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Angiogenesis Synthetic Emphasis on Fumagillin Keith Korthals Literature Presentation July 1 2004 Rodeschini V Boiteau J G Van de Weghe P Tarnus C Eustache J Journal of Organic Chemistry 2004 69 2 357 373 Picoul W Bedel O Haudrechy A Langlois Y Pure Appl Chem 2003 75 2 3 235 249 Vosburg D A Weiler S Sorensen E J Angewandte Chemie International Edition 1999 38 7 971 974 Ingber D Fujita T Kishimoto S Sudo K Kanamaru T Brem H Folkman J Nature 1990 348 6301 555 7 Corey E J Snider B B Journal of the American Chemical Society 1972 94 7 2549 Overview Story of Angiogenesis First Total Synthesis Fumagillin 1972 Recent Total Synthesis 1999 Synthesis of Analogs 2004 IC50 of the Analogs What is Angiogenesis Simply this is the process of new blood vessel growth It is important in fetal development cancer diabetic retinopathy Current State of Drug Developement The first angiogenesis stimulating medicine is a prescription gel called Regranex Ortho McNeil Pharmaceuticals that became FDA approved to heal diabetic foot ulcers in December 1997 Currently no FDA approved angiogenesis inhibitor Many current clinical trials 60 How was the concept of Angiogenesis Inhibition Discovered Pioneer Work Dr Judah Folkman who when removing cancerous tissue made a simple observation that cancer tumors were hot bloody and full of vessels Attached a living tumor to the cornea In rabbits Within two days blood vessels were observed growing into the cornea to the tumor When the vessels reached the tumor it grew 16 000 times its original size When the tumor was removed the blood vessels went away But what is the mechanism Put your tumor in a blender Start your column Lose some hair turn grey Ten years later you have a compound Luckily it sticks to heparin anticoagant Absorbed onto a matrix slow release pellet when placed on rabbit eyes blood vessels grow in When removed blood vessels die off VEGF Vascular endothelial growth factor A C How to find an Angiogenesis Inhibitor This was Bob Langer s job Step one Kill a few cows 1970 s Take over some space at Harvard Hire an army of postdocs and scape out some bone cartilage Get your column and get a chair because you are going to be there a while As luck would have it a fungus starting growing in a cell culture of capillary cells The cells withered away from this fungus Breaking all the rules Dr Don Ingber cultured them This was Aspergillus fumigatus which secreted fumagillin Analog is in clinical trials TNP 470 Ingber D Fujita T Kishimoto S Sudo K Kanamaru T Brem H Folkman J Nature 1990 348 6301 555 7 McCowen M C Callender M Lawilis J F Science 1951 113 202 Other Compounds Endostatin cleaved product of the carboxyl terminal domain of collagen phase I Angiostatin large protein fragment phase I CH OH 2 Methoxyestradiol phase II completed MeO HO Can be purchased from Aldrich 3 Diabetic Retinopathy Leading cause of blindness Diabetes damages the blood vessels in the retina of the eye Mild Nonproliferative Retinopathy At this earliest stage small areas of balloon like swelling in the retina s tiny blood vessels occur Moderate Nonproliferative Retinopathy As the disease progresses some blood vessels that nourish the retina are blocked Severe Nonproliferative Retinopathy Many more blood vessels are blocked depriving several areas of the retina with their blood supply These areas of the retina send signals to the body to grow new blood vessels for nourishment Diabetic Retinopathy Proliferative Retinopathy At this advanced stage the signals sent by the retina for nourishment trigger the growth of new blood vessels This condition is called proliferative retinopathy These new blood vessels are abnormal and fragile They grow along the retina and along the surface of the clear vitreous gel that fills the inside of the eye These blood vessels do not cause symptoms or vision loss However they have fragile walls If they leak blood vision loss and blindness can result Vision Effects Treatment Methods Laser surgery is currently the only treatment Fumagillin and Analogs Fumagillin first shown to inhibit angiogenesis in 1990 It was known to have anti cancer properties since 1958 First discovered in 1951 Used as an antibiotic Analog TNP 470 is currently in clinical trials for cancer treatment as an angiogenesis inhibitor The binding of this compound to an enzyme MetAP 2 aminopeptidase 2 has an X ray crystal structure Ingber D Fujita T Kishimoto S Sudo K Kanamaru T Brem H Folkman J Nature 1990 348 6301 555 7 Fumagillin and Analogs MetAP 2 removes NH2terminal methionines from proteins This promotes the proliferation of endothelial cells blood vessel cells Human MetAP 2 Liu S P Widom J Kemp C W Crews C M Clardy J Science 1998 282 5392 1324 1327 First Synthesis Ph 3P SeO2 COOCH3 COOCH3 COOCH3 OHC 41 yield 84 yield 1 1 mixture CHO Br reflux K2CO3 HO TMSO Br TMSCl NEt3 Br NaBH4 wet THF COOCH3 90 yield COOCH3 98 yield CHO Br H COOCH3 80 yield Corey E J Snider B B Journal of the American Chemical Society 1972 94 7 2549 First Synthesis TMSO TMSO TMSO Br 1 eq mCPBA CH2Cl2 0 oC COOCH3 Br COOCH3 Br O O H COOCH3 H 9 1 mixture 80 H H 1 TBAF THF 2 NaOMe H H O R H O COOCH3 R COOCH3 R s are the Br and CH2OTMS O O H H 9 1 mixture COOCH3 Corey E J Snider B B Journal of the American Chemical Society 1972 94 7 2549 First Synthesis O O O COOCH3 O H H O COOCH3 OsO4 pyridine COOCH3 9 1 mixture H O HO OH seperate here 9 1 mixture 81 yield O O HO OH O O COOCH3 O MeLi excess MeI H O OMe HO OH COOCH3 COOCH3 Na t amylate HO H H 78 oC 47 yield OH O OH O 1 MsCl NEt3 THF HO O OMe 75 yield H O O OMe H 2 tetrabutylammonium bromide O 95 yield Corey E J Snider B B Journal of the American Chemical Society 1972 94 7 2549 First Synthesis O O H O OMe O O OMe HO MeOH K2CO3 O 3 1 ratio O O OMe H O OMe HO O O Cl O O HO 3 1 ratio seperated by HPLC yield not reported O O H O OMe H 4 H O Cl O O column 4 O OH O OMe H yield not reported Fumagillin Corey E J Snider B B Journal of the American Chemical Society 1972 94 7 2549 Fumagillin Synthesis 96 4 separate Taber D F Christos T E Rheingold A L Guzei I A Journal of the American Chemical Society 1999 121 23 5589 5590 Lemenez P Fargeas V Poisson J Ardisson J Lallemand J Y Pancrazi A Tetrahedron Letters 1994 35 42 7767 7770 Fumagillin Synthesis Aldehyde unstable Only diastereomer Taber D F Christos T E Rheingold A L Guzei I A Journal of the American Chemical Society 1999 121 23 5589 5590 Fumagillin Synthesis Modifications to the structure have been done The epoxides can be removed and the side


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