Syntheses and structure - Activity relationships of novel nor-seco taxoids

Iwao Ojima*, Songnian Lin, Subrata Chakravarty, Ivana Fenoglio, Young Hoon Park, Chung-Ming Sun, Giovanni Appendino, Paula Pera, Jean M. Veith, Ralph J. Bernacki

*Corresponding author for this work

Research output: Contribution to journalArticle

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Abstract

A series of novel nor-seco taxoids (4a-b, 5a-d, 6), including either a C-13 ester linkage or a C-13 amide linkage, was synthesized by means of the β-lactam synthon method using the coupling of (3R,4S)-1-acyl-β-lactams with properly protected nor-seco baccatin III derivatives (1, 2, 3) as the key step. Nor-seco baccatin III derivatives were prepared through oxidative cleavage of the A ring of 14β-hydroxy-10-deacetylbaccatin III followed by reduction, amination using Mitsunobu conditions, or reductive amination. Nor- seco taxoids with a C-13 ester linkage (4a-b) or a C-13 N-Me amide linkage (6) show reduced cytotoxicity against human cancer cell lines as compared with paclitaxel, but still retain a certain level of activity despite the destruction of the taxane A ring. However, none of the analogues with a C-13 N-H amide linkage (5a-d) exhibit appreciable activity (IC50 > 1.0 μM). A restrained molecular dynamics study reveals the inability of 5a-d to attain the proposed bioactive conformation, which accounts for the loss of activity.

Original languageEnglish
Pages (from-to)1637-1645
Number of pages9
JournalJournal of Organic Chemistry
Volume63
Issue number5
DOIs
StatePublished - 6 Mar 1998

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    Ojima, I., Lin, S., Chakravarty, S., Fenoglio, I., Park, Y. H., Sun, C-M., Appendino, G., Pera, P., Veith, J. M., & Bernacki, R. J. (1998). Syntheses and structure - Activity relationships of novel nor-seco taxoids. Journal of Organic Chemistry, 63(5), 1637-1645. https://doi.org/10.1021/jo971953r