科学研究 | 廖学斌 博士

廖学斌博士

研究员、博士生导师

1995年毕业于北京大学化学与分子工程学院,1998-2004年期间在威斯康星大学密尔沃基分校(University of Wisconsin-Milwaukee)获得有机化学博士学位;2005-2008年期间随世界著名化学家 John F. Hartwig先后在耶鲁大学以及伊利诺伊大学香槟分校从事博士后研究;2009年至2012年在诺华功能基因组研究院(GNF)以高级研究员(PI)的身份开展药学研究。2012年9月正式加入清华大学药学系,任教授、博士导师。2013-2015年获得了“Tsinghua-Janssen Investigator”awards。


研究方向

以天然产物为导向的全合成及方法学研究, 并利用新的方法学建立与此天然产物相关的化合物库,然后以其为基础筛选先导化合物研究蛋白质-蛋白质的相互作用, 最终希望发现全新的影响蛋白质-蛋白质相互作用的调整剂(modulator)以用于特定疾病的治疗剂;(2)基于先天免疫系统发展新的免疫疗法,主要包括癌症免疫疗法和针对自身性免疫病的小分子调节剂的发现。一部分工作包括发展作用于各种TLRs的新型小分子配体工具库,然后利用工具小分子研究Toll样受体对先天免疫系统的各种调控机制以及如何影响获得性免疫系统;(3)利用新的蛋白结构理性设计小分子抑制剂。

科学贡献

廖学斌实验室利用药物化学、各种筛选技术和结构生物学等手段理性设计工具小分子化合物研究先天免疫系统。例如:利用蛋白结构信息及新的筛选体系,课题组发现了新的TLR7和8的小分子激动剂以及TLR7小分子拮抗剂;并利用新的TLR7小分子激动剂开展了与PD-1抗体的癌症免疫组合治疗,不仅验证了“协同机制”,还发现了与PD-1抗体治疗效果密切相关的基因;另外,课题组基于新的蛋白结构信息,理性设计了造血祖蛋白激酶的小分子抑制剂,此抑制剂在癌症免疫治疗中极具前景;课题组还利用KMO的相关结构开展了小分子抑制剂的研究,这类小分子抑制剂将可能被用于对老年痴呆症和急性胰腺炎的治疗。

研究成果

1.以本课题组发展的新型反应为基础,完成了几种不同活性天然产物的全合成。同时利用不同金属催化剂,发展了在芳香环中引入氘代甲基以及含氟基团等几类不同偶联反应。



 

2.基于靶点的结构信息,我们设计了几类小分子免疫调节剂,其中包括:TLR2、TLR7和TLR8的小分子激动剂。基于激酶HPK1,我们发现了其激酶抑制剂,因为此激酶负调控T、B细胞的激活,所以此类抑制剂在癌症免疫治疗中具有重要价值。

荣誉和奖项

清华大学-杨森研究员(Janssen-Tsinghua Investigator)(2013-2015)

论文发表
 

1.“Nickel-catalyzed Methylation of Aryl Halides with Deuterated Methyl Iodide”Hu, L.; Liu, X. Liao, X.* Angew. Chem., Int. Ed. 2016 DOI: 10.1002/anie.201604406R2(*corresponding  author)
2.“Access to the Pyrroloindoline Core via [3 + 2] Annulation as well as the Application in the Synthetic Approach to (±)​-​Minfiensine ”Ji, W.; Yao, L.; Liao, X. * Org. Lett. 2016, 18, 628.(*corresponding  author)
3.“Enantioselective and Diastereoselective Azo-coupling/Iminium-Cyclization: A Unified Strategy for the Total Synthesis of (-)-Psychotriasine and (+)-Pestalazine B ”Li, Q.; Xia, T.; Yao, L.; Deng, H.*; Liao, X. * Chem. Sci. 2015, 6, 3599.(*corresponding  author)
4.“Fluorescent Probes for the Detection of Hydrogen Peroxidein Biological Systems”Liu, Y.*, Liao,X.* Curr. Org. Chem. 2013, 17, 654.(*corresponding author)
5.“Stereospecific Approach to the Synthesis of Ring‑A Oxygenated Sarpagine Indole Alkaloids. Total Synthesis of the Dimeric Indole Alkaloid P‑(+)-Dispegatrine and Six Other Monomeric Indole Alkaloids”  Edwankar, C. R.; Edwankar, R. V.; Namjoshi, O. A.; Liao, X.; Cook, J. M. J. Org. Chem. 2013, 78, 6471.
6.“2‑Bromopalmitate Analogues as Activity-Based Probes To Explore Palmitoyl Acyltransferases” Zheng, B.; DeRan, M.; Li, X.; Liao, X.; Fukata, M.; Wu, X. J. Am. Chem. Soc. 2013, 135, 7082.
7. “Enantioselective Total Syntheses of (–)-Taiwaniaquinone H and (–)-Taiwaniaquinol B by Iridium-Catalyzed Borylation and Palladium-Catalyzed Asymmetric α-Arylation” Liao, X.; Stanley, L. M.; Hartwig, J. F.; J. Am. Chem. Soc.2011, 133, 2088.
8.“ Small Molecule Antagonists in Distinct Binding Modes Inhibit Drug Resistant Mutant of Smoothened” Tao, H.; Jin, Q.; Koo, D.; Liao, X.; Englund, N. P.; Wang, Y.; Ramamurthy, A.; Schultz, P. G.; Dorsch, M.; Kelleher, J.; Wu, X. Chem. Biol. 2011, 18, 432.
9.“Cyanation of Arenes via Iridium-catalyzed Borylation” Liske, C. W.; Liao, X.; Hartwig, J. F.; J. Am. Chem. Soc. 2010, 132, 11389.
10.“Enantioselective a-Arylation of Ketones with Aryl Triflates Catalyzed by Difluorphos Complexes of Palladium and Nickel” Liao, X.; Weng, Z.; Hartwig, J. F.; J. Am. Chem. Soc. 2008, 130, 195.(published and highlighted in SYNFACTS issue 04/08)
11.“General Approach to the Total Synthesis of 9-Methoxy-Substituted Indole Alkaloids: Synthesis of Mitragynine, as well as 9-Methoxygeissoschizol and 9-Methoxy-Nb-methylgeissoschizol” Ma, J.; Yin, W.; Zhou, H.; Liao, X; Cook, J. M. J. Org. Chem.  2009, 74, 264.
12.“Synthesis and structure-activity relationship studies on tryprostatin A, an inhibitor of breast cancer resistance protein” Jain, H. D.; Zhang, C.; Zhou, S.; Zhou, H.; Ma, J.; Liu, X.; Liao, X.; Deveau, A. M.; Dieckhaus, C. M.; Johnson, M. A.; Smith, K. S.; Macdonald, T. L.; Kakeya, H.; Osada, H.; Cook, J. M. Bioorg. Med. Chem. 2008, 16, 4626.
13.“meta-Halogenation of 1,3-Disubstituted Arenes via Iridium-catalyzed Arene Borylation” Murphy, J. M.; Liao, X.; Hartwig, J. F.; J. Am. Chem. Soc. 2007, 129, 15434.
14.“Palladium-Catalyzed α-Arylation of Trimethylsilyl Enol Ethers with Aryl Bromides and Chlorides: The Synergistic Effect of Two Metal Fluorides as Additives” Su, W; Raders, S; Verkade, J. G.;*,†Liao, X.;  and Hartwig, J. F.*,‡ Angew. Chem., Int. Ed. 2006, 45, 5852. a VIP paper and highlighted at the cover. (two group’s work)
15.“A Cascade Approach Toward the Core Structure of Neosarpagine” Liao, X.; Huang, S.; Zhou, H.; Parrish, D.; Cook, J. M. Org Lett. 2007, 9, 1469.
16. Improved Total Synthesis of (+)-Macroline and Alstonerine as well as the Formal Total Synthesis of (-)-Talcarpine and (-)-Anhydromacrosalhine-methine” Liao, X.; Zhou, H.; Cook, J. M.; J. Org. Chem.  2006, 71, 8884. (most-accessed articles: October-December, 2006)
17.eral Approach for the Synthesis of 12-Methoxy-Substituted Sarpagine Indole Alkaloids Including (-)-12-Methoxy-Nb-methylvoachalotine, (+)-12-Methoxy-Na-methylvellosimine, (+)-12-Methoxyaffinisine, and (-)-Fuchsiaefoline” Zhou, H.; Liao, X.; Yin, W.; Ma, J.; Cook, J. M. J. Org. Chem. 2006, 71, 251.
18. First Regiospecific, Enantiospecific Total Synthesis of 6-Oxoalstophylline and an Improved Total Synthesis of Alstonerine and Alstophylline as well as the Bisindole Alkaloid Macralstonine” Liao, X.; Zhou, H.; Wearing, X.; Ma, J.; Cook, J. M. Org. Lett. 2005,7, 3501.
19.irst Regiospecific, Enantiospecific Total Synthesis of Gardnerine and Gardnutine” Zhou, H.; Han, D.; Liao, X.; Cook, J. M.; Tetrahedron Lett. 2005, 46, 4219.
20.giospecific, Enantiospecific Total Synthesis of the 12-Alkoxy-Substituted Sarpagine Alkaloids, (+)-12-Methoxy-Na-methylvellosimine, (+)-12-Methoxyaffinisine and (-)-Fuchsiaefoline” Zhou, H.; Liao, X.; Cook, J. M. Org. Lett. 2004, 6, 249.
21.neral Approach for the Synthesis of Sarpagine Indole Alkaloids. Enantiospecific Total Synthesis of (+)-Vellosimine, (+)-Normacusine B, (-)-Alkaloid Q3, (-)-Panarine, (+)-Na-Methylvellosimine, and (+)-Na-Methyl-16-epipericyclivine” Yu, J.; Wang, T.; Liu, X.; Deschamps, J.; Flippen-Anderson, J.; Liao, X.; Cook, J. M. J. Org. Chem. 2003, 68, 7565. (highlighted at the cover)
22.e Enantiospecific, Stereospecific Total Synthesis of the Ring-A Oxygenated Sarpagine Indole Alkaloids (+)-Majvinine, (+)-10-Methoxyaffinisine, and (+)-Na-Methylsarpagine, as well as the Total Synthesis of the Alstonia Bisindole Alkaloid Macralstonidine”  Zhao, S.; Liao, X.; Wang, T.; Flippen-Anderson, J.; Cook, J. M. J. Org. Chem. 2003, 68, 6279
23.antiospecific Total Synthesis of the Enantiomer of the Indole Alkaloid Intermediate Macroline” Liu, X.; Zhang, C.; Liao, X; Cook, J. M. Tetrahedron Lett. 2002, 43, 7373.
24.ereospecific, Enantiospecific Total Synthesis of the Sarpagine Indole Alkaloids (E)16-Epiaffinisine, (E)16-Epinormacusine B, and Dehydro-16-epiaffinisine” Yu, J.; Liao, X.; Cook, J. M. Org. Lett. 2002, 4, 4681.
25.antiospecific, Stereospecific Total Synthesis of (+)-Majvinine, (+)-10-Methoxyaffinisine, and (+)-Na-Methylsarpagine as well as the Total Synthesis of the Alstonia Bisindole Macralstonidine” Zhao, S.; Liao, X.; Cook, J. M. Org. Lett. 2002, 4, 687.