Ecteinascidin 743 CH3 0 HO CH H3C H3C. 1969 Found Activity 1990 Structure Deter In Illinois Uni. 0 1996 Total Syn. H HO In Harvard Uni.Corey Et743对晚期软组织癌症如直肠癌，乳腺癌，肺癌，黑色素瘤等有显 著的疗效。Eur&USAI&II（European Medicines Agency) In Europe Used to soft-tissue sarcoma by Sep.2007.ET-743 represents the first active agent against sarcomas developed in the past 25 years and has demonstrated a therapeutic potential in pretreated ovarian cancer
Ecteinascidin 743 • Et 743 对晚期软组织癌症如直肠癌，乳腺癌，肺癌，黑色素瘤等有显 著的疗效。Eur & USA II & III （ European Medicines Agency ） • In Europe Used to soft-tissue sarcoma (肉瘤) by Sep. 2007. ET-743 represents the first active agent against sarcomas developed in the past 25 years and has demonstrated a therapeutic potential in pretreated ovarian cancer. 1969 Found Activity 1990 Structure Deter In Illinois Uni. 1996 Total Syn. In Harvard Uni. Corey N NH N S O O H3C O O H3C H H OH HO CH3 O O O HO O H3C H3C CH3 H
HO OMe MeO 0 Me AcO Kenneth L.Rinehart教授 Me 1929-2005 伊利诺州立大学 HN OMe HO Me ET743(2) R=CHa.X=OH AcO ET729(1) R=H,X=OH ET745(3) R=CH3.X=H Me ET 745B R=H,X=OH,S-oxide ET759A(4) R=CH3,X==O(lactam) ET759B(5) R=CH3.X=OH,S-oxide ET786 R=CHa.X=CN,S-oxide N12-oxide ET 743(7)R=CH3.O,X=OH ET722 R=H.X=OH ET770(6) R=CH3.X=CN ET 736(53)R=CH3,X=OH N12-formyl ET 729(8)R=CHO,X=OH ET738 R=CHa.X=H ET808 R=CH3,X=CH(CHO)2 ET815 R=CH3,X=CH(CHO)2 ET752 R=CHa,X=OH,S-oxide ET731 R=X=H Ecteinascidinsdidemnins (YondelisTMAplidineTM)
1929-2005 Ecteinascidins与didemnins (YondelisTM与AplidineTM) 伊利诺州立大学
Semi-Synthesis of Et-743 PharmaMar chemists performed an elegant semisynthesis from the marine Pseudomonas fluorescens metabolite cyanosafracin B.This was feasible despite a low overall yield of 1.4%because the starting material could be obtained on a large scale (in Kg-scale)by fermentation. CH3 CH3 HO CH3 H3C. CH 1.4% H 14-21-step 0 0 NH2 荧光假单胞菌 HO Cyanosafracin B 氰基番红菌素 PharmaMar研发部主任
Semi-Synthesis of Et-743 • PharmaMar chemists performed an elegant semisynthesis from the marine Pseudomonas fluorescens metabolite cyanosafracin B. This was feasible despite a low overall yield of 1.4% because the starting material could be obtained on a large scale (in Kg-scale) by fermentation. Cyanosafracin B 1.4% 14-21-step N NH N S O O H3C O O H3C H H OH HO CH3 O O O HO O H3C CH3 CH3 H N N NH O O H3C H H CN HO CH3 O H3CO O CH3 CH3 H NH2 氰基番红菌素 荧光假单胞菌 PharmaMar研发部主任
O-CHg E.James Corey O-CHg Cyanosafracin B HO HO CH3 海鞘 CH- 18-21 steps 1% HO David Y.Gin Yondelis(Et-743) C.Cuevas 荧光假单胞菌 曲贝替定 Rinehart K L Trabectedin(曲贝替定，商品名Yondelis)治疗晚期软组织肉瘤(advanced soft tissue sarcoma),2007年EMEA批准其在欧洲首次上市。 E.J.Corey小组于1996年完成了全合成，路线包括40多步，总收率0.72%。 1999年C.Cuevas开始利用荧光假单胞菌(Pseudomonas fluorescens)的生物发酵 过程生产抗生素safracin B,如果在发酵结束时加入氯化钾可以解决该反应的不稳 定性，并能得到更稳定的cyanosafracin B分子，并对Coreyt的合成步骤进行改进， 在2001年底实现了工业化
N NH N S O O H3C O O H3C H H OH HO CH3 O O O HO O H3C CH3 CH3 H N N NH O O H3C H H CN HO CH3 O H3CO O CH3 CH3 H NH2 18-21 steps Cyanosafracin B Yondelis (Et-743) 1% Trabectedin（曲贝替定，商品名Yondelis）治疗晚期软组织肉瘤(advanced soft tissue sarcoma)，2007年EMEA批准其在欧洲首次上市。 E. J. Corey小组于1996年完成了全合成，路线包括40多步，总收率0.72%。 1999年C. Cuevas开始利用荧光假单胞菌（Pseudomonas fluorescens）的生物发酵 过程生产抗生素safracin B, 如果在发酵结束时加入氰化钾可以解决该反应的不稳 定性，并能得到更稳定的cyanosafracin B分子，并对Corey的合成步骤进行改进， 在2001年底实现了工业化。 C. Cuevas 荧光假单胞菌 Rinehart K L 海鞘 曲贝替定 E. James Corey David Y. Gin
Halichondramide OMe OMe Me OMe O D.John Faulkner 含恶唑环的大环内酯 Halichondria sp (1942-2002) Halichondramide was a 25-membered macrolide,which accommodates an unusual system of three contiguous oxazole rings in the macrocyclic ring was isolated from sponge Halichondria sp Kernan,M.R.;Faulkner,D.J.Halichondramide,an antifungal macrolide from the sponge Halichondria sp.Tetrahedron Lett.1987,28,2809-2812
Halichondramide Halichondramide was a 25-membered macrolide, which accommodates an unusual system of three contiguous oxazole rings in the macrocyclic ring was isolated from sponge Halichondria sp Kernan, M. R.; Faulkner, D. J. Halichondramide, an antifungal macrolide from the sponge Halichondria sp. Tetrahedron Lett. 1987, 28, 2809-2812. N H O OMe O OMe Me O O N O N O N O HO O OMe 19 1 4 5 D. John Faulkner (1942–2002) Halichondria sp