Design, Synthesis, and Anticancer Activity of Phosphonic Acid Diphosphate Derivative of Adenine-Containing Butenolide and Its Water-Soluble Derivatives of Paclitaxel With High Antitumor Activity

Design, Synthesis, and Anticancer Activity of Phosphonic Acid Diphosphate Derivative of Adenine-Containing Butenolide and Its Water-Soluble Derivatives of Paclitaxel With High Antitumor Activity Publisher Pubmed

Moosavimovahedi AA¹ ; Hakimelahi S² ; Chamani J¹ ; Khodarahmi GA³ ; Hassanzadeh F³ ; Luo FT⁴ ; Ly TW⁴ ; Shia KS⁵ ; Yen CF⁵ ; Jain ML⁶ ; Kulatheeswaran R⁴ ; Xue C⁴ ; Pasdar M² ; Hakimelahi GH^{1, 4, 5}

Show Affiliations

1. Institute of Biochemistry-Biophysics, Tehran University, Tehran, Iran
2. Department of Cell Biology, Faculty of Medicine, University of Alberta, Edmonton, Alta. T6G 2H7, Canada
3. Department of Medicinal Chemistry, Faculty of Pharmacy, Isfahan Univ. of Medical Sciences, Isfahan, Iran
4. Institute of Chemistry, Academia Sinica, Taipei 115, Taiwan
5. TaiGen Biotechnology, Taipei 114, 138 Shin Ming Rd., Taiwan
6. Dept. of Chemistry and Biochemistry, University of Arkansas, Fayetteville, AR 72701, United States

Source: Bioorganic and Medicinal Chemistry Published:2003

Abstract

Synthesis of adenine derivative of triphosphono-γ -(Z)-ethylidene-2,3-dimethoxybutenolide 4 was accomplished by treatment of phosphonate 3 with 5-phosphoribosyl 1-pyrophosphate in the presence of 5-phosphoribosyl 1-pyrophosphate synthetase. It was found that triphosphonate 4 functions as an irreversible stoichiometric inactivator of the Escherichia coli ribonucleoside diphosphate reductase (RDPR). Triphosphonate 4 exhibited potent inhibitory activity against murine leukemias (L1210 and P388), breast carcinoma (MCF7), and human T-lymphoblasts (Molt4/C8 and CEM/0) cell lines. Paclitaxel ester derivatives of adenine-containing triphosphono-γ -(Z)-ethylidene-2,3-dimethoxybutenolide 8-10 were also synthesized. Like triphosphonate 4, compound 8 exhibited inhibitory property toward RDPR. It also induced microtubule assembly similar to paclitaxel (5). The structure of the chlorodiester linker in 8 was found to account for this dual property. After treatment of MCF7 cells with compounds 4, 5, and 8, fluorescence microscope examination demonstrated the presence of nucleus shrinkage or segmentation. Bifunctional prodrug 8 exhibited higher lipophilicity than 4 and higher water-solubility than 5. Pro-dual-drug 8 exhibited more pronounced anticancer activity relative to that of the triphosphonate 4 and paclitaxel (5). In contrast, compound 9, resulting from the linkage of triphosphonate 4 and paclitaxel (5) through a diester unit, was only found to function as a highly water-soluble prodrug for paclitaxel (5). It induced microtubule assembly in vitro, but did not show inhibitory property toward RDPR. On the other hand, compound 10, an aggregate of triphosphonate 4 and paclitaxel (5), neither functioned as an inhibitor of RDPR nor exhibited microtubule assembly stimulating activity in vitro. © 2003 Elsevier Ltd. All rights reserved.

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Style	Citing Format
MLA	Moosavimovahedi AA, et al.. "Design, Synthesis, and Anticancer Activity of Phosphonic Acid Diphosphate Derivative of Adenine-Containing Butenolide and Its Water-Soluble Derivatives of Paclitaxel With High Antitumor Activity." Bioorganic and Medicinal Chemistry, vol. 11, no. 20, 2003, pp. 4303-4313.
APA	Moosavimovahedi AA, Hakimelahi S, Chamani J, Khodarahmi GA, Hassanzadeh F, Luo FT, Ly TW, Shia KS, Yen CF, Jain ML, Kulatheeswaran R, Xue C, Pasdar M, Hakimelahi GH (2003). Design, Synthesis, and Anticancer Activity of Phosphonic Acid Diphosphate Derivative of Adenine-Containing Butenolide and Its Water-Soluble Derivatives of Paclitaxel With High Antitumor Activity. Bioorganic and Medicinal Chemistry, 11(20), 4303-4313.
Chicago	Moosavimovahedi AA, Hakimelahi S, Chamani J, Khodarahmi GA, Hassanzadeh F, Luo FT, Ly TW, et al.. "Design, Synthesis, and Anticancer Activity of Phosphonic Acid Diphosphate Derivative of Adenine-Containing Butenolide and Its Water-Soluble Derivatives of Paclitaxel With High Antitumor Activity." Bioorganic and Medicinal Chemistry 11, no. 20 (2003): 4303-4313.
Harvard	Moosavimovahedi AA et al. (2003) 'Design, Synthesis, and Anticancer Activity of Phosphonic Acid Diphosphate Derivative of Adenine-Containing Butenolide and Its Water-Soluble Derivatives of Paclitaxel With High Antitumor Activity', Bioorganic and Medicinal Chemistry, 11(20), pp. 4303-4313.
Vancouver	Moosavimovahedi AA, Hakimelahi S, Chamani J, Khodarahmi GA, Hassanzadeh F, Luo FT, et al.. Design, Synthesis, and Anticancer Activity of Phosphonic Acid Diphosphate Derivative of Adenine-Containing Butenolide and Its Water-Soluble Derivatives of Paclitaxel With High Antitumor Activity. Bioorganic and Medicinal Chemistry. 2003;11(20):4303-4313.
BibTex	@article{ author = {Moosavimovahedi AA and Hakimelahi S and Chamani J and Khodarahmi GA and Hassanzadeh F and Luo FT and Ly TW and Shia KS and Yen CF and Jain ML and Kulatheeswaran R and Xue C and Pasdar M and Hakimelahi GH}, title = {Design, Synthesis, and Anticancer Activity of Phosphonic Acid Diphosphate Derivative of Adenine-Containing Butenolide and Its Water-Soluble Derivatives of Paclitaxel With High Antitumor Activity}, journal = {Bioorganic and Medicinal Chemistry}, volume = {11}, number = {20}, pages = {4303-4313}, year = {2003} }
RIS	TY - JOUR AU - Moosavimovahedi AA AU - Hakimelahi S AU - Chamani J AU - Khodarahmi GA AU - Hassanzadeh F AU - Luo FT AU - Ly TW AU - Shia KS AU - Yen CF AU - Jain ML AU - Kulatheeswaran R AU - Xue C AU - Pasdar M AU - Hakimelahi GH TI - Design, Synthesis, and Anticancer Activity of Phosphonic Acid Diphosphate Derivative of Adenine-Containing Butenolide and Its Water-Soluble Derivatives of Paclitaxel With High Antitumor Activity JO - Bioorganic and Medicinal Chemistry VL - 11 IS - 20 SP - 4303 EP - 4313 PY - 2003 ER -

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