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Metabolism and Pharmacokinetics of the Cyclin-Dependent Kinase Inhibitor R-Roscovitine in the Mouse

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Metabolism and Pharmacokinetics of the Cyclin-Dependent Kinase Inhibitor R-Roscovitine in the Mouse Molecular Cancer Therapeutics 125 Metabolism and pharmacokinetics of the cyclin-dependent kinase inhibitor R-roscovitine in the mouse Bernard P. Nutley,1 Florence I. Raynaud,1 COOH-R-roscovitine could be inhibited by replacement Stuart C. Wilson,1 Peter M. Fischer,2 of metabolically labile protons with deuterium. After 1 1 Angela Hayes, Phyllis M. Goddard, 60 minutes of incubation of R -roscovitine-d9 or Steven J. McClue,2 Michael Jarman,1 R-roscovitine with mouse liver microsomes, formation of 2 1 f David P. Lane, and Paul Workman COOH-R-roscovitine-d9 was decreased by 24% com- pared with the production of COOH-R-roscovitine. In 1 Cancer Research UK Centre for Cancer Therapeutics, Institute of addition, the levels of R-roscovitine-d remaining were Cancer Research, Surrey, United Kingdom and 2Cyclacel Ltd., 9 Dundee, United Kingdom 33% higher than those of R-roscovitine. However, formation of several minor R-roscovitine metabolites was enhanced with R-roscovitine-d9, suggesting that metabolic Abstract switching from the major carbinol oxidation pathway had occurred. Synthetic COOH-R-roscovitine and C8-oxo- R-roscovitine (seliciclib, CYC202) is a cyclin-dependent R-roscovitine were tested in functional cyclin-dependent kinase inhibitor currently in phase II clinical trials in patients kinase assays and shown to be less active than with cancer. Here, we describe its mouse metabolism and R-roscovitine, confirming that these metabolic reactions pharmacokinetics as well as the identification of the are deactivation pathways. [Mol Cancer Ther 2005; principal metabolites in hepatic microsomes, plasma, and 4(1):125–39] urine. Following microsomal incubation of R-roscovitine at 10 Ag/mL (28 Amol/L) for 60 minutes, 86.7% of the parent drug was metabolized and 60% of this loss was due to Introduction formation of one particular metabolite. This was identified Mammalian cell division is tightly regulated by the as the carboxylic acid resulting from oxidation of the activation of the cyclin-dependent kinase (CDK) family of hydroxymethyl group of the amino alcohol substituent at cell cycle regulatory proteins (1). This regulation is required C2 of the purine core present in R-roscovitine. Identifica- for the processes that govern cell proliferation and to allow tion was confirmed by chemical synthesis and comparison DNA replication and mitosis to occur in proper sequence of an authentic sample of the R-roscovitine-derived and at the correct time. Activation of the CDKs is controlled carboxylate metabolite (COOH-R-roscovitine). Other minor by various signal transduction pathways and requires metabolites were identified as C8-oxo-R-roscovitine and 9 formation of a complex consisting of the catalytic CDK unit N -desisopropyl-R-roscovitine; these accounted for 4.9% and the appropriate regulatory cyclin subunit (2). Once and 2.6% of the parent, respectively. The same metabolic activated, these cyclin-CDK complexes in turn regulate pattern was observed in vivo, with a 4.5-fold lower AUC11 other factors (e.g., phosphorylation of the retinoblastoma for R-roscovitine (38 Amol/L/h) than for COOH-R-roscovi- protein) leading to an orderly progression through the cell tine (174 Amol/L/h). Excretion of R-roscovitine in the urine cycle. Several such cyclin-CDK complexes have been up to 24 hours post-dosing accounted for an average of identified and these were shown to regulate various points only 0.02% of the administered dose of 50 mg/kg, of the cell cycle (1). Control of the cell cycle is commonly whereas COOH-R-roscovitine represented 65% to 68% deregulated in human cancers, for example, by mutation or of the dose irrespective of the route of administration (i.v., altered expression of CDKs, cyclins, and their regulatory i.p., or p.o.). A partially deuterated derivative (R-roscovi- molecules (2). Because of this, synthetic inhibitors of CDKs tine-d9) was synthesized to investigate if formation of may provide important new cancer treatments that are more selective than many of the cytotoxic drugs currently in use (2–4). Previous reports have described the discovery of 2,6,9- trisubstituted purines that were effective at inhibiting the Received 7/29/04; revised 11/3/04; accepted 11/10/04. activity of several protein kinase classes, including the CDK Grant support: Cancer Research UK and Cyclacel Ltd. D. Lane is a Gibb family and especially CDK2 (5–8). Since the first report (5) Fellow and P. Workman is a Life Fellow of Cancer Research UK. of the selective inhibition of CDK2 by the 2,6,9-trisubsti- The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked tuted purine olomoucine (Fig. 1), there has been substantial advertisement in accordance with 18 U.S.C. Section 1734 solely to progress in the development of more potent analogues. indicate this fact. Among these, CYC202 (seliciclib), a pure and chirally Requests for reprints: Florence I. Raynaud, Cancer Research UK Centre for defined form (9) of R-roscovitine (refs. 8, 10; Fig. 1), was Cancer Therapeutics, Institute of Cancer Research, Cotswold Road, Sutton, Surrey SM2 5NG, United Kingdom. Phone: 44-20-8722-4212; chosen for development from a large set of 2,6,9-trisubsti- Fax: 44-20-8770-7899. E-mail: [email protected] tuted purine analogues (11) and is currently undergoing Copyright C 2005 American Association for Cancer Research. phase II clinical trials (12, 13). Mol Cancer Ther 2005;4(1). January 2005 Downloaded from mct.aacrjournals.org on September 28, 2021. © 2005 American Association for Cancer Research. 126 Metabolism and Pharmacokinetics of R-Roscovitine (CYC202) atmosphere cooled to 0jC was added diisopropylethyl- amine (4.0 mL, 2.64 eq, 22.96 mmol) followed by benzyl- amine (1.15 mL, 1.21 eq, 10.53 mmol). The reaction mixture was stirred at 0jC for 3 hours, allowed to return to room temperature over 30 minutes, and stirred at this tempera- ture for 16 hours, when thin-layer chromatography with CH2Cl2/Et2O/MeOH (55:43:2) indicated that the reaction had gone to completion. The solvent was evaporated in vacuo, and the residue was purified by gradient column chromatography on silica gel eluted with CH2Cl2/Et2O/ MeOH (55:45:0–55:43:2) to afford 2 as a white solid (1.36 g, 64%). Melting point 240-241jC. 1Hnuclearmagnetic y resonance (NMR) (d6-DMSO, 250 MHz): 4.62 (d, 2H, J = 5.60 Hz, -HNCH2-Bz), 7.25-7.33 (m, 5H, Bz), 8.10 (s, 1H, -N = CH-NH-), 8.81 (brs, 1H, -HNCH2-Bz), 13.06 (brs, 1H, -N = CH-NH-). Fast atom bombardment mass spectroscopy (FABMS) m/z: 244 ([M + H]+, 100), 180 (15), 166 (9), 136 (5), 91 (10). Accurate mass (M + H): actual: 244.0998, measured: 244.1002. Microanalysis (expected/measured): C12H10N5F: C: 59.25:59.12, H: 4.14:4.06, N: 28.79:28.47. Benzyl-(2-fluoro-9-isopropyl-9H-purin-6-yl)amine (3a). To a stirred solution of 2 (0.83 g, 1 eq, 3.41 mmol) in Figure 1. Chemical structures of olomoucine (OLO), R-roscovitine dimethylacetamide (10 mL) at room temperature under an (ROS), COOH-R-roscovitine (COOH-ROS), and bohemine (BOH). argon atmosphere was added powdered, anhydrous K2CO3 (2.35 g, 5 eq, 17.00 mmol) followed by 2-bromopro- pane (3.2 mL, 10 eq, 34.08 mmol). The reaction mixture was stirred at room temperature for 48 hours, when thin- Identification of the biotransformation pathways is an essential component of the rational development and use of molecular therapeutics. In this article, we present the results of our in vitro and in vivo studies of the metabolism of R-roscovitine in the mouse. Our findings are supported by the synthesis of putative metabolites and of selectively deuterated derivatives. We identified the major metabolite of R-roscovitine as a carboxylic acid formed by oxidation of the hydroxymethyl moiety of the purine C2 substituent and show that the formation of this metabolite is a deactivation reaction. The results presented here contributed to the initiation of clinical trials with R- roscovitine and the basic murine pharmacokinetics and metabolism variables have been observed recently to be similar in humans (14). Materials and Methods General SKF-525A, NADPH, and formic acid (96% ACS grade) were purchased from Sigma-Aldrich (Gillingham, Dorset, United Kingdom). High-performance liquid chromatogra- phy–grade methanol was purchased from Laserchrom (Rochester, Kent, United Kingdom). Olomoucine and R-roscovitine were prepared as described previously (8, 9). Schemes for the synthesis of other compounds used in this study are given in Fig. 2. Protein kinase assays were Figure 2. Scheme for synthesis of compounds used in this study. a, j done as described previously (12). BnNH2,iPr2NEt, n-butanol, 95 C, 4 h. b, iPr-Br (for 3a)oriso-C3D7Br (for 3b), K2CO3, DMA, room temperature, 24 h. c, 8 (for 4a)or Syntheses NH2CH(CH2CH3)COOH (for 4b), DBU, NMP, 160jC, 1 h (racemiza- Benzyl-(2-fluoro-9H-purin-6-yl)amine (2). To a stirred tion during reaction). d, DIEA, n-butanol, DMSO, CH3CH2C(NH2)CH2OH, 140jC, 48 h. DMA, -bromosuccinimide, room temperature, 16 h. solution of 6-chloro-2-fluoro-9H-purine 1 (1.5 g, 1 eq, 8.69 e, N f, DMSO, NaOH aqueous, 140jC, 32 h. g, LiAlD4, monoglyme, 95jC, 16 mmol; ref. 15) in n-butanol (100 mL) under an argon h. h, 9, DIEA, n-butanol, DMSO, 140jC, 48 h. Mol Cancer Ther 2005;4(1). January 2005 Downloaded from mct.aacrjournals.org on September 28, 2021. © 2005 American Association for Cancer Research. Molecular Cancer Therapeutics 127 layer chromatography with CH2Cl2/Et2O/MeOH (55:40:5) (R)-2-(6-Benzylamino-9-isopropyl-9H-purin-2-ylami- indicated that the reaction had gone to completion.
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