Lead Optimization of N 6-Cyclopentyl-3′-amido-3′-deoxyxylofuranosyladenines as Adenosine A1 Receptor Antagonists

Abstract

Strategies toward the further lead optimization of N ⁶-cyclopentyl-3′-amido-3′-deoxyxylofuranosyladenosines as adenosine A₁ receptor antagonists including the synthesis of the 5′-deoxy-analogues and a practical method for parallel amidation are presented.     

Synthesis of N 6-Substituted 3′-Ureidoadenosine Derivatives as Highly Potent Agonists at the Mutant A3 Adenosine Receptor

Several N ⁶ -substituted 3 ′-ureidoadenosine derivatives were efficiently synthesized starting from D-glucose for the development of H272E mutant A ₃ adenosine receptor (AR) agonists. Among compounds tested, 3 ′-ureido-N ⁶ -(3-iodobenzyl)adenosine ( 2c ) exhibited the highest binding affinity (K _i = 0.22 μ M) at the H272E mutant A ₃ AR without binding to the natural A ₃ AR.     

Design and Synthesis of A3 Adenosine Receptor Ligands, 3′-Fluoro Analogues of Cl-IB-MECA

Abstract

Synthesis of 3′-deoxy-3′-fluoro-N ⁶-substituted adenosines as bioisosteres of Cl-IB-MECA and their binding affinities to A₃ adenosine receptor are described.     

Design and Synthesis of A3 Adenosine Receptor Ligands, 2′-Fluoro Analogues of Cl-IB-MECA

Abstract

Synthesis of 2′-deoxy-2′-fluoro-N ⁶-substituted adenosines as bioisosteres of Cl-IB-MECA and their binding affinities to A₃ adenosine receptor are described.     

Acyclic Nucleoside Analogues: III. A Synthesis of New 2′,3′-Dideoxy-2′,3′-Didehydronucleoside Analogues

The coupling of 5-acetoxy-1,1-dimethoxypent-2-ene with cytosine and thymine trimethylsilyl derivatives, as well as the reaction of 5-acetoxy-1-bromopent-2-ene with adenine sodium salt, yielded acyclic analogues of the corresponding nucleosides containing 5-acetoxy groups. They were deprotected with a saturated methanolic solution of ammonia to the target analogues of nucleosides, which were characterized with ¹H NMR, IR, and UV spectra.     

Structure-Activity Relationships Among a New Class of Antiviral Heterosubstituted 2′,3′-Dideoxynucleoside Analogues

Abstract

3′-Oxa-4′-thiocytidine nucleoside analogues 14–17 were prepared from oxathiolanes 10 and 11, and evaluated for activity against HIV-1 and HBV in vitro. The nucleoside analogues were found to possess potent activities against HIV-1 in a panel of cell lines. Compound 16 is moderately active against HBV in 2.2.15 cells.     

Synthesis of 3′-Acetamidoadenosine Derivatives as Potential A3 Adenosine Receptor Agonists

On the basis of high binding affinity of 3′-aminoadenosine derivatives 2b at the human A₃ adenosine receptor (AR), 3′-acetamidoadenosine derivatives 3a–e were synthesized from 1,2:5,6-di-O-isopropylidene-D-glucose via stereoselective hydroboration as a key step. Although all synthesized compounds were totally devoid of binding affinity at the human A₃AR, our results revealed that 3′-position of adenosine can only be tolerated with small size of a hydrogen bonding donor like hydroxyl or amino group in the binding site of human A₃AR.     

Novel Analogues of the Anti-HIV-1 Agent TSAO-T Modified at the 3′-Spiro Moiety

Abstract

Novel TSAO-T analogues, in which the 3′-spiroaminooxatioledioxide moiety has been replaced by other 3′-spiro moieties bearing a NH group at the same position as the 4″-NH₂ of TSAO-T have been prepared and evaluated for their inhibitory effect on HIV replication in cell culture. In contrast to the prototype compound TSAO-T, the novel TSAO derivatives were inactive at subtoxic concentrations.     

New Neplanocin Analogues II. Enzymatic One-Step Synthesis and Antitumor Activity of 6′-(3-sn-Phosphatidyl)Neplanocin a Derivatives

Abstract

A novel series of neplanocin analogues, 6′-(3-sn-phosphatidyl)neplanocin As bearing a variety of fatty acyl or alkyl residues in the glyceride moiety (2b-2h), were synthesized by means of phospholipase D-catalyzed transphosphatidylation. Among them, 2b, 2c, and 2e each exhibited significant antitumor effect against P388 leukemia in mice, which evidently surpassed that of parent compound neplanocin A.     

“Reverse” Carbocyclic Fleximers: Synthesis of a New Class of Adenosine Deaminase Inhibitors

A series of flexible carbocyclic pyrimidine nucleosides has been designed and synthesized. In contrast to previously reported “fleximers” from our laboratory, these analogues have the connectivity of the heterocyclic base system “reversed”, where the pyrimidine ring is attached to the sugar moiety, rather than the five membered imidazole ring. As was previously seen with the ribose fleximers, their inherent flexibility should allow them to adjust to enzyme binding site mutations, as well as increase the affinity for atypical enzymes. Preliminary biological screening has revealed surprising inhibition of adenosine deaminase, despite their lack of resemblance to adenosine.     

A Novel Class of 4′-Aza Analogues of 2′,3′-Dideoxynucleosides as Potential Anti-HIV Drugs

Abstract

The 1,3 dipolar cycloaddition approach represents the most valuable strategy for the preparation of isoxazolidine nucleosides. The latter posses more conformational degrees of freedom than the corresponding dideoxyribosides. Side reactions due to the presence of formaldehyde in the reaction media can be avoided by proper derivatization of the vinyl-nucleobase.     

Design,Synthesis, and Anti-Tumor Activity of 4′-Thionucleosides as Potent and Selective Agonists at the Human A3 Adenosine Receptor

On the basis of potent and selective binding affinity of Cl-IB-MECA to the human A₃ adenosine receptor, its 4′-thioadenosine derivatives were efficiently synthesized starting from D-gulonic γ -lactone. Among compounds tested, 2-chloro-N ⁶-(3-iodobenzyl)- and 2-chloro-N ⁶-methyl-4′ -thioadenosine-5′ -methyluronamides (7a and 7b) exhibited nanomolar range of binding affinity (K _i = 0.38 nM and 0.28 nM, respectively) at the human A₃AR. These compounds showed anti-growth effects on HL-60 leukemia cell, which resulted from the inhibition of Wnt signaling pathway.     

Steric Effect of a Bulky Substituent At 5′-Position on the Regioselectivity of 2′ vs. 3′-O-Methylation of N6- Cyclohexyladenosine

Abstract

Steric effect of a trityl or substituted trityl group at 5′-OH of N⁶-cyclohexyladenosine on the regioselective 2′ vs. 3′-O-methylation under phase transfer catalysis conditions was investigated. Compound 4 showed only a modest increase in the selectivity of 2′ over 3′-O-methylation compared to compound 1.     

Sucrochemistry : Part VI. Further reactions of 6,6′-DI-O-tosylsucrose and a comparison of the reactivity at the 6 and 6′ positions

Reaction of 6,6′-di-O-tosylsucrose hexa-acetate (1) with sodium chloride in hexamethylphosphoric triamide gave a mixture containing preponderantly the hexa-acetates of 6,6′-dichloro-6,6′-dideoxysucrose (2) and 6-chloro-6-deoxy-6′-O-tosyl-sucrose (3). Reaction of 3 with sodium benzoate in (Me₂N)₃PO gave the 6-chloro-6-deoxy-6′-O-benzoyl derivative 4. Subsequent O-de-esterification afforded syrupy 6-chloro-6-deoxysucrose (5), which gave a crystalline heptamethanesulphonate. The chloro groups in the heptabenzoate 7 and the hexa-acetate 2 were replaced by azide in (Me₂N)₃PO to give the corresponding derivatives of 6-azido-6-deoxysucrose (12) and 6,6′-diazido-6,6′-dideoxysucrose (8), respectively. O-De-esterification of the hexa-acetates 2 and 8 yielded the parent 6,6′-dichloride 6 and 6,6′-diazide 9, respectively. 6,6′-Di-O-tosylsucrose hexabenzoate (10) reacted with sodium bromide in (Me₂N)₃PO to give the 6,6′-dibromide 11, in high yield, which afforded 6-deoxy-β-D-xylo-hex-5-enopyranosyl 6′-deoxy-β-D-threo-hex-5′-enofuranoside hexabenzoate on treatment with silver fluoride in pyridine.     

A Short Syhthesis of 3′-(Methylsulfinyl)-3′-Deoxythymidine and Related Analogues

Abstract

The ring opening of the O-2,3′-anhydrothymidine 5 with the anion of methyl mercaptan gave the 3′-methylthio derivaative 6. Subsequent oxidation and deprotection afforded 3′-(methyl-sulfinyl)-3′-deoxythymidine 2 and its sulfone analogue 3.     

Effect of Adenosine on Na+ and Cl− Currents in A6 Monolayers. Receptor Localization and Messenger Involvement

The effect of adenosine regulation on sodium and chloride transport was examined in cultured A₆ renal epithelial cells. Adenosine and its analogue N⁶-cyclopentyladenosine (CPA) had different effects on short-circuit current (I _sc) depending on the side of addition. Basolateral CPA addition induced an approximately threefold increase of the I _sc that reached a maximum effect 20 min after addition and was completely inhibited by preincubation with either an A₂ selective antagonist, CSC, or the sodium channel blocker, amiloride. Apical CPA addition induced a biphasic I _sc response characterized by a rapid fourfold transient increase over its baseline followed by a decline and a plateau phase that were amiloride insensitive. The A₁ adenosine antagonist, CPX, completely prevented this response. This I _sc response to apical CPA was also strongly reduced in Cl⁻-free media and was significantly inhibited either by basolateral bumetanide or apical DPC preincubation. Only basolateral CPA addition was able to induce an increase in cAMP level. CPA, added to cells in suspension, caused a rapid rise in [Ca²⁺] _i that was antagonized by CPX, not affected by CSC and prevented by thapsigargin preincubation. These data suggest that basolateral CPA regulates active sodium transport via A₂ adenosine receptors stimulating adenylate cyclase while apical CPA regulates Cl⁻ secretion via A₁ receptor-mediated changes in [Ca²⁺] _i .     

2′,3′-Isopropylidene Group,A Molecular Scaffold to Study the Activity of Adenosine and Adenylate Deaminase on Adenosine Analogues Modified in the Ribose Moiety

2 ′,3 ′-Isopropylidene group can be used as a molecular scaffold for the introduction of modifications at 5 ′ and 1 ′ positions of adenosine and these modified nucleosides are used to evaluate the biocatalytic activity of adenosine and adenylate deaminase.     

Sucrochemistry : Part X. 1′,4,6′-tri-O-mesylsucrose penta-acetate: A comparison of the reactivity at the 4 and 1′ positions

The 1′,4,6′-trisulphonate 2, obtained by mesylation of sucrose 2,3,3′,4′,6-penta-acetate (1), undergoes nucleophilic substitution with sodium benzoate in hexamethylphosphoric triamide at positions 1′,4, and 6′ to give 1,6-di-O-benzoyl-β-D-fructofuranosyl 4-O-benzoyl-α-D-galactopyranoside penta-acetate (3), and selectively at positions 4 and 6′ to give 6-O-benzoyl-1-O-mesyl-β-D-fructofuranosyl 4-O-benzoyl-α-D-galactopyranoside penta-acetate (4). The products 3 and 4 were identified from their ¹H-n.m.r. spectra and by O-deacylation to give β-D-fructofuranosyl α-D-galactopyranoside (5) and its 1-methanesulphonate 6, respectively. Treatment of the trisulphonate 2 with sodium azide gave analogous products, namely, 1,6-diazido-1,6-dideoxy-β-D-fructofuranosyl 4-azido-4-deoxy-α-D-galactopyranoside penta-acetate (8) and 6-azido-6-deoxy-1-O-mesyl-β-D-fructofuranosyl 4-azido-4-deoxy-α-D-galactopyranoside penta-acetate (7).