Designed epothilones: Combinatorial synthesis, tubulin assembly properties, and cytotoxic action against taxol-resistant tumor cells

Angewandte Chemie (International Edition in English)

Volumn 36, Issue 19, 1997, Pages 2097-2103

  Nicolaou, K C ^a,b   Vourloumis, Dionisios ^a,b   Li, Tianhu ^a,b   Pastor, Joaquin ^a,b   Winssinger, Nicolas ^a,b   He, Yun ^a,b   Ninkovic, Sacha ^a,b   Sarabia, Francisco ^a,b   Vallberg, Hans ^a,b   Roschangar, Frank ^a,b   Paul King, N ^a,b   Finlay, M Ray V ^a,b   Giannakakou, Pareskevi ^c   Verdier Pinard, Pascal ^d   Hamel, Ernest ^d  

^a SCRIPPS RESEARCH INSTITUTE   (United States)

^b UNIVERSITY OF CALIFORNIA   (United States)

^c NATIONAL CANCER INSTITUTE   (United States)

^d NATIONAL CANCER INSTITUTE   (United States)

Author keywords

Antitumor agents; Combinatorial chemistry; Epothilones; Microreactors; Structure activity relationships

Indexed keywords

EID: 0030779208     PISSN: 05700833     EISSN: None     Source Type: Journal    
DOI: 10.1002/anie.199720971     Document Type: Article

References (64)

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38. These fragments were synthesized by standard synthetic operations and according to similar known sequences [11·13·15·16].
39. We thank Dr. M. P. Nova of IRORI Quantum Microchemistry, San Diego, CA, for a gift of an AccuTag-100 instrument and SMART Microreactors (MicroKans and MicroTubes). The reported combinatorial chemistry was performed by using MicroKans, while a single MicroTube was utilized to synthesize a set of four epothilones A (i.e. 42, 47, 95, and 100, Table 1). K. C. N. is an advisor of IRORI Quantum Microchemistry.
40. For the development of the olefin metathesis as a ring forming reaction, see: a) W. J. Zuercher, M. Hashimoto, R. H. Grubbs, J. Am. Chem. Soc. 1996, 118, 6634-6640 b) P. R. Schwab, H. Grubbs, J. W. Ziller, ibid. 1996, 118, 100-110 c) R. H. Grubbs, S. J. Miller, G. C. Fu, Acc Chem. Res. 1995, 28, 446-452 and references therein d) J. Tsuji, S. Hashiguchi, Tetrahedron Lett. 1980, 21, 2955-2959; for some earlier pioneering studies on this reaction, see e) T. J. Katz, S. J. Lee, N. Acton, ibid. 1976, 4247-4250 f) T. J. Katz, N. Acton, ibid. 1976, 4241-4254 g) T. J. Katz, J. McGinnis, C. Altus, J. Am. Chem. Soc. 1976, 98 606-608 h) T. J. Katz, Adv. in Organomet. Chem. 1977, 16, 283-317.
41. For the development of the olefin metathesis as a ring forming reaction, see: a) W. J. Zuercher, M. Hashimoto, R. H. Grubbs, J. Am. Chem. Soc. 1996, 118, 6634-6640 b) P. R. Schwab, H. Grubbs, J. W. Ziller, ibid. 1996, 118, 100-110 c) R. H. Grubbs, S. J. Miller, G. C. Fu, Acc Chem. Res. 1995, 28, 446-452 and references therein d) J. Tsuji, S. Hashiguchi, Tetrahedron Lett. 1980, 21, 2955-2959; for some earlier pioneering studies on this reaction, see e) T. J. Katz, S. J. Lee, N. Acton, ibid. 1976, 4247-4250 f) T. J. Katz, N. Acton, ibid. 1976, 4241-4254 g) T. J. Katz, J. McGinnis, C. Altus, J. Am. Chem. Soc. 1976, 98 606-608 h) T. J. Katz, Adv. in Organomet. Chem. 1977, 16, 283-317.
42. For the development of the olefin metathesis as a ring forming reaction, see: a) W. J. Zuercher, M. Hashimoto, R. H. Grubbs, J. Am. Chem. Soc. 1996, 118, 6634-6640 b) P. R. Schwab, H. Grubbs, J. W. Ziller, ibid. 1996, 118, 100-110 c) R. H. Grubbs, S. J. Miller, G. C. Fu, Acc Chem. Res. 1995, 28, 446-452 and references therein d) J. Tsuji, S. Hashiguchi, Tetrahedron Lett. 1980, 21, 2955-2959; for some earlier pioneering studies on this reaction, see e) T. J. Katz, S. J. Lee, N. Acton, ibid. 1976, 4247-4250 f) T. J. Katz, N. Acton, ibid. 1976, 4241-4254 g) T. J. Katz, J. McGinnis, C. Altus, J. Am. Chem. Soc. 1976, 98 606-608 h) T. J. Katz, Adv. in Organomet. Chem. 1977, 16, 283-317.
43. For the development of the olefin metathesis as a ring forming reaction, see: a) W. J. Zuercher, M. Hashimoto, R. H. Grubbs, J. Am. Chem. Soc. 1996, 118, 6634-6640 b) P. R. Schwab, H. Grubbs, J. W. Ziller, ibid. 1996, 118, 100-110 c) R. H. Grubbs, S. J. Miller, G. C. Fu, Acc Chem. Res. 1995, 28, 446-452 and references therein d) J. Tsuji, S. Hashiguchi, Tetrahedron Lett. 1980, 21, 2955-2959; for some earlier pioneering studies on this reaction, see e) T. J. Katz, S. J. Lee, N. Acton, ibid. 1976, 4247-4250 f) T. J. Katz, N. Acton, ibid. 1976, 4241-4254 g) T. J. Katz, J. McGinnis, C. Altus, J. Am. Chem. Soc. 1976, 98 606-608 h) T. J. Katz, Adv. in Organomet. Chem. 1977, 16, 283-317.
44. For the development of the olefin metathesis as a ring forming reaction, see: a) W. J. Zuercher, M. Hashimoto, R. H. Grubbs, J. Am. Chem. Soc. 1996, 118, 6634-6640 b) P. R. Schwab, H. Grubbs, J. W. Ziller, ibid. 1996, 118, 100-110 c) R. H. Grubbs, S. J. Miller, G. C. Fu, Acc Chem. Res. 1995, 28, 446-452 and references therein d) J. Tsuji, S. Hashiguchi, Tetrahedron Lett. 1980, 21, 2955-2959; for some earlier pioneering studies on this reaction, see e) T. J. Katz, S. J. Lee, N. Acton, ibid. 1976, 4247-4250 f) T. J. Katz, N. Acton, ibid. 1976, 4241-4254 g) T. J. Katz, J. McGinnis, C. Altus, J. Am. Chem. Soc. 1976, 98 606-608 h) T. J. Katz, Adv. in Organomet. Chem. 1977, 16, 283-317.
45. For the development of the olefin metathesis as a ring forming reaction, see: a) W. J. Zuercher, M. Hashimoto, R. H. Grubbs, J. Am. Chem. Soc. 1996, 118, 6634-6640 b) P. R. Schwab, H. Grubbs, J. W. Ziller, ibid. 1996, 118, 100-110 c) R. H. Grubbs, S. J. Miller, G. C. Fu, Acc Chem. Res. 1995, 28, 446-452 and references therein d) J. Tsuji, S. Hashiguchi, Tetrahedron Lett. 1980, 21, 2955-2959; for some earlier pioneering studies on this reaction, see e) T. J. Katz, S. J. Lee, N. Acton, ibid. 1976, 4247-4250 f) T. J. Katz, N. Acton, ibid. 1976, 4241-4254 g) T. J. Katz, J. McGinnis, C. Altus, J. Am. Chem. Soc. 1976, 98 606-608 h) T. J. Katz, Adv. in Organomet. Chem. 1977, 16, 283-317.
46. For the development of the olefin metathesis as a ring forming reaction, see: a) W. J. Zuercher, M. Hashimoto, R. H. Grubbs, J. Am. Chem. Soc. 1996, 118, 6634-6640 b) P. R. Schwab, H. Grubbs, J. W. Ziller, ibid. 1996, 118, 100-110 c) R. H. Grubbs, S. J. Miller, G. C. Fu, Acc Chem. Res. 1995, 28, 446-452 and references therein d) J. Tsuji, S. Hashiguchi, Tetrahedron Lett. 1980, 21, 2955-2959; for some earlier pioneering studies on this reaction, see e) T. J. Katz, S. J. Lee, N. Acton, ibid. 1976, 4247-4250 f) T. J. Katz, N. Acton, ibid. 1976, 4241-4254 g) T. J. Katz, J. McGinnis, C. Altus, J. Am. Chem. Soc. 1976, 98 606-608 h) T. J. Katz, Adv. in Organomet. Chem. 1977, 16, 283-317.
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