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31. Synthesis and Biological Evaluation of 2‘-Carbamate-Linked and 2‘-Carbonate-Linked Prodrugs of Paclitaxel:  Selective Activation by the Tumor-Associated Protease Plasmin

Author

Groot, F. M. H. de, Berkom, L. W. A. van, and Scheeren, H. W.

Abstract

The nontoxic paclitaxel-2‘-carbamate prodrugs 2−5 and paclitaxel-2‘-carbonate prodrug 6 were synthesized and tested for activation by the tumor-associated enzyme plasmin. A generally applicable method for the synthesis of paclitaxel-2‘-carbamates was developed. In buffer solution, prodrug 2, which contained an unsubstituted ethylenediamine spacer, was not stable, whereas prodrugs 3−6 were highly stable. Prodrugs 3−6 showed on average a decrease in cytotoxicity of more than 8000-fold in comparison with the parent drug in seven human tumor cell lines. Prodrugs 5 and 6 are the most nontoxic prodrugs of paclitaxel that yield the free parent drug upon selective activation currently reported. Enzyme hydrolysis and spacer elimination rates were determined by incubation of prodrugs 5 and 6 in the presence of human plasmin. From these results, prodrug 6 was selected as the promising prodrug for further in vivo studies.

Published
2000

32. Synthesis and Biological Evaluation of Novel Prodrugs of Anthracyclines for Selective Activation by the Tumor-Associated Protease Plasmin

Author

Groot, F. M. H. de, Bart, A. C. W. de, Verheijen, J. H., and Scheeren, H. W.

Abstract

New prodrugs of daunorubicin and doxorubicin designed for selective activation by the serine protease plasmin are described. The low toxic prodrugs 3, 4, and 5 are converted to the corresponding cytotoxic drugs upon proteolysis by the tumor-associated protease plasmin. Application of a self-eliminating spacer was essential for enzyme activation. A prodrug containing a chloro-substituted spacer was synthesized with the aim of enhancing the rate of conversion by plasmin. All prodrugs were highly stable in buffer solution and in serum and on the average 15-fold less cytotoxic than the parent drugs in seven human tumor cell lines. A marked in vitro selectivity was demonstrated by incubation of the doxorubicin prodrugs with a plasmin generating MCF-7 breast cancer cell line transfected with urokinase-type plasminogen activator (u-PA) in comparison with the nontransfected nonplasmin generating cell line. Prodrugs 4 and 5 showed the same cytotoxic effect as the free parent drug doxorubicin in the u-PA transfected cells, indicating complete conversion of the prodrug by plasmin. Addition of the plasmin inhibitor Trasylol drastically increased the ID50 values in the u-PA transfected MCF-7 cells for both prodrugs 4 and 5.

Published
1999

37. Identification of Six Taxine Alkaloids from Taxus baccata Needles

Author

Jenniskens, L. H. D., Rozendaal, E. L. M. van, Beek, T. A. van, Wiegerinck, P. H. G., and Scheeren, H. W.

Abstract

Six taxine alkaloids were isolated from Taxus baccata needles and partially separated. An HPLC method for the analysis of the taxine fraction was developed. By NMR and deamination/hydrolysis studies it was established that the taxine fraction consisted mostly of taxicin-I and taxicin-II derivatives in a variable ratio. Four of the six taxine alkaloids isolated have not been reported before. All of the alkaloids were found to be unstable under neutral and basic conditions, and some of them were very easily interconverted.

Published
1996

38. Rearrangement of O-Cinnamoyltaxicin I to a Novel C-13 Spiro-Taxane

Author

Rozendaal, E. L. M. van, Veldhuis, H., Veldhuizen, B. van, Beek, T. A. van, Groot, A. de, Beusker, P. H., and Scheeren, H. W.

Abstract

During the large-scale synthesis of an O-cinnamoyltaxicin I acetonide, an intermediate for the semisynthesis of 7-deoxypaclitaxel derivatives, side-product 3 was formed via a vinylogous retro-aldol reaction and a long-range hydride shift from O-cinnamoyltaxicin I (1) under alkaline reaction conditions. Compound 3 has two hemi-acetal bridges at C-1,C-9 and C-10,C-13. Compound 4 was formed from side-product 3 under acidic reaction conditions and is the first C-13 spiro-taxane described in the literature. This spiro-taxane has two acetal bridges between C-1,C-13 and C-10,C-13.

Published
2000

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