Current Literature Anguinomycins and Deriva2ves: Total Syntheses, Modeling, and Biological Evalua2on of the Inhibi2on of Nucleocytoplasmic Transport liv Eidam, Ulrike Kutay, Karl Gadermann, et al, JACS, ASAP, 2010 Junyan an Dr. Wipf Group Jan. 23, 2010 1 Junyan an @ Wipf Group Page 1 of 14 1/27/2010
' Anguinomycin A: = C 3, ' = C 2 Anguinomycin B: = C 2 5, ' = C 2 Anguinomycin C: = C 3, ' = C 3 Anguinomycin D: = C 2 5, ' = C 3 Isolated from Streptomyces strains IC50 0.15 1.7 nm against normal and transformed rat cells Selec>ve induce apoptosis of p B inac>vated tumor cells, while inducing growth arrest in normal cells Inhibits nucleocytoplasmic transport ayakawa, Y, et al, J. An>biot. 1987, 40, 1349; ayakawa, Y, et al, J. An>biot. 1995, 48, 954 2 Junyan an @ Wipf Group Page 2 of 14 1/27/2010
' C 2 Anguinomycin A: = C 3, ' = C 2 Anguinomycin B: = C 2 5, ' = C 2 Anguinomycin C: = C 3, ' = C 3 Anguinomycin D: = C 2 5, ' = C 3 IC 50 = 0.1-1.7 nm Leptomycin B (LMB) over 1000 pubs C 2 (-)-Kazusamycin A (-)-Callystatin A IC 50 = 10PM C ighly Cytotoxic, Leptofuranin D Structure Similar Polyke>des 3 Junyan an @ Wipf Group Page 3 of 14 1/27/2010
etro Synthesis Negishi coupling Wittig eaction Evans Syn-aldol Jacobson's Cr(III) etero D-A B-alkyl Suzuki-Miyaura Coupling Me Br PPh Br Et 3 Br TES TIPS A B C D E 4 Junyan an @ Wipf Group Page 4 of 14 1/27/2010
Synthesis of C1 C11 Fragment Me Cp 2 ZrCl; ZnCl 2 ; Pd(PPh 3 ) 4, DIBA then b 81 % Me 2.3 mol% a + 4 A MS, r.t. TES 86 % i Pr Br TIPS 96 % ee TES Pd(PPh 3 ) 4, Me 2 Zn or PdCl 2 (dpeps) Et 2 Zn, TF 1. PTSA, i Pr 2. TBAF, TF 84 % i Pr i Pr = Me, 68 % = Et, 84 % TIPS TBAF; PPh 3, imidazole I 2, toluene, ether i Pr = Me, 75 % = Et, 88 % I N Cr Cl a Br Br b TIPS 5 Junyan an @ Wipf Group Page 5 of 14 1/27/2010
Me ighly Enan>o and egioselec>ve Quinone Diels Alder eac>ons Catalyzed by a Tridentate Schiif Base CrIII Complex + Me TES Me 5 mol% a toluene, 0 ºC Me TES DBU, air Me TES Me Me Me Me TES TES TES 96 % ee 12:1 93 % ee > 30:1 97 %ee 25:1 90 % ee 9:1 E. Jacobson, et al, ACIE, 2005, 6043 E. Jacobson, et al, ACIE, 2005, 6047 Me Me Me Me Colombiasin A N Cr Cl a 6 Junyan an @ Wipf Group Page 6 of 14 1/27/2010
i Pr Negishi Coupling with Selec>ve Inversion and eten>on of the Configura>on Br TIPS 5-10 mol% catalyst Et 2 Zn, 0.05-0.1 M i Pr TIPS + i Pr TIPS 7 Junyan an @ Wipf Group Page 7 of 14 1/27/2010
Synthesis of C12 C24 Fragment N Br N 1. LA, Et 2, 0 ºC Ph Ph c LDA, -78 ºC Ph Ph 92 % dr > 97:3 2. xalyl chloride, DMS C 2 Cl 2, then Et 3 N 99 % ent-c, Bu 2 BTf, Et 3 N 77 % Ph Ph N dr > 87:13 1. MeNMe Cl, AlMe3 2. TBSTf, 2,6-lutidine 3. DIBA 86 % TBS PPh 1. ent-c, Bu TBS Et 3 2 BTf,Et 3 N 2. LA, toluene, -17 ºC toluene, 20-35 ºC 99 % 99 % Et dr > 97:3 TBS 1. DIBA, TF, -78 to -10 ºC I TBS 2. Mn 2, C 2 Cl 2 3. CrCl 2, CI 3, TF, 0 ºC 75 % dr > 97:3 8 Junyan an @ Wipf Group Page 8 of 14 1/27/2010
Comple>on of the Synthesis i Pr I 9-Me-9-BBN, tbuli ether, -78 ºC to r.t. i Pr B + I TBS Me = C 3 or C 2 5 5 mol% Pd(dppf)Cl 2 C 2 Cl 2 i Pr 1. PPTS, water, acetone 15 mol% AsPh 3, Cs 2 C 3 2, DMF = C 3, 80% = C 2 5, 48 % TBS 2. = C 3, DMP, then Mn 2 or = C 2 5, PCC 3. F pyridine, pyridine 4.5 d Anguinomycin C 30 % Anguinomycin D 57 % 9 Junyan an @ Wipf Group Page 9 of 14 1/27/2010
i Pr mixture fraction 17 TBS Compounds Generated Using a Mixture of Diastereoisomers at C17 Anguinomycin D (2) 4 44 10 Junyan an @ Wipf Group Page 10 of 14 1/27/2010
Biological Evalua>on as Inhibitor of Nucleocytoplasmic Transport = C3, 1 = C25, 2 44 C2 LMB ela cell and io2 protein 3 4 11 Junyan an @ Wipf Group Page 11 of 14 1/27/2010
Chromosome maintenance region 1 (CM1) and SNUPN Complex A. X-ay structure of the CM1-SNUPN complex B. Close-up view on the N-terminal nuclear export signal (NES) of SNUPN C. ydrophobic residues of SNUPN NES define five pockets in the CM1 groove 12 Junyan an @ Wipf Group Page 12 of 14 1/27/2010
Models of CM1 Inhibitor Complex Sphere models of Leptomycin B adduct (A) and compound 4 adduct (B). C. Superposition of LMB adduct with NES residues of SNUPN. LMB depicted in yellow with hydrogen white. D. Atom numbering of LMB adduct. 13 Junyan an @ Wipf Group Page 13 of 14 1/27/2010
Conclusion Total synthesis of Anguinomycin C (6.7%) and D (6%)were obtained in 18 steps (longest linear sequence). Inhibitors of CM1, shut down protein export at > 10 nm Structure basis for this inhibi>on. Lactone ring and side chain effects. 14 Junyan an @ Wipf Group Page 14 of 14 1/27/2010