Magdalena R. Mejillano

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.

Taxol Photoaffinity Label: 7-(p-Azidobenzoyl)taxol Synthesis and Biological Evaluation

Abstract An efficient semi-synthetic approach utilizing the appropriately functionalized (3R,4S)-3-hydroxy-4-phenyl-2-azetidinone ( 4 ) and 7-(p-azidobenzoyl)baccatin III ( 3 ) is described which leads to the targeted biologically active taxol photoaffinity label 6 .

Stabilization of microtubules by GTP analogues.

We recently demonstrated that the nonhydrolyzable analogues of GTP (GMPPCP and GMPPNP) and ATP support the elongation phase of tubulin assembly and are incorporated into the E-site of polymerized tubulin. In this report we studied the stability of microtubules containing GTP analogues by examining length redistributions after shearing at polymer steady state. The mean length of a population of microtubules containing GMPPCP increased only by 37% over a 150 min time period after shearing. Microtubules which contained 70% ATP and 30% GDP at the E-site increased in length by 88%. In contrast, the mean length of microtubules assembled in the presence of GTP increased by 410% in the same time period. These results suggest that microtubules containing GMPPCP or ATP at their ends are stabilized from depolymerization.

Semisynthesis and biological activity of taxol analogues: baccatin III 13-(N-benzoyl-(2′R,3′S)-3′-(p-tolyl)isoserinate), baccatin III 13-(N-(p-toluoyl)-2′R,3′S)-3′-phenylisoserinate), baccatin III 13-(N-benzoyl-(2′R,3′S)-3′-(p-trifluoromethylphenyl)isoserinate), and baccatin III 13-(N-(p-trifluoromethylbenzoyl)-(2′R,3′S)-3′-phenylisoserinate)

Abstract The semisynthesis of the four novel taxol analogues baccatin III 13-(N-benzoyl-(2′R,3′S)-3′-(p-tolyl)isoserinate) ( 2 ), baccatin III 13-(N-(p-toluoyl)-(2′R,3′S)-3′-phenylisoserinate) ( 3 ), baccatin III 13-(N-benzoyl-(2′R,3′S)-3′(p-trifluoromethylphenyl)isoserinate) ( 4 , and baccatin III 13-(N-(p-trifluoromethylbenzoyl)-(2′R,3′S)-3′-phenylisoserinate) ( 5 ) from 7-triethylsilyl baccatin III ( 6 ) and the N-acyl-3-ethoxyethyl-4-aryl-2-azetidinones ( 11–14 ) is descrived. Derivatives 2 , 3 , and 5 demonstrated activity comparable to taxol ( 1 ) in the microtubule assembly assay and cytotoxicity against B16 melanoma cells. Derivative 4 ), however, was found to be an unstable product.

Nucleotide stereochemistry in the formyltetrahydrofolate synthetase reaction

In a recent study, we have shown that N10-formyltetrahydrofolate synthetase prefers (Sp)-MgATP beta S over the Rp isomer in the forward reaction. In this report the stereochemistry of ATP beta S produced from prochiral ADP beta S in the reverse reaction was determined. The ATP beta S product was purified and tested as a substrate for hexokinase (preference for the Rp isomer), adenylate kinase (preference for the Sp isomer) and N10-formyltetrahydrofolate synthetase. A comparison of kinetic constants for the product and the authentic Sp and Rp isomers shows that the product is the Sp diastereomer. 31P NMR was also used to identify the product as (Sp)-ATP beta S.