Synthesis of Tubercidin, 6-Chlorotubercidin and Related Nucleosides

Abstract

Tubercidin (7-deazaadenosine, 1a) and several 6-chlorotuber-cidin derivatives were synthesized including 4-amino-6-chloro-7-β-D-ribofuranosylpyrrolo[2,3-d]pyrimidine-3′,5′-cycyclic phosphate 9. Isolation of a side product found in the glycosylation step of the reaction sequence proved to be the N-1 ribosyl-attached isomer as shown by X-ray diffraction analysis. All derivatives were tested for in vitro antiviral and antitumor activity.     

Synthesis of Base Substituted 2-Hydroxy-3-(purin-9-yl)-propanoic Acids and 4-(Purin-9-yl)-3-butenoic Acids

Abstract

Alkylation of 6-chloropurine and 2-amino-6-chloropurine with bromoacetaldehyde diethyl acetal afforded 6-chloro-9-(2,2-diethoxyethyl)purine (3a) and its 2-amino congener (3b). Treatment of compounds 3 with primary and secondary amines gave the N⁶-substituted adenines (5a–5c) and 2,6-diaminopurines (5d–5f). Hydrolysis of 3 resulted in hypoxanthine (6a) and guanine (6b) derivatives, while their reaction with thiourea led to 6-sulfanylpurine (7a) and 2-amino-6-sulfanylpurine (7b) compounds. Treatment with diluted acid followed by potassium cyanide treatment and acid hydrolysis afforded 6-substituted 3-(purin-9-yl)- and 3-(2-aminopurin-9-yl)-2-hydroxypropanoic acids (8–10). Reaction of compounds 3 with malonic acid in aqueous solution gave exclusively the product of isomerisation, 6-substituted 4-(purin-9-yl)-3-butenoic acids (15).     

Thiocyanation of Tubercidin and Its Derivatization to 6-Propyl-and 6-Cyano Derivatives (Nucleosides and Nucleotides. 411.)

Abstract

Thiocyanation of tubercidin with thiocyanogen chloride gave the 5-thiocyanate, which was converted to the 5-methylthio, 5-methylsulfonyl as well as 6-propyl and 6-cyano derivatives. The 6,5′-O-cyclotubercidins were also prepared.     

Nucleophilic Substitution Reactions of 5-Bromo-6-methyluridines

Abstract

The reactions of the 5-bromo-6-methyl-2′,3′-O-isopropylideneuridines 9 and 10 with a number of nucleophiles in hot DMF have been investigated. With acetate ion as the nucleophile, either the 5-acetoxy- (11,12) or the 6-acetoxymethyl- (15) products can be obtained in modest yield depending upon the exact reaction conditions. With nitrogen nucleophiles (aniline or p-methoxybenzylamine) reaction takes place at the 6-methyl carbon, whereas with sulfur nucleophiles (thiophenol, thioacetate) only the 5-substituted products are obtained.     

As-Triazine Derivatives with Potential Therapeutic Action. XXVI.1 Synthesis of 5-Substituted-6-Azauracil Acyclonucleosides

Abstract

5-Substituted 6-azauracils were alkylated with (2-acetoxyethoxy)methyl bromide to give protected acyclic nucleosides which were deprotected to afford acyclonucleosides of 5-substituted 6-azauracils. Their structures have been established by the UV and ¹H-NMR spectra and by elemental analysis.     

Synthetic and Antiviral Studies on Certain Acyclic Nucleosides of 5-Benzyl-6-Azauracil Derivatives

Abstract

Several 5-(4-substituted benzyl)-6-azauracils have been synthesized from the corresponding benzaldehydes. The 5-benzyl-6-azauracils were silylated with hexamethyldisilazane and then glycosylated with aliphatic halides, e.g., (2-acetoxyethoxy)methyl bromide and 1,3-dibenzyloxy-2-chloromethoxypropane, to give protected acyclic nucleosides which were deprotected to afford acyclonucleosides of 5-(4-substituted benzyl)-6-azauracils. None of the compounds exhibited significant antiviral activity against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) in vitro.     

Synthesis of 6-Sulfur Analogues of Oxanosine and Closely Related Derivatives Thereof

Abstract

Novel β-D-ribofuranosides having a 5-substituted imidazo [4,5-d] [1,3]thiazine ring, including the S⁶-congener 3 of oxanosine 2, were synthesized for screening their anticancer and antiviral activities.     

A Convenient Approach to N-3 Alkylation of 9-Substituted Guanines

Abstract

Aryl or tert-butyl substituent in the 6 position of 3,9-dihydro-3-[(2-hydroxy-ethoxy)methyl]-9-oxo-6-R-5H-imidazo[1,2-α]purine 1 directs the benzylation reaction partly into N-4 position to give 3. Cleavage of the third ring of 3 gives 3-benzylacycloguanosine 5, a first 3-aralkilo-9-substituted guanine.     

Synthesis of 2′-Deoxyribonucleoside Derivatives of 1-Deazapurine

Abstract

5, 7-Dichloro-3H-imidazo[4, 5-b]pyridine (4) is a versatile base which can be coupled with a variety of sugar moieties and transformed in a series of 7-alkyl(aryl)amino-derivatives by reacting with the corresponding amines. In this paper synthesis, structure elucidation and ADA inhibitory activity of 2′-deoxyribonucleoside derivatives of N⁶-substituted 1-deazaapurines are described.     

Synthesis of 2′-Deuterio Tubercidin and Adenosine and the Corresponding Arabino Analogs

Abstract

The 2′-deuterio arabino analogs of tubercidin and adenosine have been prepared by Swern oxidation of the 3′,5′-TPDS derivatives of tubercidin and adenosine and reduction with NaBD_4. Subsequent inversion of stereochemistry at C-2′ yielded [2′-²H]tubercidin and [2′-²H]adenosine with 98% deuterium incorporation.     

A Functional Screening of Adenosine Analogues at the Adenosine A2B Receptor: A Search for Potent Agonists

Abstract

Various adenosine analogues were tested at the adenosine A_2B receptor. Agonist potencies were determined by measuring the cyclic AMP production in Chinese Hamster Ovary cells expressing human A_2B receptors. 5′-.N-Substituted carboxamidoadenosines were most potent. 5′-N-Ethylcarboxamidoadenosine (NECA) was most active with an ECso value of 3.1 μM. Other ribose modified derivatives displayed low to negligible activity. Potency was reduced by substitution on the exocyclic amino function (N⁶) of the purine ring system. The most active N⁶-substituted derivative N⁶-methyl-NECA was 5 fold less potent than NECA. C8-and most C2-substituted analogues were virtually inactive. 1-Deaza-analogues had a reduced potency, 3-and 7-deazaanalogues were not active.     

Synthesis and Anti-HIV Activity of 6-Substituted Purine 2′-Deoxy-2′-fluororibosides

Abstract

3′,5′-Di-O-protected 6-chloropurine arabinoside 4b was treated with diethylaminosulfur trifluoride (DAST) and subsequently deprotected with pyridinium p-toluenesulfonate to give 6-chloropurine 2′-deoxy-2′-fluororiboside 6a. The displacement with nucleophile afforded the 6-substituted congener 6b-e. Treatment of 5′-O-protected 6-chloropurine arabinoside 3c with DAST gave lyxoepoxide 7.     

Synthesis and Anti-juvenile Hormone Activity of 1-Citronellyl-5-substituted Imidazoles

A number of 1-citronellyl-5-substituted imidazoles were synthesized and bioassayed on the silkworm, Bombyx mori, in order to assess their anti-juvenile hormone activity. Most of the 1-citronellyl-5-substituted imidazoles induced precocious metamorphosis in the 3rd and 4th instar larvae of B. mori by topical application. The percentage of precocious metamorphosis correlated well with the dosage. Among the compounds tested, l-citronellyl-5-(2-chlorophenyl)imidazole (8) and the 2-methylphenyl analog 10 showed the highest activity. When compounds 8 and 10 were applied to the 4th instar larvae at 10 μg/larva, precocious pupation was induced in 100% without any lethal effects.     

SYNTHESIS AND BIOLOGICAL ACTIVITY OF 5-SUBSTITUTED ANTI-CONSTRAINED ACYCLIC ANALOGS OF CYTIDINE AND URIDINE

Abstract

Abstract. A number of 5-substituted constrained acyclic analogs of cytidine and uridine have been prepared in which the glycosyl torsion angle is constrained in the anti conformation. Compounds 2a-c, 3a-c, 4, 5 and 6 were tested for activity against HCMV and HSV-1. Compounds 2a and 2b showed moderate activity against HCMV. Compound 2c exhibited a weak inhibitory activity against HSV-1. Compounds 2a, 3a, 4, 5, 6, 8, and 9 were screened for their anti-HIV or antitumor activity. None of them were active against HIV. However, compound 9 showed a 50% inhibition on MDA-MB-231/ATTC breast cancer cell growth at a concentration of 0.15 μM.     

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.     

Substituent — Directed Aralkylation and Alkylation Reactions of the Tricyclic Analogues of Acyclovir and Guanosine

Abstract

Aryl or tert-butyl substituent in the 6 position of 3,9-dihydro-3-[(2-hydroxyethoxy)methyl]-9-oxo-6-R-5H-imidazo[1,2-α]purine (6-R-TACV)¹ 1 partly directs aralkylation reactions into unusual positions: N-4 to give 3 and C-7 to give N-5, 7-disubstituted or N-4, 7-disubstituted derivatives. In the case of alkylation the effect is limited to aryl substituent and position N-4. Replacement of acyclic moiety of 1 with a ribosyl one like in 7 prevents N-4 substitution. Cleavage of the third ring of 3b to give 3-benzylacyclovir 10 is an example of a new short route to 3-aralkyl-9-substituted guanines.     

Design,Synthesis, and Evaluation of Anti-HBV Activity of Hybrid Molecules of Entecavir and Adefovir: Exomethylene Acycloguanine Nucleosides and Their Monophosphate Derivatives

Exomethylene acycloguanine nucleosides 4, 6 and its monophosphate derivatives 5, 7, and 8 have been synthesized. Mitsunobu-type coupling of 2-N-acetyl-6-O-diphenylcarbamoylguanine (11) with primary alcohols proceeded regioselectively to furnish the desired N⁹-substituted products in moderate yield. Evaluation of 4-8 for anti-HBV activity in HepG2 cells revealed that the phosphonate derivative 8 was found to exhibit moderated activity (EC₅₀ value of 0.29 μM), but cytotoxicity (CC₅₀ value of 39 μM) against the host cells was also observed.     

Lithiation-Stannylation Chemistry of Nucleosides

Abstract

Two examples of anionic stannyl migration practically useful for nucleoside synthesis are presented. One involves the migration from the 8- to 2-position of 6-chloropurine derivatives, which provided a new entry to 2-substituted purine nucleosides. The other is that from the 6- to 2′-position of 1′,2′-unsaturated uridine. The latter enabled the preparation of a hitheroto unknown class of nucleoside analogues, 2′-substituted 1′,2′-unsaturated uridines.     

Synthesis and characterization of biologically significant 5,5′-(1,4-phenylene)bis(1-N-alkoxyphthalimido-3-aryl-2-pyrazoline) derivatives

A facile synthesis of 5,5′-(1,4-phenylene)bis(3-aryl-2-pyrazolines) 4a-g has been achieved by the cyclo-addition reaction of hydrazine hydrate with bis-substituted chalcones 3a-g, which in turn were prepared by the Clasien-Schmidt condensation of p-substituted acetophenones 1a-g with terephthaldehyde. Condensation of 4a-g with ω-bromoalkoxyphthalimides 5a-b afforded the titled compounds 6a-n, some of which exhibited significant antimalarial as well as antimicrobial activity.     

Formation of 5- and 6-Aminocytosine Nucleosides and Nucleotides from the Corresponding 5-Bromocytosine Derivatives: Synthesis and Reaction Mechanism

Abstract

An improved method for the synthesis of 5-aminocytidine (3a), 5-amino-2′-deoxycytidine (3b), and their 5′-monophosphates (3c,d) from the corresponding 5-bromo pyrimidines, using liquid ammonia, is described. The respective 6-aminocytosine derivatives (4a,b,c,d), minor products of the amination reaction, were isolated and characterized. A plausible mechanism is proposed to account for the formation of both 5-and 6-substituted products.