- Design, synthesis, and antifungal activities in vitro of novel tetrahydroisoquinoline compounds based on the structure of lanosterol 14α-demethylase (CYP51) of fungi
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Novel tetrahydroisoquinoline compounds were designed by coupling structure-based de novo design based on the structure of lanosterol 14α-demethylase (CYP51). The chemical synthesis and the antifungal activities in vitro of them were reported. The results exhibited that all of the lead compounds showed potent antifungal activities, in which compounds 6 and 7 had equal or stronger antifungal activities against five test fungi than that of fluconazole. The studies presented here provided the antifungal lead compounds. The affinity of the lead molecules for CYP51 was mainly attributed to their non-bonding interaction with the apoprotein, which was different from the azole antifungal agents.
- Zhu, Ju,Lu, Jiaguo,Zhou, Youjun,Li, Yaowu,Cheng, Jun,Zheng, Canhui
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- Structure-Based Discovery of Pyrimidine Aminobenzene Derivatives as Potent Oral Reversal Agents against P-gp- And BCRP-Mediated Multidrug Resistance
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Overexpression of ATP binding cassette (ABC) transporters, including P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), is an important factor leading to multidrug resistance (MDR) in cancer treatments. Three subclasses of dual inhibitors of P-gp and BCRP were designed based on the active moieties of BCRP inhibitors, tyrosine kinase inhibitors, and P-gp inhibitors, of which compound 21 possessed low cytotoxicity, high reversal potency, and good lipid distribution coefficient. 21 also increased the accumulation of Adriamycin (ADM) and Mitoxantrone (MX), blocked Rh123 efflux, and made no change in the protein expression of P-gp and BCRP. Importantly, coadministration of 21 can significantly improve the oral bioavailability of paclitaxel (PTX). It was also demonstrated that 21 significantly inhibited the growth of K562/A02 xenograft tumors by increasing the sensitivity of ADM in vivo. In summary, 21 has the potential to overcome MDR caused by P-gp and BCRP and to improve the oral bioavailability of PTX.
- Qiu, Qianqian,Zou, Feng,Li, Huilan,Shi, Wei,Zhou, Daoguang,Zhang, Ping,Li, Teng,Yin, Ziyu,Cai, Zilong,Jiang, Yuxuan,Huang, Wenlong,Qian, Hai
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p. 6179 - 6197
(2021/06/01)
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- Design, synthesis and biological evaluation of N-(4-(2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)phenyl)-4-oxo-3,4-dihydrophthalazine-1-carboxamide derivatives as novel P-glycoprotein inhibitors reversing multidrug resistance
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The overexpression of P-glycoprotein plays an important role in the process of multidrug resistance (MDR). P-gp inhibitors are one of the effective strategies to reverse tumor MDR. Novel P-gp inhibitors with phthalazinone scaffolds were designed, synthesized and evaluated. Compound 26 was found to be the most promising for further study. Compound 26 possessed high potency (EC50 = 46.2 ± 3.5 nM) and low cytotoxicity.26 possessed high MDR reversal activity towards doxorubicin-resistant K56/A02 cells. Reversal fold (RF) value reach to 44.26. 26 also increased accumulation of doxorubicin (DOX or ADM) or other MDR-related anticancer drugs with different structures. In conclusion, compound 26 deserves more research for its good features as P-gp inhibitor.
- Qiu, Qianqian,Zhou, Jiaqi,Shi, Wei,Kairuki, Mutta,Huang, Wenglong,Qian, Hai
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p. 166 - 175
(2019/02/03)
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- Designed P-glycoprotein inhibitors with triazol-tetrahydroisoquinoline-core increase doxorubicin-induced mortality in multidrug resistant K562/A02 cells
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Multidrug resistance (MDR) refers to the cross-resistance of cancer cells to one drug, accompanied by other drugs with different mechanisms and structures, which is one of the main obstacles of clinical chemotherapy. Overexpression of P-glycoprotein (P-gp) was an extensively studied cause of MDR. Therefore, inhibiting P-gp have become an important strategy to reverse MDR. In this study, two series of triazole-tetrahydroisoquinoline-core P-gp inhibitors were designed and synthesized. Among them, compound I-5 had a remarkable reversal activity of MDR activity and the preliminary mechanism study was also carried out. All the results proved that compound I-5 was considered as a promising P-gp-mediated MDR reversal candidate.
- Kairuki,Qiu, Qianqian,Pan, Miaobo,Li,Zhou,Ghaleb, Hesham,Huang, Wenlong,Qian, Hai,Jiang
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p. 3347 - 3357
(2019/06/17)
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- Discovery of aromatic amides with triazole-core as potent reversal agents against P-glycoprotein-mediated multidrug resistance
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P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) is a major impediment for clinical cancer therapy. 19 novel aromatic amides with triazole-core as MDR reversal agents were designed and synthesized via click chemistry to reverse MDR. Among them, compound 42 was identified as the most promising candidate with high potency (EC50 = 78.1 ± 5.4 nM), low cytotoxity (SI > 1282) and persistent duration in reversing doxorubicin (DOX) resistance in K562/A02 cells. 42 also enhanced the potency of other P-gp associated cytotoxic agents with different structures. In further study, remarkably increased intracellular accumulation of Rh123 and DOX in K562/A02 cells was achieved by compound 42, while CYP3A4 activity had no change by compound 42. These results indicate that compound 42 as a relatively safe modulator of P-gp-mediated MDR has good potential for further development.
- Qiu, Qianqian,Zhu, Jilan,Chen, Qiutong,Jiang, Ziqian,Xu, Jiting,Jiang, Xueting,Huang, Wenlong,Liu, Zhongquan,Ye, Jing,Xu, Xiaojuan
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- Discovery to solve multidrug resistance: Design, synthesis, and biological evaluation of novel agents
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Chemotherapy remains a pillar in the treatment and management of various cancers. However, multidrug resistance (MDR) becomes a severe problem after long-term administration of chemotherapy drugs. Overexpression of P-glycoprotein (P-gp) is a significant cause for tumor MDR. Therefore, P-gp inhibition is considered as an effective strategy to reverse MDR. A third-generation P-gp inhibitor tariquidar was selected as a lead compound, and a new series of triazol-N-ethyl tetrahydroisoquinoline based compounds were designed as novel P-gp inhibitors and synthesized through click chemistry. These compounds presented higher reversal activities than the positive-control verapamil (VRP). Among 18 compounds, compound 11 without cytotoxicity reversed MDR in a dose-dependent manner, with a persistent longer chemosensitizing effect and reversibility compared to others. Mechanism studies discovered that compound 11 could escalate the intracellular accumulation of rhodamine-123 and doxorubicin in K562/A02 cells as well as inhibit their efflux from cells. The results obtained suggest that compound 11 is more potent than VRP administered under the same conditions; it may be a potent and safe candidate for P-gp modulation for further development.
- Qiu, Qianqian,Shi, Wei,Zhao, Shiyuan,Zhu, Yan,Ding, Zhengquan,Zhou, Shaoyang,Kairuki, Mutta,Huang, Wenlong,Qian, Hai
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- Triazole-N-tetrahydroisoquinoline compounds as well as preparation method and application thereof
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The invention relates to compounds shown in a general formula (I) and salt thereof. The compounds have stronger functions of reversing multiple drug resistance (MDR) of tumor, the activity of a part of the compounds is much higher than that of verapamil, and the compounds have lower cell toxicity. The invention also relates to a preparation method of the compounds and a pharmaceutical preparationcontaining the compounds. According to the compounds as well as the preparation and application thereof disclosed by the invention, a series of compounds shown in the general formula (1) and the pharmaceutically acceptable salt are synthesized. The formula (1) is shown in the description.
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Paragraph 0109; 0110; 0111
(2018/03/26)
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- Design, synthesis and biological evaluation of novel tetrahydroisoquinoline derivatives as P-glycoprotein-mediated multidrug resistance inhibitors
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Multidrug resistance (MDR) is one of the main obstacles of clinical chemotherapy. A great deal of research shows that the occurrence of drug resistance in various malignant tumors is closely related to the expression of P-glycoprotein (P-gp) on the surface of the cell membrane. In this paper, based on the structure-activity relationship of phenylethyl tetrahydroisoquinoline, we choose tariquidar as the lead compound for the design and synthesis of 17 novel tetrahydroisoquinoline P-gp inhibitors. Additionally, in vitro and in vivo cytotoxicity assays and reversed MDR activity assays were evaluated. Among them, compound 3 had a good reversal of MDR activity and the reversal mechanism study of it was carried out. All of these results demonstrated that compound 3 was considered to be a promising P-gp-mediated MDR reversal candidate.
- Gao, Yang,Shi, Wei,Cui, Jian,Liu, Chunxia,Bi, Xinzhou,Li, Zhuo,Huang, Wenlong,Wang, Guangji,Qian, Hai
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supporting information
p. 2420 - 2427
(2018/04/10)
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- PROCESS FOR THE PREPARATION OF SUBSTITUTED-1,2,3,4-TETRAHYDROISOQUINOLINE DERIVATIVES
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The present invention is directed to a process for the synthesis of substituted-1,2,3,4-tetrahydroisoquinoline derivatives, useful as intermediates in the synthesis of pharmaceutical agents.
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Page/Page column 10-11
(2008/06/13)
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