Phosphoramidate ProTides of the anticancer agent FUDR successfully deliver the preformed bioactive monophosphate in cells and confer advantage over the parent nucleoside.

The fluorinated pyrimidine family of nucleosides continues to represent major current chemotherapeutic agents for treating solid tumors. We herein report their phosphate prodrugs, ProTides, as promising new derivatives, which partially bypass the dependence of the current drugs on active transport and nucleoside kinase-mediated activation. They are also resistant to metabolic deactivation by phosphorolytic enzymes. We report 39 ProTides of the fluorinated pyrimidine FUDR with variation in the aryl, ester, and amino acid regions. Notably, only certain ProTide motifs are successful in delivering the nucleoside monophosphate into intact cells. We also find that the ProTides retain activity in mycoplasma infected cells, unlike FUDR. Data suggest these compounds to be worthy of further progression.

[1]  E. Gorovits,et al.  Design, synthesis and evaluation of a novel double pro-drug: INX-08189. A new clinical candidate for hepatitis C virus. , 2010, Bioorganic & medicinal chemistry letters.

[2]  J. Balzarini,et al.  Improvement of purine and pyrimidine antimetabolite-based anticancer treatment by selective suppression of mycoplasma-encoded catabolic enzymes. , 2009, The Lancet. Oncology.

[3]  W. Parker.  Enzymology of purine and pyrimidine antimetabolites used in the treatment of cancer. , 2009, Chemical reviews.

[4]  J. Balzarini,et al.  The cytostatic activity of pyrimidine nucleosides is strongly modulated by Mycoplasma hyorhinis infection: Implications for cancer therapy. , 2008, Biochemical pharmacology.

[5]  M. Erion,et al.  Prodrugs of phosphates and phosphonates. , 2008, Journal of medicinal chemistry.

[6]  W. Lipscomb,et al.  Discovery of potent and specific fructose-1,6-bisphosphatase inhibitors and a series of orally-bioavailable phosphoramidase-sensitive prodrugs for the treatment of type 2 diabetes. , 2007, Journal of the American Chemical Society.

[7]  William A. Lee,et al.  Cathepsin A Is the Major Hydrolase Catalyzing the Intracellular Hydrolysis of the Antiretroviral Nucleotide Phosphonoamidate Prodrugs GS-7340 and GS-9131 , 2006, Antimicrobial Agents and Chemotherapy.

[8]  M. Mason,et al.  Novel potential anticancer naphthyl phosphoramidates of BVdU: separation of diastereoisomers and assignment of the absolute configuration of the phosphorus center. , 2006, Journal of medicinal chemistry.

[9]  M. Mason,et al.  Anti-cancer ProTides: tuning the activity of BVDU phosphoramidates related to thymectacin. , 2005, Bioorganic & medicinal chemistry.

[10]  E. De Clercq,et al.  Application of phosphoramidate pronucleotide technology to abacavir leads to a significant enhancement of antiviral potency. , 2005, Journal of medicinal chemistry.

[11]  J. Balzarini,et al.  Aryloxy phosphoramidate triesters as pro-tides. , 2004, Mini reviews in medicinal chemistry.

[12]  P. Johnston,et al.  5-Fluorouracil: mechanisms of action and clinical strategies , 2003, Nature Reviews Cancer.

[13]  R. Martino,et al.  Clinical studies of three oral prodrugs of 5-fluorouracil (capecitabine, UFT, S-1): a review. , 2002, The oncologist.

[14]  R. Stroud,et al.  Enzyme-catalyzed therapeutic agent (ECTA) design: activation of the antitumor ECTA compound NB1011 by thymidylate synthase. , 2001, Biochemical pharmacology.

[15]  J. Grem.  5-Fluorouracil: Forty-Plus and Still Ticking. A Review of its Preclinical and Clinical Development , 2000, Investigational New Drugs.

[16]  N. Suzuki,et al.  Different mechanisms of acquired resistance to fluorinated pyrimidines in human colorectal cancer cells. , 2000, International journal of oncology.

[17]  E. De Clercq,et al.  Characterization of the activation pathway of phosphoramidate triester prodrugs of stavudine and zidovudine. , 1999, Molecular pharmacology.

[18]  E. De Clercq,et al.  Role of antimetabolites of purine and pyrimidine nucleotide metabolism in tumor cell differentiation. , 1999, Biochemical pharmacology.

[19]  E. De Clercq,et al.  Mechanism of anti-HIV action of masked alaninyl d4T-MP derivatives. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[20]  E. De Clercq,et al.  Aryl phosphoramidate derivatives of d4T have improved anti-HIV efficacy in tissue culture and may act by the generation of a novel intracellular metabolite. , 1996, Journal of medicinal chemistry.

[21]  E. De Clercq,et al.  Intracellular delivery of bioactive AZT nucleotides by aryl phosphate derivatives of AZT. , 1993, Journal of medicinal chemistry.

[22]  Ensminger Wd,et al.  Clinical pharmacology of hepatic arterial chemotherapy. , 1983 .

[23]  E. Yagil,et al.  Phosphorolysis of 5-Fluoro-2′-Deoxyuridine in Escherichia coli and Its Inhibition by Nucleosides , 1971, Journal of bacteriology.

[24]  C. Heidelberger,et al.  Fluorinated Pyrimidines, A New Class of Tumour-Inhibitory Compounds , 1957, Nature.

[25]  J. Homsi,et al.  Hepatic arterial infusion of chemotherapy for hepatic metastases from colorectal cancer. , 2006, Cancer control : journal of the Moffitt Cancer Center.