On the interactivity of complex synthesis and tumor pharmacology in the drug discovery process: Total synthesis and comparative in vivo evaluations of the 15-aza epothilones Journal Article
| Authors: | Stachel, S. J.; Lee, C. B.; Spassova, M.; Chappell, M. D.; Bornmann, W. G.; Danishefsky, S. J.; Chou, T. C.; Guan, Y. |
| Article Title: | On the interactivity of complex synthesis and tumor pharmacology in the drug discovery process: Total synthesis and comparative in vivo evaluations of the 15-aza epothilones |
| Abstract: | The total syntheses of 12,13,15-desoxy-15(S)-aza-epothilone B (aza-dEpoB; dEpoB-lactam) and 12,13,15-desoxy-15(R)-aza-epothilone B (15-epi-aza-dEpoB; 15-epi-dEpoB-lactam) have been accomplished via a highly convergent strategy. We have also successfully oxidized 12,13,15-desoxy-15(S)-aza-epothilone B to aza-epothilone B (aza-EpoB; EpoB-lactam). Aza-epothilone B has been advanced to phase I clinical trials by the Bristol-Myers Squibb group. Our synthesis is efficient and was amenable to the production of significant quantities of these lactams. Using our fully synthetically derived lactams, in vitro and in vivo studies were conducted in comparison with advanced clinical candidates, 12,13-desoxyepothilone B and 12,13-desoxyepothilone F, also derived by total synthesis. |
| Keywords: | controlled study; unclassified drug; human cell; antineoplastic agents; animals; mice; pharmacodynamics; antineoplastic activity; drug potency; drug structure; drug screening assays, antitumor; drug synthesis; mice, nude; tumors; neoplasm transplantation; structure analysis; thiazoles; synthesis (chemical); ixabepilone; epothilones; epothilone b; epothilone derivative; epoxy compounds; spectrum analysis; k562 cells; 12,13 desoxyepothilone b; humans; human; article; convergent strategies; 12,13 desoxyepothilone f; 12,13,15 desoxy 15 azaepothilone b |
| Journal Title: | Journal of Organic Chemistry |
| Volume: | 66 |
| Issue: | 12 |
| ISSN: | 0022-3263 |
| Publisher: | American Chemical Society |
| Date Published: | 2001-06-15 |
| Start Page: | 4369 |
| End Page: | 4378 |
| Language: | English |
| DOI: | 10.1021/jo010275c |
| PUBMED: | 11397179 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Export Date: 21 May 2015 -- Source: Scopus |
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