Biologically active taxol analogues with deleted A-ring side chain substituents and variable C-2′ configurations

Charles S. Swindell, Nancy E. Krauss, Susan Band Horwitz, Israel Ringel

Research output: Contribution to journalArticle

204 Citations (Scopus)

Abstract

Taxol (1), a potent inhibitor of cell replication, enhances the assembly of tubulin into stable microtubules and promotes the formation of microtubule bundles in cells. In addition to its unique mechanism of action, taxol exhibits unusual promise as an antitumor agent, but its application in cancer chemotherapy is hampered by its limited availability. In order to better define the structure-activity profile of taxol for the design of more accessible drugs and to provide insight into the chemical features of the taxol-microtubule interaction, taxol analogues 3-8, with deleted A-ring side chain substituents and both R and S C-2′ configurations, were synthesized from baccatin III (2) through esterification at the hindered 13-hydroxyl. Employing an improved hydroxyl protection strategy, lactate analogues 3 and 4 were prepared with reasonable efficiency owing to their simple side-chain structures, while N-benzoylisoserine analogues 7 and 8 were synthesized through esterification reactions whose rates were enhanced greatly by the participation of the amide functionality. Although less biologically active than taxol, analogues 5-7 were found to promote the polymerization of tubulin and to be cytotoxic; 5 and 6 were considerably more effective than 7, whereas 3, 4, and 8 were least active. Interestingly, tubulin polymerization was sensitive to the C-2′ configuration only when the amide substituent was present in the side chain. This observation suggests that the 3′-amide substituent plays an important role in preorganizing the taxol side chain to bind to microtubules.

Original languageEnglish (US)
Pages (from-to)1176-1184
Number of pages9
JournalJournal of Medicinal Chemistry
Volume34
Issue number3
StatePublished - 1991

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Paclitaxel
Microtubules
Tubulin
Amides
Esterification
Polymerization
Hydroxyl Radical
Chemotherapy
Antineoplastic Agents
Reaction rates
Lactic Acid
Availability
Drug Therapy
Pharmaceutical Preparations
Neoplasms

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Biologically active taxol analogues with deleted A-ring side chain substituents and variable C-2′ configurations. / Swindell, Charles S.; Krauss, Nancy E.; Band Horwitz, Susan; Ringel, Israel.

In: Journal of Medicinal Chemistry, Vol. 34, No. 3, 1991, p. 1176-1184.

Research output: Contribution to journalArticle

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AB - Taxol (1), a potent inhibitor of cell replication, enhances the assembly of tubulin into stable microtubules and promotes the formation of microtubule bundles in cells. In addition to its unique mechanism of action, taxol exhibits unusual promise as an antitumor agent, but its application in cancer chemotherapy is hampered by its limited availability. In order to better define the structure-activity profile of taxol for the design of more accessible drugs and to provide insight into the chemical features of the taxol-microtubule interaction, taxol analogues 3-8, with deleted A-ring side chain substituents and both R and S C-2′ configurations, were synthesized from baccatin III (2) through esterification at the hindered 13-hydroxyl. Employing an improved hydroxyl protection strategy, lactate analogues 3 and 4 were prepared with reasonable efficiency owing to their simple side-chain structures, while N-benzoylisoserine analogues 7 and 8 were synthesized through esterification reactions whose rates were enhanced greatly by the participation of the amide functionality. Although less biologically active than taxol, analogues 5-7 were found to promote the polymerization of tubulin and to be cytotoxic; 5 and 6 were considerably more effective than 7, whereas 3, 4, and 8 were least active. Interestingly, tubulin polymerization was sensitive to the C-2′ configuration only when the amide substituent was present in the side chain. This observation suggests that the 3′-amide substituent plays an important role in preorganizing the taxol side chain to bind to microtubules.

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