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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;
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Publikationsverlauf

Received 12 November 2001
Publikationsdatum:
01. Februar 2007 (online)

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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

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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.