Design, synthesis, and biological evaluation of novel C14-C3′BzN- linked macrocyclic taxoids

Liang Sun, Xudong Geng, Raphaël Geney, Yuan Li, Carlos Simmerling, Zhong Li, Joseph W. Lauher, Shujun Xia, Susan Band Horwitz, Jean M. Veith, Paula Pera, Ralph J. Bernacki, Iwao Ojima

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Abstract

(Figure Presented) Novel macrocyclic paclitaxel congeners were designed to mimic the bioactive conformation of paclitaxel. Computational analysis of the "REDOR-Taxol" structure revealed that this structure could be rigidified by connecting the C14 position of the baccatin moiety and the ortho position of C3′N-benzoyl group (C3′BzN), which are ca. 7.5 Å apart, with a short linker (4-6 atoms). 7-TES-14β-allyloxybaccatin III and (3R,4S)-1-(2-alkenylbenzoyl)-β-lactams were selected as key components, and the Ojima-Holton coupling afforded the corresponding paclitaxel-dienes. The Ru-catalyzed ring-closing metathesis (RCM) of paclitaxel-dienes gave the designed 15- and 16-membered macrocyclic taxoids. However, the RCM reaction to form the designed 14-membered macrocyclic taxoid did not proceed as planned. Instead, the attempted RCM reaction led to the occurrence of an unprecedented novel Ru-catalyzed diene-coupling process, giving the corresponding 15-membered macrocyclic taxoid (SB-T-2054). The biological activities of the novel macrocyclic taxoids were evaluated by tumor cell growth inhibition (i.e., cytotoxicity) and tubulin-polymerization assays. Those assays revealed high sensitivity of cytotoxicity to subtle conformational changes. Among the novel macrocyclic taxoids evaluated, SB-T-2054 is the most active compound, which possesses virtually the same potency as that of paclitaxel. The result may also indicate that SB-T-2054 structure is an excellent mimic of the bioactive conformation of paclitaxel. Computational analysis for the observed structure-activity relationships is also performed and discussed.

Original languageEnglish (US)
Pages (from-to)9584-9593
Number of pages10
JournalJournal of Organic Chemistry
Volume73
Issue number24
DOIs
StatePublished - Dec 19 2008

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Taxoids
Paclitaxel
Cytotoxicity
Conformations
Assays
Lactams
Cell growth
Tubulin
Bioactivity
Tumors
Polymerization
Atoms

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Sun, L., Geng, X., Geney, R., Li, Y., Simmerling, C., Li, Z., ... Ojima, I. (2008). Design, synthesis, and biological evaluation of novel C14-C3′BzN- linked macrocyclic taxoids. Journal of Organic Chemistry, 73(24), 9584-9593. https://doi.org/10.1021/jo801713q

Design, synthesis, and biological evaluation of novel C14-C3′BzN- linked macrocyclic taxoids. / Sun, Liang; Geng, Xudong; Geney, Raphaël; Li, Yuan; Simmerling, Carlos; Li, Zhong; Lauher, Joseph W.; Xia, Shujun; Band Horwitz, Susan; Veith, Jean M.; Pera, Paula; Bernacki, Ralph J.; Ojima, Iwao.

In: Journal of Organic Chemistry, Vol. 73, No. 24, 19.12.2008, p. 9584-9593.

Research output: Contribution to journalArticle

Sun, L, Geng, X, Geney, R, Li, Y, Simmerling, C, Li, Z, Lauher, JW, Xia, S, Band Horwitz, S, Veith, JM, Pera, P, Bernacki, RJ & Ojima, I 2008, 'Design, synthesis, and biological evaluation of novel C14-C3′BzN- linked macrocyclic taxoids', Journal of Organic Chemistry, vol. 73, no. 24, pp. 9584-9593. https://doi.org/10.1021/jo801713q
Sun, Liang ; Geng, Xudong ; Geney, Raphaël ; Li, Yuan ; Simmerling, Carlos ; Li, Zhong ; Lauher, Joseph W. ; Xia, Shujun ; Band Horwitz, Susan ; Veith, Jean M. ; Pera, Paula ; Bernacki, Ralph J. ; Ojima, Iwao. / Design, synthesis, and biological evaluation of novel C14-C3′BzN- linked macrocyclic taxoids. In: Journal of Organic Chemistry. 2008 ; Vol. 73, No. 24. pp. 9584-9593.
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abstract = "(Figure Presented) Novel macrocyclic paclitaxel congeners were designed to mimic the bioactive conformation of paclitaxel. Computational analysis of the {"}REDOR-Taxol{"} structure revealed that this structure could be rigidified by connecting the C14 position of the baccatin moiety and the ortho position of C3′N-benzoyl group (C3′BzN), which are ca. 7.5 {\AA} apart, with a short linker (4-6 atoms). 7-TES-14β-allyloxybaccatin III and (3R,4S)-1-(2-alkenylbenzoyl)-β-lactams were selected as key components, and the Ojima-Holton coupling afforded the corresponding paclitaxel-dienes. The Ru-catalyzed ring-closing metathesis (RCM) of paclitaxel-dienes gave the designed 15- and 16-membered macrocyclic taxoids. However, the RCM reaction to form the designed 14-membered macrocyclic taxoid did not proceed as planned. Instead, the attempted RCM reaction led to the occurrence of an unprecedented novel Ru-catalyzed diene-coupling process, giving the corresponding 15-membered macrocyclic taxoid (SB-T-2054). The biological activities of the novel macrocyclic taxoids were evaluated by tumor cell growth inhibition (i.e., cytotoxicity) and tubulin-polymerization assays. Those assays revealed high sensitivity of cytotoxicity to subtle conformational changes. Among the novel macrocyclic taxoids evaluated, SB-T-2054 is the most active compound, which possesses virtually the same potency as that of paclitaxel. The result may also indicate that SB-T-2054 structure is an excellent mimic of the bioactive conformation of paclitaxel. Computational analysis for the observed structure-activity relationships is also performed and discussed.",
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AU - Geng, Xudong

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AU - Simmerling, Carlos

AU - Li, Zhong

AU - Lauher, Joseph W.

AU - Xia, Shujun

AU - Band Horwitz, Susan

AU - Veith, Jean M.

AU - Pera, Paula

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N2 - (Figure Presented) Novel macrocyclic paclitaxel congeners were designed to mimic the bioactive conformation of paclitaxel. Computational analysis of the "REDOR-Taxol" structure revealed that this structure could be rigidified by connecting the C14 position of the baccatin moiety and the ortho position of C3′N-benzoyl group (C3′BzN), which are ca. 7.5 Å apart, with a short linker (4-6 atoms). 7-TES-14β-allyloxybaccatin III and (3R,4S)-1-(2-alkenylbenzoyl)-β-lactams were selected as key components, and the Ojima-Holton coupling afforded the corresponding paclitaxel-dienes. The Ru-catalyzed ring-closing metathesis (RCM) of paclitaxel-dienes gave the designed 15- and 16-membered macrocyclic taxoids. However, the RCM reaction to form the designed 14-membered macrocyclic taxoid did not proceed as planned. Instead, the attempted RCM reaction led to the occurrence of an unprecedented novel Ru-catalyzed diene-coupling process, giving the corresponding 15-membered macrocyclic taxoid (SB-T-2054). The biological activities of the novel macrocyclic taxoids were evaluated by tumor cell growth inhibition (i.e., cytotoxicity) and tubulin-polymerization assays. Those assays revealed high sensitivity of cytotoxicity to subtle conformational changes. Among the novel macrocyclic taxoids evaluated, SB-T-2054 is the most active compound, which possesses virtually the same potency as that of paclitaxel. The result may also indicate that SB-T-2054 structure is an excellent mimic of the bioactive conformation of paclitaxel. Computational analysis for the observed structure-activity relationships is also performed and discussed.

AB - (Figure Presented) Novel macrocyclic paclitaxel congeners were designed to mimic the bioactive conformation of paclitaxel. Computational analysis of the "REDOR-Taxol" structure revealed that this structure could be rigidified by connecting the C14 position of the baccatin moiety and the ortho position of C3′N-benzoyl group (C3′BzN), which are ca. 7.5 Å apart, with a short linker (4-6 atoms). 7-TES-14β-allyloxybaccatin III and (3R,4S)-1-(2-alkenylbenzoyl)-β-lactams were selected as key components, and the Ojima-Holton coupling afforded the corresponding paclitaxel-dienes. The Ru-catalyzed ring-closing metathesis (RCM) of paclitaxel-dienes gave the designed 15- and 16-membered macrocyclic taxoids. However, the RCM reaction to form the designed 14-membered macrocyclic taxoid did not proceed as planned. Instead, the attempted RCM reaction led to the occurrence of an unprecedented novel Ru-catalyzed diene-coupling process, giving the corresponding 15-membered macrocyclic taxoid (SB-T-2054). The biological activities of the novel macrocyclic taxoids were evaluated by tumor cell growth inhibition (i.e., cytotoxicity) and tubulin-polymerization assays. Those assays revealed high sensitivity of cytotoxicity to subtle conformational changes. Among the novel macrocyclic taxoids evaluated, SB-T-2054 is the most active compound, which possesses virtually the same potency as that of paclitaxel. The result may also indicate that SB-T-2054 structure is an excellent mimic of the bioactive conformation of paclitaxel. Computational analysis for the observed structure-activity relationships is also performed and discussed.

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