Mechanistic Studies on Regioselective Dephosphorylation of Phosphate Prodrugs During a Facile Synthesis of Antitumor Phosphorylated 2-phenyl-6,7-methylenedioxy-1H-quinolin-4-one

Overview

Journal Molecules

Publisher MDPI

Specialty Biology

Date 2013 Jul 26

PMID 23884134

Authors

Yung-Yi Cheng

Chin-Yu Liu

Li-Jiau Huang

Chi-Hung Huang

Kuo-Hsiung Lee

Cheng-Tung Lin

Sheng-Chu Kuo

Affiliations

Soon will be listed here.

Abstract

Phosphorylation of 2-(3-hydroxy-5-methoxyphenyl)-6,7-methylenedioxy-1H-quinolin-4-one (1) afforded diphosphate 2. We found that, upon treatment with methanol under mild conditions, 2 can undergo facile and highly regioselective dephosphorylation to give the monophosphate 3, with a phosphate group remaining on the phenyl ring. The details of the dephosphorylation process were postulated and then probed by LC-MS and HPLC analyses. Furthermore, as a preliminary study, the water soluble monophosphate prodrug 4 was tested for antitumor activity against a MCF-7 xenograft nude mice model.

References

Pettit G, Grealish M, Jung M, Hamel E, Pettit R, Schmidt J . Antineoplastic agents. 465. Structural modification of resveratrol: sodium resverastatin phosphate. J Med Chem. 2002; 45(12):2534-42. DOI: 10.1021/jm010119y. View

Edsall A, Agoston G, Treston A, Plum S, McClanahan R, Lu T . Synthesis and in vivo antitumor evaluation of 2-methoxyestradiol 3-phosphate, 17-phosphate, and 3,17-diphosphate. J Med Chem. 2007; 50(26):6700-5. DOI: 10.1021/jm070639e. View

Tomayko M, Reynolds C . Determination of subcutaneous tumor size in athymic (nude) mice. Cancer Chemother Pharmacol. 1989; 24(3):148-54. DOI: 10.1007/BF00300234. View

Rautio J, Kumpulainen H, Heimbach T, Oliyai R, Oh D, Jarvinen T . Prodrugs: design and clinical applications. Nat Rev Drug Discov. 2008; 7(3):255-70. DOI: 10.1038/nrd2468. View

Chou L, Tsai M, Hsu M, Wang S, Way T, Huang C . Design, synthesis, and preclinical evaluation of new 5,6- (or 6,7-) disubstituted-2-(fluorophenyl)quinolin-4-one derivatives as potent antitumor agents. J Med Chem. 2010; 53(22):8047-58. DOI: 10.1021/jm100780c. View

Denmark S, Regens C, Kobayashi T . Total synthesis of papulacandin D. J Am Chem Soc. 2007; 129(10):2774-6. DOI: 10.1021/ja070071z. View

Kuo S, Lee H, Juang J, Lin Y, Wu T, Chang J . Synthesis and cytotoxicity of 1,6,7,8-substituted 2-(4'-substituted phenyl)-4-quinolones and related compounds: identification as antimitotic agents interacting with tubulin. J Med Chem. 1993; 36(9):1146-56. DOI: 10.1021/jm00061a005. View

Simoni D, Romagnoli R, Baruchello R, Rondanin R, Rizzi M, Pavani M . Novel combretastatin analogues endowed with antitumor activity. J Med Chem. 2006; 49(11):3143-52. DOI: 10.1021/jm0510732. View

Shaw J, Sueoko C, Oliyai R, Lee W, Arimilli M, Kim C . Metabolism and pharmacokinetics of novel oral prodrugs of 9-[(R)-2-(phosphonomethoxy)propyl]adenine (PMPA) in dogs. Pharm Res. 1998; 14(12):1824-9. DOI: 10.1023/a:1012108719462. View

10.

Li L, Wang H, Kuo S, Wu T, LEDNICER D, Lin C . Antitumor agents. 150. 2',3',4',5',5,6,7-substituted 2-phenyl-4-quinolones and related compounds: their synthesis, cytotoxicity, and inhibition of tubulin polymerization. J Med Chem. 1994; 37(8):1126-35. DOI: 10.1021/jm00034a010. View

11.

Chou L, Chen C, Lee J, Way T, Huang C, Huang S . Synthesis and preclinical evaluations of 2-(2-fluorophenyl)-6,7-methylenedioxyquinolin-4-one monosodium phosphate (CHM-1-P-Na) as a potent antitumor agent. J Med Chem. 2010; 53(4):1616-26. DOI: 10.1021/jm901292j. View

12.

Vincent L, Kermani P, Young L, Cheng J, Zhang F, Shido K . Combretastatin A4 phosphate induces rapid regression of tumor neovessels and growth through interference with vascular endothelial-cadherin signaling. J Clin Invest. 2005; 115(11):2992-3006. PMC: 1253622. DOI: 10.1172/JCI24586. View

13.

Oslob J, Heumann S, Yu C, Allen D, Baskaran S, Bui M . Water-soluble prodrugs of an Aurora kinase inhibitor. Bioorg Med Chem Lett. 2009; 19(5):1409-12. DOI: 10.1016/j.bmcl.2009.01.043. View

14.

Stella V, Nti-Addae K . Prodrug strategies to overcome poor water solubility. Adv Drug Deliv Rev. 2007; 59(7):677-94. DOI: 10.1016/j.addr.2007.05.013. View

15.

Witterland A, Koks C, Beijnen J . Etoposide phosphate, the water soluble prodrug of etoposide. Pharm World Sci. 1996; 18(5):163-70. DOI: 10.1007/BF00820727. View

16.

Cheng Y, Yang J, Tsai S, Liaw C, Chung J, Huang L . The newly synthesized 2-(3-hydroxy-5-methoxyphenyl)-6,7-methylenedioxyquinolin-4-one triggers cell apoptosis through induction of oxidative stress and upregulation of the p38 MAPK signaling pathway in HL-60 human leukemia.... Oncol Rep. 2012; 28(4):1482-90. DOI: 10.3892/or.2012.1923. View

17.

Heimbach T, Oh D, Li L, Forsberg M, Savolainen J, Leppanen J . Absorption rate limit considerations for oral phosphate prodrugs. Pharm Res. 2003; 20(6):848-56. DOI: 10.1023/a:1023827017224. View

18.

Brooks D, Srinivas N, Alberts D, Thomas T, Igwemzie L, McKinney L . Phase I and pharmacokinetic study of etoposide phosphate. Anticancer Drugs. 1995; 6(5):637-44. DOI: 10.1097/00001813-199510000-00002. View

19.

Perry C, McTavish D . Estramustine phosphate sodium. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in prostate cancer. Drugs Aging. 1995; 7(1):49-74. DOI: 10.2165/00002512-199507010-00006. View

20.

Sorme P, Arnoux P, Kahl-Knutsson B, Leffler H, Rini J, Nilsson U . Structural and thermodynamic studies on cation-Pi interactions in lectin-ligand complexes: high-affinity galectin-3 inhibitors through fine-tuning of an arginine-arene interaction. J Am Chem Soc. 2005; 127(6):1737-43. DOI: 10.1021/ja043475p. View