Synthesis and biological evaluation of novel cryptophycin analogs with modification in the β-alanine region

Bioorganic and Medicinal Chemistry Letters

Volumn 9, Issue 1, 1999, Pages 69-74

  Chuan, Shih ^a,b   Gossett, Lynn S ^a,b   Gruber, Joseph M ^a,b   Sue Grossman, C ^a,b   Andis, Sherri L ^a,b   Schultz, Richard M ^a,b   Worzalla, John F ^a,b   Corbett, Tom H ^a,b   Metz, James T ^a,b  

^a ELI LILLY AND COMPANY   (United States)

^b WAYNE STATE UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIMITOTIC AGENT; CRYPTOPHYCIN 52; CRYPTOPHYCIN DERIVATIVE; PEPTIDE DERIVATIVE; UNCLASSIFIED DRUG;

AMINO ACID SEQUENCE; ARTICLE; COLON CARCINOMA; CYANOBACTERIUM; DRUG ISOLATION; DRUG STRUCTURE; HUMAN; HUMAN CELL; SOLID TUMOR; TREATMENT INDICATION;

AMINO ACID SUBSTITUTION; ANIMALS; ANTINEOPLASTIC AGENTS; BETA-ALANINE; CARCINOMA; COLONIC NEOPLASMS; DEPSIPEPTIDES; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG SCREENING ASSAYS, ANTITUMOR; HUMANS; MICE; MODELS, MOLECULAR; PANCREATIC NEOPLASMS; PEPTIDES, CYCLIC; PROTEIN CONFORMATION; STRUCTURE-ACTIVITY RELATIONSHIP; TUMOR CELLS, CULTURED;

EID: 0032897323     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(98)00682-9     Document Type: Article

References (15)

1. Schwartz, R. E.; Hirsch, C. F.; Sesin, D. F.; Flor, J. E.; Chartrain, M.; Fromcling, R. E.; Harris, G. H.; Salvatore, M. J.; Liesch, J. M.; Yudin, K. J. Ind. Microbiol. 1990, 5, 118.
2. Golakoti, T.; Ohtani, I.; Patterson, G. M. L; Moore, R. E.; Corbett, T. H.; Valeriote, F. A.; Demchik, L. J. Am. Chem. Soc. 1994, 116, 4729.
3. Barrow, R. A.; Hemscheidt, T.; Liang, J., Paik, S.; Moore, R. E.; Tius, M. A. J. Am. Chem. Soc., 1995, 117, 2479.
4. Worzalla, J. F.; Cao, J.; Ehlhardt, W. J.; Harrison, S. D.; Law, K. L.; Martinelli, M. J.; Self, T. D.; Starling, J. J.; Shih, C.; Theobald, K. S.; Toth, J. E.; Zimmermann, J. L.; Corbett, T. H. Proc. Am. Assoc. Cancer Res. 1997, 38, Abstract 1516. Corbett, T.; Valeriote, F.; Simpson, C.; Moore, R.; Tius, M.; Barrow, R.; Hemscheidt, T.; Liang, J.; Paik, S.; Polin, L.; Pugh, S.; Kushner, J.; Harrison, S.; Shih, C.; Martinelli, M. Proc. Am. Assoc. Cancer Res. 1997, 38, Abstract 1515.
5. Worzalla, J. F.; Cao, J.; Ehlhardt, W. J.; Harrison, S. D.; Law, K. L.; Martinelli, M. J.; Self, T. D.; Starling, J. J.; Shih, C.; Theobald, K. S.; Toth, J. E.; Zimmermann, J. L.; Corbett, T. H. Proc. Am. Assoc. Cancer Res. 1997, 38, Abstract 1516. Corbett, T.; Valeriote, F.; Simpson, C.; Moore, R.; Tius, M.; Barrow, R.; Hemscheidt, T.; Liang, J.; Paik, S.; Polin, L.; Pugh, S.; Kushner, J.; Harrison, S.; Shih, C.; Martinelli, M. Proc. Am. Assoc. Cancer Res. 1997, 38, Abstract 1515.
6. Kobayashi, M.; Aoki, S.; Ohyabu, N.; Kurosu, M.; Wang, W.; Kitagawa, I. Tetrahedron Lett. 1994, 35, 7969. Kobayashi, M.; Kurosu, M.; Ohyabu, N.; Wang, W.; Fujii, S.; Kitagawa, I. Chem. Pharm. Butt. 1994, 42, 2196.
7. Kobayashi, M.; Aoki, S.; Ohyabu, N.; Kurosu, M.; Wang, W.; Kitagawa, I. Tetrahedron Lett. 1994, 35, 7969. Kobayashi, M.; Kurosu, M.; Ohyabu, N.; Wang, W.; Fujii, S.; Kitagawa, I. Chem. Pharm. Butt. 1994, 42, 2196.
8. (3R)-3-Butyl-oxycarbonylamino-3-substituted-propionic acids were prepared in two steps: (a) TFA, (b) di-t-butyl-dicarboxylate, NaOH, from the commercially available t-butyl-(3R)-3-substituted-3- aminopropionic acids (Oxford Asymmetry, UK).
9. Compounds 4 and 9 were prepared according to the routes/methods described in ref 3. We are greatly indebted to Dr. Mike Martinelli's group at Chemical Process R&D Division of Lilly Research Laboratories for the supply of these valuable intermediates.
10. The α-epoxides of these new analogs were found significantly less active (10- to 60-fold) than the corresponding β isomers, an observation that is consistent with previous reports.
11. A more detailed description on the preparation of the C-D amide cryptophycin analogs will appear in the future publication: Norman, B.H.; Hemscheidt, T.; Schultz, R.M.; Andis, S.L., J. Org. Chem., 1998, submitted for publication.
12. The antiproliferative activity of the cryptophycin analogs was determined by using a 72h MTT based assay. The GC3 human colon carcinoma cells were kindly supplied by Dr. Janet Houghton of St. Jude Children's Hospital, Memphis, TN.
13. The X-ray structure of Crypto 52 (Martinelli, M., Moher E. and Stephenson G., unpublished result, Lilly Research Laboratories) was used as the basis for molecular modelling effort. The coordinates of Crypto 52 were imported into the Quanta97, all hydrogens were added and atomic charges were assigned using the molecular editor. Initial structures for Crypto 1 and 13a were generated from the X-ray structure of Crypto 52. The C6 (S) methyl and C7 methylene group was removed in each case, respectively, all hydrogens were added, and atomic charges were assigned using the molecular editor. The modified structure was then subjected to 1000 steps of ABNR minimization. The electrostatic potential surfaces of Crypto 1 and 13a were generated and displayed using Quanta. The color mapping for each electrostatic potential surface was "normalized" by assigning blue (electro-negative) and red (electro-positive) to represent the same extreme of the potentials for both molecules (-20.0 and +20.0).
14. Corbett, T.; Valeriote, F.; Lorusso, P.; Polin, L.; Panchapor, C. Int. J. Pharmacognosy. 1995, 33 (Suppl.):102.
15. Golakoti, T.; Ogino, J.; Heltzel, C. E.; Le Husebo, T.; Jensen, C.M.; Larsen, L. K.; Patterson, G. M. L.; Moore, R. E.; Mooberry, S. L.; Corbett T. H.; Valeriote, F. A. J. Am. Chem. Soc. 1995, 117, 12030.