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. 2008 Jun 15;16(12):6319-32.
doi: 10.1016/j.bmc.2008.05.013. Epub 2008 May 9.

Synthesis and potency of novel uracil nucleotides and derivatives as P2Y2 and P2Y6 receptor agonists

Hyojin Ko  1 , Rhonda L Carter, Liesbet Cosyn, Riccardo Petrelli, Sonia de Castro, Pedro Besada, Yixing Zhou, Loredana Cappellacci, Palmarisa Franchetti, Mario Grifantini, Serge Van Calenbergh, T Kendall Harden, Kenneth A Jacobson
Affiliations

Synthesis and potency of novel uracil nucleotides and derivatives as P2Y2 and P2Y6 receptor agonists

Hyojin Ko et al. Bioorg Med Chem. .

Abstract

The phosphate, uracil, and ribose moieties of uracil nucleotides were varied structurally for evaluation of agonist activity at the human P2Y(2), P2Y(4), and P2Y(6) receptors. The 2-thio modification, found previously to enhance P2Y(2) receptor potency, could be combined with other favorable modifications to produce novel molecules that exhibit high potencies and receptor selectivities. Phosphonomethylene bridges introduced for stability in analogues of UDP, UTP, and uracil dinucleotides markedly reduced potency. Truncation of dinucleotide agonists of the P2Y(2) receptor, in the form of Up(4)-sugars, indicated that a terminal uracil ring is not essential for moderate potency at this receptor and that specific SAR patterns are observed at this distal end of the molecule. Key compounds reported in this study include 9, alpha,beta-methylene-UDP, a P2Y(6) receptor agonist; 30, Up(4)-phenyl ester and 34, Up(4)-[1]glucose, selective P2Y(2) receptor agonists; dihalomethylene phosphonate analogues 16 and 41, selective P2Y(2) receptor agonists; 43, the 2-thio analogue of INS37217 (P(1)-(uridine-5')-P(4)-(2'-deoxycytidine-5')tetraphosphate), a potent and selective P2Y(2) receptor agonist.

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Figures

Figure 1
Figure 1
Activity of compounds 2 (the native agonist, UDP) and 9 (α,β-methylene-UDP) at the P2Y6 receptor as indicated by activation of PLC in stably transfected astrocytoma cells.
Figure 2
Figure 2
Activity of compound 30 (uridine 5′-tetraphosphate δ-phenyl ester) at P2Y2, P2Y4, and P2Y6 receptors as indicated by activation of PLC in stably transfected astrocytoma cells. The effect of UTP corresponds to 100%.
Figure 3
Figure 3
Activity of compounds 34 – 37 (uridine 5′-tetraphosphate δ-sugars) at the P2Y2 receptor as indicated by activation of PLC in stably transfected astrocytoma cells.
Scheme 1
Scheme 1
Synthesis of UDP analogues containing a methylene-bridged substitute for the diphosphate group. Reagents and conditions: (a) DCC, ROH, DMF, rt.
Scheme 2
Scheme 2
Synthesis of UTP analogues containing a β,γ-dihalomethylene-bridge in the triphosphate group. Reagents and conditions: (a) PO(OH)2CX2PO(OH)2, DMF, rt.
Scheme 3
Scheme 3
Synthesis of UTP analogues with modified uracil and ribose moieties. Reagents and conditions: (a) (i) POCl3, proton sponge, PO(OMe)3, 0°C; (ii) (Bu3NH)2H2P2O7, Bu3N, DMF, 0°C; (iii) TEAB 0.2M rt.; (b) (i) POCl3, PO(OMe)3, 4 h, 0°C; (ii) conc. NH4OH; (iii) Bu3N, CDI, DMF, 48; (iv) (Bu3NH)2H2P2O7; TEAB 1M for 19; (c) (i) POCl3, PO(OMe)3, 49 or 50, 0°C; (ii) conc. NH4OH; (iii) CDI, DMF, rt; (iv) (Bu3NH)2H2P2O7, DMF, rt for 20 or 21. Note that the UDP analogue 6 (not shown in scheme) was prepared by a similar method to (a), except for use of a phosphoric acid salt in the second step: (ii) (Bu3NH)2H2PO4, Bu3N, DMF, 0°C.
Scheme 4
Scheme 4
Synthesis of a 5-iodo analogue of INS48823. Reagents and conditions: (a) phenylacetaldehyde dimethylacetal, TFA, rt; (b) 5-iodo-uridine-5′-diphosphoimidazolidate, DMF, rt.
Scheme 5
Scheme 5
Synthesis of 5′-tetraphosphate analogues, including Up4-sugars and dinucleotides. The 2′-deoxyguanosine derivative 44 was prepared in the same manner as 43. Reagents and conditions: (a) (i) DCC, DMF, rt; (ii) RPO(OH)2, DMF, rt.
Scheme 6
Scheme 6
Synthesis of nucleoside intermediates. Reagents and conditions: A, benzotriazole-1-carboxamide, DMF; B, (a) silylated 2-thiouracil, SnCl4, C2H4Cl2; (b) Lawesson’s reagent, toluene, 80°C, overnight; (c) NaOMe, MeOH, reflux, 4 h; C, (a) H2S, Et3N, DMF, 200 psi, 2 days; D, (a) (i) 1,2-dichloroethane, hexamethyldisilazane, trimethylsilylchloride, 80°C, 4 h; (ii) SnCl4, rt, 4 h; (b) NH3/CH3OH, rt, overnight.
Chart 1
Chart 1
Agonists of the P2Y2 and P2Y6 receptors.
See this image and copyright information in PMC

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