Design, synthesis, and biological evaluation of new-generation taxoids

Iwao Ojima, Jin Chen, Liang Sun, Christopher P. Borella, Tao Wang, Michael L. Miller, Songnian Lin, Xudong Geng, Larisa Kuznetsova, Chuanxing Qu, David Gallager, Xianrui Zhao, Ilaria Zanardi, Shujun Xia, Susan Band Horwitz, Jon Mallen-St. Clair, Jennifer L. Guerriero, Dafna Bar-Sagi, Jean M. Veith, Paula PeraRalph J. Bernacki

Research output: Contribution to journalArticle

75 Citations (Scopus)

Abstract

Novel second-generation taxoids with systematic modifications at the C2, C10, and C3′N positions were synthesized and their structure-activity relationships studied. A number of these taxoids exhibited exceptionally high potency against multidrug-resistant cell lines, and several taxoids exhibited virtually no difference in potency against the drug-sensitive and drug-resistant cell lines. These exceptionally potent taxoids were termed "third- generation taxoids". 19 (SB-T-1214), 14i (SB-T-121303), and 14i (SB-T-1213031) exhibited excellent activity against paclitaxel-resistant ovarian cancer cell lines with mutations in β-tubulin as well, wherein the drug resistance is mediated by the β-tubulin mutation. These taxoids were found to possess exceptional activity in promoting tubulin assembly, forming numerous very short microtubules similar to those formed by discodermolide. Taxoids 19 and 14g also showed excellent cytotoxicity against four pancreatic cancer cell lines, expressing three to four multidrug-resistant genes. Moreover, taxoid 19 exhibited excellent in vivo efficacy against highly drug-resistant CFPAC-1 pancreatic as well as DLD-1 human colon tumor xenografts in mice.

Original languageEnglish (US)
Pages (from-to)3203-3221
Number of pages19
JournalJournal of Medicinal Chemistry
Volume51
Issue number11
DOIs
StatePublished - Jun 12 2008

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Taxoids
Tubulin
Cells
Cell Line
Pharmaceutical Preparations
Mutation
Structure-Activity Relationship
Cytotoxicity
Paclitaxel
Pancreatic Neoplasms
Drug Resistance
Heterografts
Microtubules
Ovarian Neoplasms
Tumors
Colon
Genes

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Ojima, I., Chen, J., Sun, L., Borella, C. P., Wang, T., Miller, M. L., ... Bernacki, R. J. (2008). Design, synthesis, and biological evaluation of new-generation taxoids. Journal of Medicinal Chemistry, 51(11), 3203-3221. https://doi.org/10.1021/jm800086e

Design, synthesis, and biological evaluation of new-generation taxoids. / Ojima, Iwao; Chen, Jin; Sun, Liang; Borella, Christopher P.; Wang, Tao; Miller, Michael L.; Lin, Songnian; Geng, Xudong; Kuznetsova, Larisa; Qu, Chuanxing; Gallager, David; Zhao, Xianrui; Zanardi, Ilaria; Xia, Shujun; Band Horwitz, Susan; Mallen-St. Clair, Jon; Guerriero, Jennifer L.; Bar-Sagi, Dafna; Veith, Jean M.; Pera, Paula; Bernacki, Ralph J.

In: Journal of Medicinal Chemistry, Vol. 51, No. 11, 12.06.2008, p. 3203-3221.

Research output: Contribution to journalArticle

Ojima, I, Chen, J, Sun, L, Borella, CP, Wang, T, Miller, ML, Lin, S, Geng, X, Kuznetsova, L, Qu, C, Gallager, D, Zhao, X, Zanardi, I, Xia, S, Band Horwitz, S, Mallen-St. Clair, J, Guerriero, JL, Bar-Sagi, D, Veith, JM, Pera, P & Bernacki, RJ 2008, 'Design, synthesis, and biological evaluation of new-generation taxoids', Journal of Medicinal Chemistry, vol. 51, no. 11, pp. 3203-3221. https://doi.org/10.1021/jm800086e
Ojima I, Chen J, Sun L, Borella CP, Wang T, Miller ML et al. Design, synthesis, and biological evaluation of new-generation taxoids. Journal of Medicinal Chemistry. 2008 Jun 12;51(11):3203-3221. https://doi.org/10.1021/jm800086e
Ojima, Iwao ; Chen, Jin ; Sun, Liang ; Borella, Christopher P. ; Wang, Tao ; Miller, Michael L. ; Lin, Songnian ; Geng, Xudong ; Kuznetsova, Larisa ; Qu, Chuanxing ; Gallager, David ; Zhao, Xianrui ; Zanardi, Ilaria ; Xia, Shujun ; Band Horwitz, Susan ; Mallen-St. Clair, Jon ; Guerriero, Jennifer L. ; Bar-Sagi, Dafna ; Veith, Jean M. ; Pera, Paula ; Bernacki, Ralph J. / Design, synthesis, and biological evaluation of new-generation taxoids. In: Journal of Medicinal Chemistry. 2008 ; Vol. 51, No. 11. pp. 3203-3221.
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