Fluorine-containing taxoids

Syntheses, Biological Activity, and Conformational Analysis of Fluorine-Containing Taxoids Ojima, I. Kuduk, S.D. Slater, J.C. Gimi, R. H. Sun, C.M Chakravarty, S. Ourevitch, M. Abouabdellah, A. Bonnet-Delpon. D. in Biomedical Frontiers of Fluorine Chemistry Ojima, I. McCarthy, J. R. Welch, J. T., Eds. ACS Symposium Series 639 American Chemical Society Washington, DC, 1996 pp 228-243. 

A. Fluorine-Containing Taxoids Synthesis and Biological Activity.92... 

In this chapter, we describe an account of our research on the chemistry and biology of paclitaxel and taxoid anticancer agents (taxoid = taxol-like compound). The topics covered in this chapter include (i) the development of a practical and efficient method for the semisynthesis of paclitaxel and docetaxel using chiral 3-hydroxy-P-lactams as synthetic intermediates, (ii) structure-activity relationship (SAR) studies of various taxoids that led to the discovery of the extremely potent second-generation taxoids, and (iii) biological and conformational studies with the use of fluorine-containing taxoids as probes. ... 

IV. FLUORINE-CONTAINING TAXOIDS SAR STUDY AND FLUORINE PROBE APPROACH TO THE IDENTIFICATION OF BIOACTIVE CONFORMATIONS... 

Table 9. Cytotoxicity of Fluorine-Containing Taxoids (IC50, nM)a...

Metabolism studies on these fluorine-containing taxoids to obtain evidence for their ability to block metabolic pathways, e.g. suppression of P-450 oxidation (vide supra), have just started. Results will be reported elsewhere in the future. 

Ojima, L Inoue, T. Chadravarty, S. Enantiopure fluorine-containing taxoids potent anticancer agents and versatile prohes for biomedical problems. J. Fluorine Chem., 1999, 97 3-10. 

In another application, 19F NMR studies have provided critical information on the bioactive conformation of taxoids. Fluorine-containing taxoids have been used as probes for NMR analysis of the conformational dynamics of paclitaxel in conjunction with molecular modeling [166], The dependence of the 19F chemical shifts and the Jm--ny values of these fluorinated analogues is examined through 19F and H variable-temperature (VT) NMR measurements. The experiments clearly indicate highly dynamic behavior of these molecules and the existence of equilibrium between conformers. The analysis of the VT NMR data in combination with molecular modeling, including restrained molecular dynamics (RMD), has identified three key conformers, which were further confirmed by the 19F- H heteronuclear NOE measurements. 

Ojima, I., Kuduk, S. D., Slater, J. C., et al. (1996) Syntheses of new fluorine-containing taxoids by means of (i-lactam synthon method. Tetrahedron, 52, 209-24. 

Ojima I, Kuduk SD, Slater JC, Gimi RH, Sun CM (1996) Syntheses of New Fluorine-Containing Taxoids by Means of /5-Lactam Synthon Method. Tetrahedron 52 209... 

Ojima I, Kuduk SD, Slater JC, Gimi RH, Sun CM, Chakravarty S, Ourevitch M, Abouabdellah A, Bonnet-Delpon D, Begue J-P, Veith JM, Pera P, Bemacki RJ (1996) Syntheses, Biological Activity, and Conformational Analysis of Fluorine-Containing Taxoids. In Ojima I, McCarthy J, Welch JT (ed) Biomedical Frontiers of Fluorine Chemistry. American Chemical Society, Washington, DC, p 228... 

Ojima I, Inoue T, Chakravarty S (1999) Enantiopure Fluorine-containing Taxoids Potent Anticancer Agents and Versatile Probes for Biomedical Problems. J Fluorine... 

J. Seitz, J. G. Vineberg, E. S. Zuniga and I. Ojima, Fluorine-Containing Taxoid Anticancer Agents and Their Tumor-Targeted Drug Delivery, / Fluorine Chem., 2013, 152, 157. 

Synthesis of Enatiopure Fluorine-Containing Taxoids and Their Use as Anticancer Agents as well as Probes for Biomedical Problems... 

The syntheses of fluorine-containing taxoids 8 were carried out through the coupling of 1-acyl-P-lactams 7 and C-2 modified baccatins 5 with proper protecting groups at C-7 and/or C-10 by means of the protocol developed in our laboratories (iP-22) (Scheme 3). 

Bioassay for new fluorine-containing taxoids. The in vitro cytotoxicity of the new... 

As Table I shows, several of the new fluorine-containing taxoids exhibit similar or slightly weaker activity as compared to paclitaxel and docetaxel. 3 -(4-Fluorophenyl)paclitaxel (SB-T-3101) shows slightly decreased activity compared to the parent compound, while 3 -(4-fluorophenyl)docetaxel (SB-T-3001) and 10-acetyl-3 -(4-fluorophenyl)docetaxel (SB-T-3002) show comparable activity to docetaxel. 3 -(iV-Fluorobenzoyl)paclitaxel (SB-T-13103) is similar to SB-T-3101 in activity, while 3 -A/-fluorobenzoyl-3 -(4-fluorophenyl)paclitaxel (SB-T-31031) is about 10-fold weaker as compared to paclitaxel, showing that the incorporation of two fluorines at these positions is unfavorable to the activity. Thus, it appears that fluorine incorporation at the para-position on the side chain aromatic rings of paclitaxel decreases the activity, while exhibiting little effect on docetaxel analogs. 

Table I. Cytotoxicities (IC50 nM) of Fluorine Containing Taxoids F-Taxoid AU A549 HT 29 MCF7 MCF7R...

Metabolism study of new fluorine-containing taxoids. Enzyme inhibition studies have shown that the cytochrome P-450 (CYP) family of enzymes is playing a key role in the biotransformation of paclitaxel and docetaxel. It has been found that the CYP 2C enzyme subfamily is responsible for the 6a-hydroxylation of paclitaxel, while the CYP 3 A subfamily plays a key role in the hydroxylation of the Boc group of docetaxel as well as that of the 3 -phenyl and 2-benzoyl groups of paclitaxel (Figure 1) (11,25)... 

Synthesis and biological activity of 3 -trifluoromethyl-docetaxel analogs (15,26). During the course of the structure-activity relationship study of fluorine-containing taxoids, we designed a series of taxoids bearing a trifluoromethyl moiety at the C-3 position in place of the phenyl group. For the synthesis of a series of 3 -CF3-taxoids... 

Figure 2. Metabolism of fluorine-containing taxoids by P450 enzymes.

The use of F-NMR for a variable temperature (VT) NMR study of fluorine-containing taxoids is obviously advantageous over the use of H-NMR because of... 

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