陈曙辉教授

文章出处: 作者: 发布时间: 2015-02-13 访问次数: 559

 

SHU-HUI CHEN, Ph. D.

Business Address Home Address

WuXi PharmaTech Co., Ltd. 3789 Camino Codorniz

Building 1, 288 FuTe ZhongLu Calabasas, CA 91302

WaiGaoQiao Free Trade Zone USA

Shanghai, 200131, P. R. China Office Phone: 86-21-50463721

 

Major Achievements in Biomedical Research

• Key inventor of 2nd generation paclitaxel (Taxol) analogs for the treatment of various solid

tumors (advanced to Phase II trials)

• Key inventor of 3-AP phosphate prodrugs (a ribonucleotide reductase inhibitor) as antitumor

agents (selected for Phase I trials)

• Key inventor of HCV protease inhibitor Telaprevir (VX-950) for the treatment of HCV

infections (approved by FDA on May 23, 2011)

Patent: US7,820,671B2 (Oct. 26, 2010); PCT Patent Appl. No. 13/955,249 (July 31, 2013)

Educational Background

1990 Ph.D., Organic Chemistry, Yale University

Research Advisor: Professor Samuel Danishefsky

1985 B.Sc., Chemistry, Fudan University, Shanghai, China

Professional Experience

4/2004 – Present Chief Scientific Officer, WuXi PharmaTech

1/1998 – 4/2004 Research Advisor, Eli Lilly and Company

1/1997 - 12/1997 Associate Director of Chemistry, Vion Pharmaceuticals, Inc.

9/1995 - 12/1996 Chemistry Group Leader, Vion Pharmaceuticals, Inc.

4/1994 - 8/1995 Senior Research Investigator I, Bristol-Myers Squibb

2/1992 - 3/1994 Research Investigator II, Bristol-Myers Squibb

9/1990 - 1/1992 Research Investigator I, Bristol-Myers Squibb

9/1986 - 8/1990 Research Assistant, Yale University

Industrial Experience (Bristol-Myers Squibb, Vion Pharmaceuticals, Eli Lilly & Company, and WuXi PharmaTech, Co.)

8/2009 – 9/2011 Design of Novel Agent with Tickcidal Activity for Dogs / Food Animals

8/2008 – 9/2010 Design of Tramadol Analogs for Chronic Pain (Dogs and Cats)

9/2006 – 4/2007 Design of CXCR-2 Chemokine Antagonists

11/2001 – 4/2004 Design of BACE Inhibitors for the treatment of Alzheimer’s Disease

3/2001 - 2/2002 Design of Rhinovirus 3C Protease Inhibitors as Antiviral Agents

8/1999 - 11/2001 Design of HCV Protease NS3/4A Inhibitors as anti-HCV Agents

12/1998 - 7/1999 Design of Inhibitors of Prostate Specific Antigen (Prostate Cancer)

1/1998 - 3/1999 Pseudomycin Prodrugs and Analogs as novel Antifungal Agents

9/1995 - 12/1997 Prodrugs of Ribonucleotide Reductase Inhibitors 3-AP and 3-AMP

9/1995 - 12/1997 Development of beta-L-Fd4C as anti-HBV agent

9/1990 - 8/1995 Second Generation Paclitaxel Analog Program

9/1990 - 6/1992 Design of Novel Phosphate bearing Paclitaxel Prodrugs

Academic Experience (Yale University)

1/1989 - 8/1990 Studies Towards the Total Synthesis of Rapamycin

8/1988 - 12/1988 Total Synthesis of FR900483

7/1987 - 7/1988 Total Synthesis of Tunicamycins

12/1986 - 6/1987 Total Synthesis of KDO

NIH Grant Applications (Vion Pharmaceuticals, Inc.)

1. Principal Investigator of the Phase I grant application (1R43CA/GM72567-01) entitled

“Inhibitors of Ribonucleotide Reductase”.

Status: $100,000. Awarded (July 1996 – Dec. 1996)

2. Principal Investigator of the Phase II grant application (2R44CA72567-02) entitled “Inhibitors of

Ribonucleotide Reductase”.

Status: $750,000. Awarded (Jan. 1997 to Dec. 1998)

Domestic Grant Application

1、国家重点基础研究发展计划(973 计划)

生物活性分子的结构与功能的关系研究

编号:2012CB724500

2、国家重点基础研究发展计划(973 计划)

新药研制过程化学机理子课题——“创新药物的设计与优化研究

编号:2010CB735601

3、科技部重大新药创制科技重大专项综合性新药研究开发技术大平台子课题

先导化合物研究技术平台的建设

编号:2009ZX09301-008-P-08

4、国家高技术产业化示范工程

药物模板及药用化合物库高技术产业化示范工程

编号:发改办高技[2005]1899

5、国家级火炬计划

药物模板及药物化合物库

编号:2005EB020361

6、上海市高新技术产业化2009 年度生物医药产业转化项目

新型母核结构药物模板及药用化合物库研发外包产品

7、上海市浦江人才计划

新型并环及桥环类药物模板的设计与合成

编号:05PJ14314

8、上海市科技兴贸项目

药用化合物库系列产品的研发出口

编号:05DZ07007

9、上海市重点科技攻关项目

新型并环及桥环类药物模板的研究开发

编号:054319915

10、天津市发改委重大高新技术产业化项目

药物模板及药用化合物库高技术产业化示范工程

编号:津发改高技[2007]664

11、天津市科委科技创新专项资金项目

用于新药筛选的药用化合物产业化技术研究

编号:07FDZDSH02200

Publications and Reviews

1. S-Z. Pan, J-Q. Zhang, S-H. Chen, Z. Gao, “Study on the Reaction of Esterification of Salicylic Acid by Ion-Exchange Resin Method,” Huaxue Shijie 1987, 28, 394-397.

2. S.J. Danishefsky*, M.P. DeNinno, S-H. Chen, "Stereoselective Total Synthesis of the Naturally Occuring Enantiomers of N-Acetylneuaraminic Acid and 3-Deoxy-Manno-2-Octulosonic Acid.A New and Stereospecific Approach to Sialo and 3-Deoxy-2-Octulosonic Acid Conjugates," J. Am. Chem. Soc. 1988, 110, 3929.

3. S.J. Danishefsky*, S.L. DeNinno, S-H. Chen, L. Boisvert, M. Barbachyn, "Fully SyntheticStereoselective Routes to the Differentially Protected Subunits of the Tunicamycins," J. Am.Chem. Soc. 1989, 111, 5810.

4. S-H. Chen, S.J. Danishefsky, “New Synthesis of the Novel Immunoactivator FR-900483”Tetrahedron Lett. 1990, 31, 2229.

5. S-H. Chen, R.F. Horvath, J. Joglar, M.J. Fisher, S.J. Danishefsky*, “Application of the Ibuka-Yamamoto Reaction to a Problem of Stereochemical Communication: A Strategy for theStereospecific Synthesis and Stabilization of the Triene Substructure of Rapamycin ThroughSulfone Substitution,” J. Org. Chem. 1991, 56, 5834-45.

6. M.J. Fisher, C.D. Myers, J. Joglar, S-H. Chen, S.J. Danishefsky*,”Synthetic Studies TowardsRapamycin: A Solution to a Problem of Chirality Merger Through Use of the Ireland Reaction,”J. Org. Chem. 1991, 56, 5826-34.

7. S-H. Chen*, C.M. Combs, S.E. Hill, V. Farina, T.W. Doyle, “The Photochemistry of Taxol:Synthesis of a Novel Pentacyclic Taxol Isomer,” Tetrahedron Lett. 1992, 33, 7679.

8. S-H. Chen*, J. Wei, D.M. Vyas, T.W. Doyle, V. Farina, “A Facile Synthesis of 7,10-DideoxyTaxol and 7-epi-10-Deoxy Taxol,” Tetrahedron Lett. 1993, 34, 6845.

9. S-H. Chen*, C. Fairchild, S.W. Mamber, V. Farina, "Taxol Structure-Activity Relationships:

Synthesis and Biological Evaluation of 10-Deoxytaxol," J. Org. Chem. 1993, 58, 2927.

10. S-H. Chen*, S. Huang, J. Wei, V. Farina, "Serendipitous Synthesis of a Cyclopropane-Containing Taxol Analog via Anchimeric Participation of an Unactivated Angular Methyl Group," J. Org. Chem. 1993, 58, 4520.

11. S-H. Chen*, J. Wei, V. Farina, “Taxol Structure-Activity Relationships: Synthesis andBiological Evaluation of 2-Deoxytaxol,” Tetrahedron Lett. 1993, 34, 3205.

12. S-H. Chen*, S. Huang, J. Wei, V. Farina, “The Chemistry of Taxanes: Reaction of Taxol and Baccatin Derivatives with Lewis Acids in Protic and Aprotic Media,” Tetrahedron 1993, 49,2805.

13. S-H. Chen*, S. Huang, J.M. Wei, V. Farina, “Synthesis of 7-Deoxy and 7, 10-Dideoxy TaxolVia Radical Intermediates,” J. Org. Chem. 1993, 58, 5028.

14. S-H. Chen*, S. Huang, V. Farina, “On the Reaction of Taxol with DAST,” Tetrahedron Lett.1994, 35, 41.

15. S-H. Chen*, J. Kant, S.W. Mamber, G.P. Roth, J. Wei, D. Marshall, D.M. Vyas, V. Farina,"Taxol Structure-Activity Relationships: Synthesis and Biological Evaluation of Taxol Analogs Modified at C-7," Bioorg. Med. Chem. Lett. 1994, 4, 2223.

16. S-H. Chen*, J.F. Kadow, V. Farina, C. Fairchild, B.H. Long, "First Syntheses of NovelPaclitaxel Analogs Modified at the C-4 Position," J. Org. Chem. 1994, 59, 6165.

17. S-H. Chen*, V. Farina, J. Wei, B. Long, C. Fairchild, S.W. Mamber, J.F. Kadow, D.M. Vyas,T.W. Doyle, “Structure-Activity Relationships of Taxol: Synthesis and Biological Evaluation of C-2 Taxol Analogs,” Bioorg. Med. Chem. Lett. 1994, 4, 479.

18. J. Kant*, W. O’Keeffe, S-H. Chen, V. Farina, C. Fairchild, K. Johnston, J.F. Kadow, B.H.Long, D.M. Vyas, “A Chemoselective Approach to Functionalized the C-10 Position of 10-Deacetylbaccatin III,” Tetrahedron Lett. 1994, 35, 5543.

19. S-H. Chen*, S. Huang, Q. Gao, J. Golic, V. Farina, “The Chemistry of Taxanes: SkeletalRearrangements of Baccatin Derivatives via Radical Intermediates,” J. Org. Chem. 1994, 59,1475.

20. S-H. Chen*, V. Farina, S. Huang, Q. Gao, J. Golik, T.W. Doyle, "Studies on thePhotochemistry of Taxol," Tetrahedron 1994, 50, 8633.

21. G.P. Roth*, D. Marshall, S-H. Chen, “Reaction of Paclitaxel and 10-Deacetyl Baccatin III with DAST,” Tetrahedron Lett. 1995, 36, 1609.

22. Q. Gao*, J. Wei, S-H. Chen*, “Crystal Structure of 20Debenzoyl-2-Acetoxy Paclitaxel:Conformation of the Paclitaxel Side Chain,” Pharmaceutical Res. 1995, 12, 337.

23. Review S-H. Chen, V. Farina, "Paclitaxel Chemistry and Structure-Activity Relationships" In:TheChemistry and Pharmacology of Paclitaxel and Its Derivatives; V. Farina, Ed; Elsevier,Amsterdam, 1995; p.165-255.

24. Review S-H. Chen, V. Farina, “Paclitaxel Structure-Activity Relationships and Core Skeletal Rearrangements” In: Taxane Anticancer Agent – Basic Science and Current Status; G.I. Georg.;T.T. Chen.; I. Ojima.; D.M. Vyas., Eds; ACS Symposium Series 583, American ChemicalSociety, Washington, D.C., 1995, p. 247-261.

25. S-H. Chen*, C. Fairchild, B.H. Long, “Synthesis and Biological Evaluation of Novel C-4Aziridine-Bearing Paclitaxel Analogs,” J. Med. Chem. 1995, 38, 2263.

26. S-H. Chen*, S. Huang, G.P. Roth, “An Interesting C-Ring Contraction in Paclitaxel,”Tetrahedron Lett. 1995, 36, 8933.

27. S-H. Chen, V. Farina,* “Paclitaxel (Taxol) chemistry and structure-activity relationships” Pharmacochemistry Library 1995, 22, 165.

28. S-H. Chen*, J.M. Wei, B.H. Long, C.A. Fairchild, J. Carboni, S.W. Mamber, W.C. Rose, K. Johnston, A.M. Casazza, J.F. Kadow, V. Farina, D.M. Vyas, T.W. Doyle, "Novel C-4 PaclitaxelAnalogs: Potent Antitumor Agents" Bioorg. Med. Chem. Lett. 1995, 5, 2741.

29. J. Golik*, H.S.L. Wong, S-H. Chen, T.W. Doyle, J. Knipe, W.C. Rose, A.M. Casazza, D.M.Vyas, “Synthesis and Antitumor Evaluation of Paclitaxel Phosphonooxymethyl Ethers: a NovelClass of Water Soluble Paclitaxel Prodrugs,” Bioorg. Med. Chem. Lett. 1996, 6, 1837.

30. S-H. Chen*, J. Knipe, W.C. Rose, J.F. Kadow, “Synthesis and Biological Evaluation of Several C-2’ Carbonate Bearing C-7 Phosphonooxymethyl Ether Containing Water-Soluble TaxolProdrugs,” manuscript approval (BMS) pending

31. S-H. Chen*, V. Farina, D.M. Vyas, T.W. Doyle, B.H. Long, C.A. Fairchild, “Synthesis andBiological Evaluation of C-13 Amide-Linked Paclitaxel Analogs,” J. Org. Chem. 1996, 61,2065.

32. Q. Gao*, S-H. Chen, “An Unprecedented Side Chain Conformation of Paclitaxel: CrystalStructure of 7-Mesylate Paclitaxel,” Tetrahedron Lett. 1996, 37, 3425.

33. S-H. Chen, “First Synthesis of C-4 Methyl Ether Paclitaxel Analogs and the UnexpectedReactivity of 4-Deacetyl-4-Methyl Ether Baccatin III,” Tetrahedron Lett. 1996, 37, 3935.

34. Dischino, D. D.; Chen, S. H.; Golik, J.; Walker, D. W.; Wong, H. S. L. “Synthesis ofmonosodium salt of Carbon-14-labeled paclitaxel 2’-ethyl carbonate-7-phosphonooxymethylether, a potential prodrug of paclitaxel” J. Labeled Compounds and Radiopharmaceuticals 1997,39, 173.

35. S-H. Chen*, M. Xue, S. Huang, B.H. Long, C.A. Fairchild, W.C. Rose, J.F. Kadow, D.M.Vyas, “Structure-Activity Relationships Study at the 3’-N Position of Paclitaxel 1: Synthesisand Biological Evaluation of 3’-(t)-Butylaminocarbonyloxy Paclitaxel Analogs,” Bioorg. Med.Chem. Lett. 1997, 7, 3057.

36. S-H. Chen*, X. Li, J. Li, C. Niu, E. CarMichael, T.W. Doyle, “Stereoselective Syntheses of beta-L-Fd4C and beta-L-FddC,” J. Org. Chem. 1997, 62, 3449.

37. S-H. Chen, “On the Stille Vinylation Reactions with α-Styryltrimethyltin,” Tetrahedron Lett.1997, 38, 4741.

38. X. Li, M. Feng, I. King, E. Carmichael, T.W. Doyle, S-H. Chen,* “Bis-S-Acyl-2-Thioethyl(SATE) Bearing Monophosphate Prodrug of beta-L-Fd4C as Potent Antiviral Agent,” Bioorg.

Med. Chem. Lett. 1998, 8, 57.

39. S-H. Chen,* V. Farina, D.M. Vyas, T.W. Doyle, “Synthesis of Novel Paclitaxel Isomer: C-2-Acetoxy-C-4-Benzoate Paclitaxel ,” Bioorg. Med. Chem. Lett. 1998, 8, 2227.

40. X. Li,* J. Li, C. Niu, S-H. Chen, “Large-Scale Preparation of a-Phenylseleno-r-Lactone, A Key Intermediate for the Synthesis of dd- and d4-Nucleosides,’ manuscript in preparation

41. C. Niu,* J. Li,* T.W. Doyle, S-H. Chen, “A Practical Synthesis of the Potent Anticancer Agent:3-AP,” Tetrahedron 1998, 54, 6311.

42. J. Li,* S-H. Chen*, X. Li, C. Niu, T.W. Doyle, “Highly Efficient Synthesis of a RibonucleotideReductase Inhibitor: 3-AMP,” Tetrahedron 1998, 54, 393.

43. Review S-H. Chen,* T.W. Doyle, J. Li*, C. Niu,* “Highly Efficient Syntheses of Two PotentInhibitors of Ribonucleotide Reductase: 3-AP and 3-AMP,” Recent Res. Devel. In Org. Chem.1998, vol. 2, pp 15-29.

44. M. Kuhhanova, X. Li, S-H. Chen, I. King, T.W. Doyle, W. Prusoff, Y-C. Cheng, “Interactionof beta-L-Fd4C 5’-triphosphate with HIV-1 reverse transcriptase and human DNA polymerases:implication for HIV drug design,” Molecular Pharmacology 1998, 53, 801.

45. J. Li,* X. Luo, Q. Wang, L-M. Zheng, I. King, T.W. Doyle, S-H. Chen,* “Synthesis andBiological Evaluation of a Water Soluble Phosphate Prodrug of 3-AP,” Bioorg. Med. Chem.Lett. 1998, 8, 3159.

46. S-H. Chen,* J. Li, J. Mao, T.W. Doyle, “Design and Synthesis of a Disulfide Prodrug of 3-AP,”manuscript approval (Vion) pending

47. S-H. Chen,* Q. Wang, J. Mao, I. King, G.E. Dutschmann, E.A. Gullen, Y-C. Cheng, T.W.

Doyle, “Synthesis and Biological Evaluation of a Series of 2’-Fluorinated 2’,3’-Dideoxy-2’,3’-

Didehydro-(L)-Nucleosides,” Bioorg. Med. Chem. Lett. 1998, 8, 1589.

48. J. Li,*, V. Karra, T.W. Doyle, S-H. Chen, “Syntheses of Water Soluble Phosphate BearingProdrugs of 3-AP via Curtius Rearrangements,” manuscript in preparation

49. S-H. Chen,* S. Lin, I. King, T. Spinka, G. Dutschmann, E. A. Gullen, Y-C. Cheng, T.W. Doyle,“Synthesis and Comparative Evaluation of Two Antiviral Agents: beta-L-FD4C and beta-DFD4C,”Bioorg. Med. Chem. Lett. 1998, 8, 3245.

50. J. Jamison, S. Levy, X. Sun, D. Zeckner, W. Current, M. Zweifel, M. Rodriguez, W. Turner,and S-H. Chen,* "Synthesis and Antifungal Activity of Pseudomycin Side Chain Analogs: Part1" Bioorg. Med. Chem. Lett. 2000, 10, 2101.

51. S-H. Chen*, X. Sun, R. Boyer, J. Paschal, D. Zeckner, W. Current, M. Zweifel, and M.Rodriguez “Synthesis and Biological Evaluation of Novel Side Chain Beaing PseudomycinAnalogs: Part 2” Bioorg. Med. Chem. Lett. 2000, 10, 2107.

52. Y. Zhang, R. Boyer, X. Sun, J. Paschal, and S-H. Chen* “Serendipitous Synthesis of NovelDehydro- and Dechloro-Pseudomycin B (PSB) Derivatives” Bioorg. Med. Chem. Lett. 2000, 10,775.

53. F. L. Guerhier, C. Pichoud, S. Guerret, M. Chevaller, C. Jamard, O. Hantz, X-Y. Li, S-H. Chen,I. King, C. Trepo, Y-C. Cheng, and F. Zoulim* “Characterization of the Antiviral Effect of2’,3’-Dideoxy-2’,3’-Didehydro-β-L-5-Fluorocytidine in the Duck Hepatitis B Virus InfectionModel” Antimicrob. Agent Chemother. 2000, 44, 111.

54. M. Xue, B. H. Long, C. Fairchild, K. Johnston, W. C. Rose, J. F. Kadow, D. M. Vyas, and S-H.Chen* “SAR Study at the 3’-N Position of Paclitaxel. Part 2: Synthesis and BiologicalEvaluation of 3’-N-Thiourea- and 3’-N-Thiocarbamate-Bearing Paclitaxel Analogs” Bioorg.Med. Chem. Lett. 2000, 10, 1327.

55. Review J. Li, L-M. Zheng, I. King, T. W. Doyle, and S-H. Chen* “Synthesis and AntitumorActivities of Ribonucleotide Reductase Inhibitors: 3-AP and Its Phosphate Bearing Water-Soluble Prodrugs” In Frontiers of Biotechnology & Pharmaceuticals; Zhao, Reiner, Chen Eds.;Science Press, 2000, Vol. 1, pp 314-335.

56. Review S-H. Chen “Synthesis and Evaluation of L-Fd4C and Related Nucleoside Analogs asNovel Antiviral Agents” In Frontiers of Biotechnology & Pharmaceuticals; Huang, Guo,Reiner, Zhao Eds.; Science Press, 2001, Vol. 2, pp 307-328.

57. Y. Zhang, X. Sun, D. Zeckner, R. Sachs, W. L. Current, and S-H. Chen* “8-Amido-Pseudomycin B (PSB) Analogs: Novel Antifungal Agents” Bioorg. Med. Chem. Lett. 2001, 11,123.

58. Y. Zhang, X. Sun, D. Zeckner, R. Sachs, W. L. Current, J. Gidda, M. Rodriguez, andS-H. Chen* “Synthesis and Antifungal Activities of Novel 3-Amido Bearing PseudomycinAnalogs” Bioorg. Med. Chem. Lett. 2001, 11, 903.

59. Review J. Li, L-M. Zheng, I. King, T. W. Doyle, and S-H. Chen* “Synthesis and AntitumorActivities of Potent Inhibitors of Ribonucleotide Reductase: 3-AMP, 3-AP and its Water-Soluble Prodrugs” Current Medicinal Chemistry 2001, 8, 121-133.

60. Review J.F. Kadow, T. Alstadt, S-H. Chen et al. “Some Recent Developments in the Synthesisand SAR of Novel Taxanes,” ACS Symposium (2001), 796, p. 43-58.

61. X. Sun, Y. Zhang, D. Zeckner, W. Current, S-H. Chen* “Synthesis and Evaluation of NovelPseudomycin Side-Chain Analogues: Part 3” Bioorg. Med. Chem. Lett. 2001, 11, 3055.

62. X. Sun, D. Zeckner, W. Current, R. Boyer, C. McMillian, N. Yumibe, and S-H. Chen* “NAcyloxymethyl

carbamate Linked Prodrugs of Pseudomycins as Novel Antifungal Agents”Bioorg. Med. Chem. Lett. 2001, 11, 1875.

63. X. Sun, M. Rodriguez, D. Zeckner, B. Sachs, W. Current, R. Boyer, J. Paschal , C. McMillian,

and S-H. Chen* “Synthesis and Evaluation of Oxo-dioxolenyl Methyl Carbamate Prodrugs of

Pseudomycins” J. Med. Chem. 2001, 44, 2671.

64. X. Sun, D. Zeckner, Y. Zhang, B. Sachs, W. Current, M. Rodriguez, and S-H. Chen*“Prodrugs of 3-Amido Bearing Pseudomycin Analogs: Novel Antifungal Agents” Bioorg. Med.Chem. Lett. 2001, 11, 1881.

65. Review S-H. Chen “Comparative Evaluation of β-L-Fd4C and Related Nucleoside Analogs asPromising Antiviral Agents” Current Medicinal Chemistry 2002, 9, 899-912.

66. Review S-H. Chen*, W. Current, M. Rodriguez, “N-Acyl Prodrugs and 3-Amido PseudomycinAnalogs are Effective and Safe Agents against Systemic Fungal Infections,” In Frontiers ofBiotechnology & Pharmaceuticals; Guo, Chen, Reiner, Zhao Eds.; Science Press, 2002, Vol. 3.243-269.