Thomas C. Boge

Schotten-Baumann acylation of N-debenzoyltaxol; an efficient route to N-acyl taxol analogues and their biological evaluation

Abstract An efficient route to N-acyl taxol analogues is described utilizing N-debenzoyltaxol ( 11 ). Acylation of 11 with various acid chlorides under Schotten-Baumann conditions led to a facile one step synthesis of several N-acyl taxol analogues from a common intermediate.

A Systematic SAR Study of C10 Modified Paclitaxel Analogues Using a Combinatorial Approach

A library with 63 paclitaxel analogues modified at the C10 position of paclitaxel has been prepared using parallel solution phase synthesis. Most of the C10 analogues were slightly less active than paclitaxel in the tubulin assembly assay and had reduced potency in the B16 melanoma and MCF-7 cell line cytotoxicity assays. These modifications at C10, however, did not lead to the total loss of activity, indicating that the C10 moiety of paclitaxel may not be directly involved in the drug-microtubule interactions, but could influence its binding affinity to P-glycoprotein. Approximately 50% of the analogues demonstrated better activity against the drug resistant cell line MCF7-ADR. However, the increase in activity was 10-fold at most. This result demonstrates that the cytotoxicity against this drug resistant cancer cell line is sensitive to structural changes at the C10 position of paclitaxel. It was also found that the presence of a nitrogen atom in the C10 substituent might play a role in the interaction of analogues with microtubules.

Selective C-2 and C-4 deacylation and acylation of taxol: The first synthesis of a C-4 substituted taxol analogue

Hydrolytic procedures for selective 2-debenzoylation and 2,4-dideacylation of 2′-O-tert-butyldimethylsilyl-7-O-(triethylsilyl)taxol are reported. The first synthesis and biological evaluation of a 4-substituted analogue, 4-deacetyl-4-isobutanoyltaxol, is presented. The chemistry described in this letter is suitable for the facile synthesis of taxol congeners modified at C-2 and/or C-4.

The oxetane conformational lock of paclitaxel: Structural analysis of D-secopaclitaxel

Analysis of the 1H NMR data of paclitaxel in comparison with its oxetane ring-opened analogue D-secopaclitaxel suggests that the oxetane moiety (D-ring) of paclitaxel serves as a conformational lock for the diterpene moiety and the C13 side chain.

Synthesis of biologically active 2-benzoyl paclitaxel analogues

Abstract The influence of aromatic substitution at the 2-benzoyl moiety of paclitaxel on biological activity was investigated, following the Topliss Operational Scheme. Twelve paclitaxel derivatives were synthesized and evaluated in a microtubule assembly assay and for cytotoxicity against B16 melanoma cells. Most of the analogues were found to possess biological properties similar to paclitaxel.

Topliss approach to the synthesis of biologically active substituted N-benzoyl taxol analogues

Abstract A series of compounds, directed by the Topliss Operational Scheme, were synthesized and evaluated to investigate structure activity relationships of the N -benzoyl moiety of taxol. Evaluation of the newly prepared derivatives in the microtubule assembly assay and for cytotoxicity revealed that they possessed biological properties similar to taxol. Nine novel substituted N -benzoyl analogues of taxol were prepared, using the Topliss approach to drug design. The taxanes were prepared from N -acyl-3-hydroxy-4-phenyl-2-azetidinones and baccatin III or by acylation of N -debenzoyltaxol. In vitro biological evaluation revealed that these analogues had activity similar to taxol.

Paclitaxel and docetaxel photoaffinity labels

Abstract The synthesis and in vitro evaluation of four novel 3-azidobenzoyl photoaffinity analogues of paclitaxel and docetaxel is detailed. Due to their good to excellent ability to stimulate the assembly of microtubules they have potential as photoaffinity probes.

7-O-acylpaclitaxel analogues: potential probes to map the paclitaxel binding site

The synthesis and biological evaluation of several 7-O-acylpaclitaxel analogues as potential photoaffinity, electrophilic, and fluorescent probes are described.