 ± 0.20 μM, when compared to the standard drug acarbose (IC50 = 817.38 ± 6.27 μM). Among the series, compound 5j (12.46 ± 0.13 μM) with strong electron-withdrawing nitro group on the arylacetamide moiety was identified as the most potent inhibitor of α-glucosidase. Molecular docking study was carried out to explore the binding interactions of these compounds with α-glucosidase. Our study identifies a novel series of potent α-glucosidase inhibitors for further investigation. 相似文献