Download PDF
Synlett 2002(1): 0164-0166
DOI: 10.1055/s-2002-19327
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis and β-Glucuronidase Mediated Cleavage of an Alcohol Prodrug Incorporating a Double Spacer Moiety

Sébastien Papot, Freddy Rivault, Isabelle Tranoy, Jean-Pierre Gesson*
UMR 6514, Université de Poitiers et CNRS, 40 avenue du Recteur Pineau, 86022 Poitiers, France
e-Mail: jean-pierre.gesson@univ-poitiers.fr;
Further Information

Publication History

Received 12 November 2001
Publication Date:
01 February 2007 (online)

    Permissions and Reprints All articles of this category

Abstract

An alcohol prodrug has been prepared by incorporation of two spacer groups between the trigger (glucuronic acid) and nitroveratryl alcohol, used as a model. Release of the latter has been observed after hydrolysis of the glycoside by β-glucuronidase. Such prodrugs may find application in ADEPT or PMT protocols in cancer chemotherapy.

Key words

prodrug - spacer - glycoside - cleavage - enzyme

    References

  • 1 Bagshawe KD. Tumor Marker Update.  1997,  34:  220 
    Google Scholar
  • 2 Melton RG. Sherwood RF. J. Natl. Cancer Inst.  1996,  21:  153 
    Google Scholar
  • 3 Niculescu-Duvaz I. Springer CJ. Adv. Drug Delivery Rev.  1997,  26:  151 
    CrossrefGoogle Scholar
  • 4 Jungheim LN. Shepherd TA. Chem. Rev.  1994,  94:  1553 
    CrossrefGoogle Scholar
  • 5a Jacquesy J.-C. Gesson J.-P. Monneret C. Mondon M. Renoux B. Florent J.-C. Koch M. Tillequin F. Sedlacek HH. Gerken M. Kolar C. Gaudel G. Bosslet K. Czech J. Hoffmann D. Seemann G. Eur. Pat. Appl.  1992,  EP 511:  917 ; Chem. Abstr. 1994, 120, 271070S
    CrossrefGoogle Scholar
  • 5b Florent J.-C. Dong X. Gaudel G. Mitaku S. Monneret C. Gesson J.-P. Jacquesy J.-C. Mondon M. Renoux B. Andrianomenjanahary S. Michel S. Koch M. Tillequin F. Gerken M. Czech J. Straub R. Bossley K. J. Med. Chem.  1998,  41:  3572 
    CrossrefGoogle Scholar
  • 6 Bosslet K. Czech J. Lorenz P. Sedlacek HH. Schuermann M. Seemann G. Br. J. Cancer  1992,  65:  234 
    Google Scholar
  • 7 Bosslet K. Czech J. Hoffmann D. Tumor Targeting  1995,  1:  45 
    Google Scholar
  • 8 Bosslet K. Czech J. Hoffmann D. Cancer Res.  1994,  54:  2151 
    Google Scholar
  • 9 Schmidt F. Florent J.-C. Monneret C. Straub R. Czech J. Gerken M. Bosslet K. Bioorg. Med. Chem. Lett.  1997,  7:  1071 
    CrossrefGoogle Scholar
  • 10 Lougerstay-Madec R. Florent J.-C. Monneret C. Nemati F. Poupon MF. Anti-Cancer Drug Design.  1998,  13:  995 
    Google Scholar
  • 11 Tietze LF. Lieb M. Herzig T. Haunert F. Schuberth I. Bioorg. Med. Chem.  2001,  9:  1929 
    Google Scholar
  • 12a Schmidt F. Ugureanu I. Duval R. Poupon A. Monneret C. Eur. J. Org. Chem.  2001,  2129 
    Google Scholar
  • 12b Desbene S. Van Dufat-Trinh H. Michel S. Tillequin F. Koch M. Schmidt F. Florent J.-C. Monneret C. Straub R. Czech M. Gerken M. Bosslet K. Anti-cancer Drug Design  1999,  14:  93 
    Google Scholar
  • 13 Papot S. Bachmann C. Combaud D. Gesson J.-P. Tetrahedron  1999,  55:  4699 
    CrossrefGoogle Scholar
  • 14a Bergman J. Brynolf A. Vuorinen E. Tetrahedron  1986,  42:  3689 
    CrossrefGoogle Scholar
  • 14b Bergman J. Norrby PO. Sand P. Tetrahedron  1990,  46:  6113 
    CrossrefGoogle Scholar
  • 15 Coyne WE. Cusic JW. J. Med. Chem.  1968,  11:  1208 
    CrossrefGoogle Scholar
  • 19 We have recently shown that 2-nitro-quinone-methides are not irreversible inhibitors of bovine β-glucuronidase: Azoulay M. Chalard F. Gesson J.-P. Florent J.-C. Monneret C. Carbohydr. Res.  2001,  332:  151 
    CrossrefGoogle Scholar
16

Preparation of 8: 6-Nitroveratryl chloroformate (85 mg, 0.30 mmol) and pyridine (0.075 mL, 0.9 mmol) were added to a stirred solution of 7 (100 mg, 0.15 mmol) in CH2Cl2 (0.65 mL) at r.t. After 3 h the mixture was worked up with a saturated solution of NaHCO3 and the aqueous layer was washed with CH2Cl2. The combined organic layers were dried (MgSO4), filtered, concentrated to dryness and the remaining yellow solid was purified by flash chromatography (petroleum ether-EtOAc 1:1) to give 8 (116 mg, 0.13 mmol, 87%). 1H NMR (300 MHz, CD3COCD3), δ: 2.04, 2.05, 2.07 (3 × s, 9 H, CH3COO), 3.26
(s, 3 H, CH3N), 3.50 (s, 3 H, OCH3), 3.70 (s, 3 H, COOCH3), 3.87 (s, 6 H, OCH3), 4.37 (d, 2 H, J = 6 Hz, CH2N), 4.65
(d, 1 H, J = 9.5 Hz, H-5), 5.00 (s, 2 H, CH2O), 5.18-5.69 (m, 6 H, H-1,2,3,4, CH2O), 6.48 (s, 1 H, Harom), 7.02 (s, 1 H, NH), 7.30-7.84 (m, 8 H, Harom) ppm; 13C NMR (75 MHz, CD3COCD3), δ: 37.9 (CH3N), 41.3 (CH2N), 53.0 (COOCH3), 56.6 (OCH3), 65.0-65.1 (CH2O), 69.9, 71.1, 72.1, 72.8 (C-2,3,4,5), 100.0 (C-1), 121.2-149.6 (Carom), 155.0-156.1 (Carom), 167.7 (COOMe), 169.5, 170.0, 170.2 (CH3CO) ppm; mp 100 °C.

17

Data for 9: [αD] = +6,4 (c 0.95, CHCl3); 1H NMR (300 MHz, CD3COCD3), δ: 3.51 (s, 3 H, CH3N), 3.59-3.62 (m, 3 H,
H-2,3,4), 3.71 (s, 3 H, COOCH3), 3.87 (s, 6 H, OCH3), 4.20 (d, 1 H, J = 9.5 Hz, H-5), 4.37 (d, 2 H, J = 6 Hz, CH2N), 5.00 (s, 2 H, CH2O), 5.33 (s, 2 H, CH2O), 5.51 (d, 1 H, J = 16 Hz, H-1), 7.00 (broad s, 1 H, HNH), 7.31-7.83 (m, 9 H, Harom) ppm; 13C NMR (75 MHz, CD3COCD3), δ: 37.9 (CH3N), 41.3 (CH2N), 52.5 (COOCH3), 56.5, 56.6 (OCH3), 65.0, 65.1 (CH2O), 72.3, 74.1, 76.4, 76.9 (C-2,3,4,5), 101.9 (C-1), 118.1-150.0 (Carom), 155.2, 157.1 (Ccarbamate), 169.5 (COOMe) ppm; mp 90 °C. The highly polar compound 10 does not lead to well resolved NMR spectra (this is observed for all glucuronylated prodrugs).

18

HPLC conditions : C-16 reverse phase column : Discovery RP amide, 5 m (15 cm × 4.6 mm) and pre-column Discovery, 5 µm, UV detection (λ 254 nm), mobile phase (acetonitrile-0.065 M acetate ammonium solution, 30:70, 1 mL min-1). Retention time: 10: 7.8 min; 4-hydroxy-3-nitrobenzyl alcohol: 3.6 min; 3 (R1 = CH3, R2 = H): 4.1 min; 6-nitroveratryl alcohol: 5.2 min; 1 (R1 = CH3, R2 = H, R3 = 6-nitroveratryl alcohol): 6.3 min.