Cyclization-activated prodrugs. Synthesis, reactivity and toxicity of dipeptide esters of paracetamol

Bioorganic and Medicinal Chemistry Letters

Volumn 15, Issue 6, 2005, Pages 1595-1598

  Santos, Cledir ^a   Mateus, Maria Luísa ^b   Dos Santos, Ana Paula ^b   Moreira, Rui ^b   De Oliveira, Eliandre ^c   Gomes, Paula ^a  

^a UNIVERSITY OF PORTO   (Portugal)

^b RESEARCH INSTITUTE FOR MEDICINES IMED ULISBOA   (Portugal)

^c Proteomics Platform   (Spain)

Author keywords

Cyclization activated; Paracetamol; Peptide carrier; Prodrug

Indexed keywords

DIPEPTIDE DERIVATIVE; ESTER DERIVATIVE; GLUTATHIONE; HYDROXYL GROUP; PARACETAMOL; PARACETAMOL DERIVATIVE; PRODRUG; PROLINE; SARCOSINE;

AMINO TERMINAL SEQUENCE; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; BULK DENSITY; CARBOXY TERMINAL SEQUENCE; CONTROLLED STUDY; CYCLIZATION; DRUG SYNTHESIS; ESTERIFICATION; HYDROLYSIS; LIVER TOXICITY; MOUSE; NONHUMAN; PH; QUANTITATIVE ANALYSIS; REACTION ANALYSIS; TEMPERATURE; TEMPERATURE DEPENDENCE; TOXICITY TESTING;

EID: 14644436965     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2005.01.065     Document Type: Article

References (21)

1. G.J. Friis, and H. Bundgaard P. Krogsgaard-Larsen T. Liljefors U. Madsen A Textbook of Drug Design and Development 2nd ed. 1996 Harwood Academic Amsterdam 351
2. T.D. Boyer, and S.L. Rouff J. Am. Med. Assoc. 218 1971 440
3. D.C. Dahlin, and S.D. Nelson J. Med. Chem. 25 1982 885
4. N.P. Vermeulen, J.G. Bessems, and R. Van de Straat Drug Metab. Rev. 24 1992 367
5. E. Bousquet, A. Marrazzo, G. Puglisi, A. Spadaro, and S. Tirendi J. Pharm. Pharmacol. 48 1996 479
6. I.M. Kovach, I.H. Pitman, and T. Higuchi J. Pharm. Sci. 70 1981 881
7. C. Goolcharran, and R.T. Borchardt J. Pharm. Sci. 87 1998 283
8. D. Shan, M.G. Nicolaou, R.T. Borchardt, and B. Wang J. Pharm. Sci. 86 1997 765
9. P. Wipf, W.L. Li, C.M. Adeyeye, J.M. Rusnak, and J.S. Lazo Bioorg. Med. Chem. 4 1996 1585
10. A.R. Hamel, F. Hubler, A. Carrupt, R.M. Wenger, and M. Mutter J. Pept. Res. 63 2004 147
11. 2SO, 75 MHz): δ 18.01, 18.86, 23.82, 29.93, 57.69, 64.85, 119.89, 121.56, 137.21, 145.17, 166.62, 168.26, 170.04; MW (Da): 307.2231 (calcd, 307.3451)
12. 3CN in aqueous buffer as HPLC solvent, and retention times for the relevant DKP, paracetamol and 4i were 9.90, 7.70 and 4.10 min, respectively
13. J.E. Purdie, and N.L. Benoiton J. Chem. Soc., Perkin Trans. 2 13 1973 1845
14. U. Meresaar, and A. Ågren Acta Pharm. Suec. 5 1968 85
15. E. Jensen, and H. Bundgaard Int. J. Pharm. 71 1991 117
16. S.W. Larsen, M. Ankersen, and C. Larsen Eur. J. Pharm. Sci. 22 2004 399
17. P.N. Craig C. Hansch Comprehensive Medicinal Chemistry Vol. 6 1990 Pergamon Oxford 245
18. Charton ν values taken from O. Exner N.B. Chapman J. Shorter Correlation Analysis in Chemistry 1978 Plenum New York 439
19. P. Lloyd-Williams, F. Albericio, and E. Giralt Chemical Approaches to the Synthesis of Peptides and Proteins 1997 CRC Boca Raton p 60
20. The effect of compounds 4d, 4h, 4i and paracetamol on the hepatic levels of glutathione was determined as follows: healthy male BALB/c mice, 17-21 g and 5 weeks old, were allowed free access to water and pelleted food; mice were randomly divided into five groups of four animals each; four groups were treated ip with a single dose of 3.3 mmol/kg of paracetamol or ester 4 (in 30% of propyleneglycol); the vehicle was administered ip to a control group; 2 h post-administration, the animals were sacrificed and the liver removed and kept on ice; glutathione in homogenized liver was immediately determined using 5,5′-dithiobis-(2-nitrobenzoic acid) (DTNB) as described in J. Sedlak, and R.H. Lindsay Anal. Biochem. 25 1968 192
21. K.F. Thomsen, and H. Bundgaard Int. J. Pharm. 91 1993 39