Zacharia S. Cheruvallath

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.

Novel Biologically Active Taxol Analogues: Baccatin III 13-(N-(p-chlorobenzoyl)-(2′R,3′S)-3′-phenylisoserinate ) and Baccatin III 13-(N-benzoyl-(2′R,3′S)-3′-(p-chlorophenyl)isoserinate )

Abstract Two novel taxol analogues, baccatin III 13-(N-(p-chlorobenzoyl)-(2′R,3′S)-phenylisoserinate) ( 2 ) and baccatin III 13-(N-benzoyl-(2′R,3′S)-3′(p-chlorophenyl)isoserinate) ( 3 ) were synthesized from 7-triethylsilyl baccatin III ( 4 ) and N-acyl 3-ethoxyethyloxy-4-aryl-2-azetidinones 5 and 6 in two steps and excellent overall yield. Both derivatives demonstrated activity in the microtubule assembly assay and cytotoxicity against B16 melanoma cells comparable to taxol.

An efficient semisynthesis of taxol from (3R,4S)-N-Benzoyl-3-[(t-butyldimethylsilyl)oxy]-4-phenyl-2-azetidinone and 7-(Triethylsilyl)baccatin III

Abstract An investigation of the ester enolate-imine cyclocondensation demonstrated that (−)-10-dicyclohexylsulfamoyl-D-isoborneol is an excellent chiral auxiliary for the formation of (3R,4S)-3-[(t-butyldimethylsilyl)oxy]-4-phenyl-2-azetidinone in high enantiomeric purity. Coupling between (3R,4S)-N-benzoyl-3-[(t-butyldimethylsilyl)oxy]-4-phenyl-2-azetidinone and 7-(triethylsilyl)baccatin III in the presence of sodium hydride as the base provided an efficient taxol semisynthesis.

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.

Stereoselective synthesis of 9β-hydroxytaxanes via reduction with samarium diiodide

Abstract Reaction of baccatin III and paclitaxel with samarium diiodide yielded the corresponding 10-deacetyl-9β-hydroxy derivatives. When 10-deacetylbaccatin III and docetaxel were subjected to the same reaction conditions the corresponding 9β-hydroxy and 10-dehydroxy-9β-hydroxy analogues were isolated.

Semisynthesis and biological evaluation of brevifoliol 13-[N-benzoyl-(-2′R,3′S)-3′-phenylisoserinate]

Coupling between brevifoliol (1) and β-lactam (2) yielded, after protecting group removal, brevifoliol 13-[N-benzoyl-(2′R,3′S)-3′-phenylisoserinate] (3). This novel taxol analogue was found to be inactive in the microtubule binding assay and had little cytotoxicity against B16 melanoma cells.

Synthesis and biology of substituted 3′-phenyl taxol analogues

Abstract A series of substituted 3′-phenyl taxol analogues, directed by the Topliss Operational Scheme, were synthesized and evaluated for their biological activity. The novel analogues were prepared from baccatin III and N-acyl β-lactams. Evaluation in the microtubule assembly assay and for cytotoxicity against B16 melanoma cells illustrated a modest influence of aromatic substitution on bioactivity.