Synthesis and purine receptor affinity of 6-oxopurine nucleosides and nucleotides containing (N)-methanocarba-pseudoribose rings

Abstract

Abstract6-Oxopurine derivatives containing a northern (N) methanocarba modification (i.e., fused cyclopropane and cyclopentane rings in place of the ribose) were synthesized and the adenosine receptor affinity measured. Guanine or hypoxanthine was coupled at the 7-position, or 1,3-dibutylxanthine was coupled at the 9-position. The pseudoribose ring was also substituted at the 5′-position with an N-methyluronamide or with phosphate groups.We recently examined conformational requirements of the ribose moiety in adenosine derivatives acting as agonists or partial agonists at P2 receptors and at subtypes of adenosine receptors (A 1 , A 2A , and A 3 ARs). 1-3 Using a methanocarba modification originally introduced by Marquez and co-workers, 4 the ribose-like moiety of these derivatives was constrained to either a northern [(N), 2′-exo] or southern [(S), 2′-endo] conformation through fused cyclopropane and cyclopentane rings. Such analogues helped to define the role of ribofuranosyl puckering in stabilizing the active AR-bound conformation, and thereby allowed identification of the (N)-methanocarba conformation as the isomer which preserved affinity at the A 3 and to a lesser extent, A 1 AR. Thus, the (N)-methanocarba analogues, 1 and 2, were highly potent as full agonist (2) 3 or partial agonist (1) at the human A 3 AR. 2 These analogues contained substituent groups known to enhance A 3 affinity in the ribose series [i.e., N 6 -(3-iodobenzyl) and 2-chloro]. The affinity of adenosine methanocarba analogues at the A 2A AR was greatly decreased for the (N)-methanocarba isomer and nearly absent for the (S)-methanocarba isomer.In this study, we combined the (N)-methanocarba modification with known purine receptor ligands containing a 6-oxo-substitution. Among the nucleoside analogues synthesized were derivatives of hypoxanthine, guanosine, and xanthine. For inosine 5,6 and xanthine-7-riboside 7 analogues, a 5′-methyluronamide modification (nucleoside numbering) known to enhance the A 3 AR affinity was included. 3,5 In comparison, xanthine-7-riboside derivatives 3 and 4 bound to and activated the rat A 3 AR with partial or full efficacy, respectively, 7,8 and

Design and in Vivo Characterization of A1 Adenosine Receptor Agonists in the Native Ribose and Conformationally Constrained (N)-Methanocarba Series

“…In fact, compared to 38 , its A 1 AR affinity is greatly enhanced to achieve ∼400-fold mA 1 AR selectivity compared to mA 3 AR. However, not all non-adenine nucleobases have this enhancing effect, as was shown with the 1,3-dialkylxanthine-7-ribosides, which display only a small rA 1 AR enhancement upon replacement of ribose with (N)-methanocarba ( K i = 24 μM for the 1,3-di- n -butyl analogue) …”

“…However, not all non-adenine nucleobases have this enhancing effect, as was shown with the 1,3-dialkylxanthine-7-ribosides, which display only a small rA 1 AR enhancement upon replacement of ribose with (N)methanocarba (K i = 24 μM for the 1,3-di-n-butyl analogue). 63 In the (N)-methanocarba series, conversion of 5′-OH to 5′-Cl either slightly (26 vs 24) or greatly reduced (27 vs 25) the A 1 AR-affinity. A comparison of 21 and 22 indicated a beneficial effect of 5′-Cl substitution in a simple (N)methanocarba derivative.…”

“…A water molecule was copied from the A 2A AR 2YDO structure (RESID 2017) and minimized with OPLS3 force field. Compound 9 was docked to the receptor using Glide , docking software of the Schrödinger suite, with XP scoring function, and constraining the compound core to the adenosine scaffold. Glu172 (EL2), Met177 (5.37), T257 (6.58), K265 (EL3), and T270 (7.34) were restored from the cryo-EM structure and finally minimized in the presence of the docked compound with OPLS3 force field .…”

“…Compound 62 (91%) was prepared from compound 59 following the same method as for compound 60. 9-((3aR,3bS,4aS,5R,5aS)-3b-(Chloromethyl)-2,2-dimethylhexahydrocyclopropa [3,4]cyclopenta[1,2-d][1,3]dioxol-5-yl)-N-(dicyclobutylmethyl)-9H-purin-6-amine (63). Thionyl chloride (0.048 mL, 0.39 mL) was added dropwise to a solution of compound 60 (58 mg, 0.13 mmol) in dry CH 3 CN at −5 °C followed by pyridine (32 L, 0.39 mmol) and the solution stirred for 30 min in the same condition.…”

Methanocarba ring as a ribose modification in ligands of G protein-coupled purine and pyrimidine receptors: synthetic approaches

“…The inosine-5 0monophosphate derivative 103 was completely inactive at the A 3 AR, while the dinucleotide 105 displayed binding at A 3 AR with a K i value of 22 mM. 33 Dimerization of an inactive ligand might increase the affinity by bridging two sites on a receptor. It is unusual for such a highly anionic molecule to bind to an AR, Fig.…”