Design and synthesis of novel protease inhibitors. Tripeptide α′,ß′-epoxyketones as nanomolar inactivators of the proteasome

Tetrahedron Letters

Volumn 37, Issue 9, 1996, Pages 1343-1346

  Spaltenstein, Andrew ^a   Leban, Johann J ^a   Huang, Jim J ^a   Reinhardt, Kelli R ^a   Viveros, O Humberto ^a   Sigafoos, Jim ^a   Crouch, Ronald ^a  

^a Burroughs Wellcome Co   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

SUIDAE;

BW 2428; PROTEASOME; TRIPEPTIDE DERIVATIVE; UNCLASSIFIED DRUG;

ANIMAL CELL; ARTICLE; CHIRALITY; CONTROLLED STUDY; DRUG DESIGN; DRUG STRUCTURE; DRUG SYNTHESIS; ENDOTHELIUM CELL; ENZYME INHIBITION; MOLECULAR DYNAMICS; NONHUMAN; NUCLEAR MAGNETIC RESONANCE; STEREOCHEMISTRY; SWINE;

EID: 0030012069     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/0040-4039(96)00018-4     Document Type: Article

References (24)

1. a. Löwe, J.; Stock, D.; Jap, B; Zwickl, P.; Baumeister, W.; Huber, R. Science 1995, 268, 533.
2. b. Seemüller, E.; Lupas, A.; Stock, D.; Löwe, J.; Huber, R.; Baumeister, W. Science 1995, 268, 579.
3. Palombella, V.J.; Rando, O.J.; Goldberg, A.L.; Maniatis, T. Cell 1994, 78, 773.
4. a. Treier, M.; Stoszewski, L.M.; Bohmann, D. Cell 1994, 78, 787.
5. b. Scheffner, M.; Werness, B.A.; Huibregtsen, J.M., Levine, A.J.; Howley, P.M. Cell 1990, 63, 1129.
6. 9Natl. Prod. Rep. 1988,. 5, 465.
7. Delbaere, L.T.J.; Brayer, G.D. J. Mol. Biol. 1985, 183, 89.
8. Betzel, C.; Pal, G.P.; Jany, K.-D.; Saenger, W. FEBS Lett. 1986, 197, 105.
9. Gelb, M.H.; Svaren, J.P.,; Abeles, R.H. Biochemistry 1985, 24, 1813.
10. a. Angelastro, M.R.; Mehdi, S.; Burkhart, J.P.; Peet, N.P.; Bey, P. J. Med. Chem. 1990, 33 , 11.
11. b. Hu, L.-Y.; Abeles, R.H. Arch. Biochem. Biophys. 1990, 281, 271.
12. Spaltenstein, A.; Leban, J.J.; Sherman, D.B.; Viveros, H.O.; Sigafoos, J., in preparation.
13. all compounds gave NMR, and high-or low resolution MS data consistent with the proposed structures as well as satisfactory combustion analyses.
14. Abbreviations are: EDCI (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, NMM (N-methyl morpholine, DCC (dicyclohexyl carbodiimide), TFA (trifluoroacetic acid), mCPBA (m-chloroperbenzoic acid), HOBT (N-hydroxybenzotriazole), Cbz (benzyloxycarbonyl), Ile (L-isoleucine), Boc (tert.-butoxycarbonyl).
15. 1H NMR(DMSO-d6): 2a 1.22(9H,s), 2.58(1H,d), 3.5(1H,m), 3.86(1H,dd), 5.03(2H,dd), 5.20(1H,d), 5.85(1H,dddd), 6.59(1H,d), 7.2(5H,m). 2b1.22(9H,s), 2.52(1H,d), 2.78(1H,dd), 3.62(1H,m), 3.92(1H,dd), 5.00(1H,d), 5.05(1H,d), 5.20(1H,d), 5.82(1H,dddd), 6.42(H,d), 7.2(5H,m). 3a 0.7-0.9(12H,m) 1.10(2H,m), 1.40(2H,m), 1.70(2H,m), 2.70(1H,dd), 2.95(1H,dd), 3.95(3H,m), 4.22(1H,t), 5.08(2H,s), 5.12(1H,d), 5.28(1H,d), 5.96(1H,dddd), 7.2-7.4(10H,m), 7.45(1H,d), 7.75(1H,d), 7.82(1H,d). 3b 0.6-0.8(12H,m), 1.00(2H,m), 1.30(2H,m), 1.65(2H,m), 2.50(1H,dd), 2.83(1H,dd), 3.90(1H,t), 3.99(2H,m), 4.18(1H,t), 5.00(2H,s), 5.02(1H,d), 5.18(2H,dd), 5.83(1H,dddd), 7.1-7.4(11H,m), 7.65(2H,m). 4a 0.65-0.85(12H,s), 1.0(1H,m), 1.18(1H,m), 1.35(1H,m), 1.45(1H,m), 1.65(1H,m), 1.78(1H,m), 2.64(2H,m), 2.76(1H,dd), 2.95(1H,m), 3.01(1H,dd), 3.13(1H,dd), 3.97(1H,t), 4.08(1H,dd), 4.18(1H,t), 5.08(2H,s), 7.2-7.4(10H,m), 7.45(1H,d), 7.71(1H,d), 7.83(1H,d). 4b 0.6-0.8(12H,m), 1.05(2H,m), 1.35(2H,m), 1.65(2H,m), 2.45(1H,dd), 2.62(2H,m), 2.82(2H,m), 3.05(1H,m), 3.85(1H,t), 4.04(1H,m), 4.18(1H,t), 4.99(2H),s), 5.38(1H,d), 7.1-7.4(11H,m), 7.72(1H,d), 7.80(1H,d). 5a 0.80(12H,m), 1.15(2H,m), 1.35(2H,m), 1.65(2H,m), 2.50(1H,dd), 2.80(2H,m), 3.05(1H,dd), 3.66(1H,m,α′-H), 3.93(1H,t), 4.20(1H,t), 4.65(1H,m), 5.00(2H,s), 7.2-7.4(10H,m), 8.15(1H,d), 8.55(1H,d). 5b 0.78(12H,m), 1.05(2H,m), 1.35(2H,m), 1.65(2H,m), 2.79(2H,m), 2.98(2H,m), 3.62(1H,mα′-H), 3.85(1H,t), 4.18(1H,t), 4.58(1H,m), 5.00(2H,s), 7.2-7.4(10H,m), 7.68(1H,d), 8.44(1H,d).
16. Nahm, S.; Weinreb, S.M. Tetrahedron Lett. 1981,22, 3815.
17. Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226.
18. (equation presented) 15. Prepared from commercially available Cbz-IleIle by treatment with DCC / N-hydroxysuccinimide in EtOAc.
19. Albright, J.D.; Goldman, L. J. Am. Chem. Soc. 1965,87, 4214.
20. Romeo, S.; Rich, D.H. Tetrahedron Lett. 1993, 34, 7187.
21. Bothner-By, A.B. Adv. Magn. Res. 1965, 1, 195. For a more detailed discussion of cyclic five-membered carbonates see: Anet, F.A.L. J. Am. Chem. Soc. 1962, 84, 747.
22. Bothner-By, A.B. Adv. Magn. Res. 1965, 1, 195. For a more detailed discussion of cyclic five-membered carbonates see: Anet, F.A.L. J. Am. Chem. Soc. 1962, 84, 747.
23. We are currently attempting to obtain X-ray quality crystals of 4 and/or 7 to further substantiate the C-2 stereochemical assignment.
24. Fluorescence-based assay (Z-IIW-AMC substrate), the proteasome was purified from pig aorta endothelial cells. The enzyme was pre-incubated with the inhibitor for 1 hour before the reaction was initiated by addition of the substrate.