Carbocyclic Nucleoside Analogues Research Articles

ChemInform Abstract: A Novel Approach to Carbocyclic Analogues of Nucleosides.

AbstractAcetoxynorbornene (I) is converted to the triol (II) which is acetalized to form (IV) and then oxidized, producing the carboxylic acid (V).

Synthesis of 6β-Hydroxyaristeromycin - A Novel Type of Carbocyclic Nucleoside Analogue

Abstract The synthesis of racemic 6β-hydroxyaristeromycin (1) is described.

A Novel Approach to Khantiokerically Pure Carbocyclic Nucleoside Analogues

Abstract Starting from (+)-endo-5-norbornen-2-yl acetate (1) (-)-1-[(1R, 3R, 4R)-3-hydroxy-4-hydroxymethylcyclopentyl]-1H, 3H-pyrinidine-2, 4-dione (7) was synthesized in a 6-step sequence.

Synthesis of cyclopentane analogs of (2′- and 3′-deoxy-erythro-pentofuranosyl and ribofuranosyl)-2-thiouracil nucleosides

Three new carbocyclic analogs of nucleosides having the 2-thiouracil base have been synthesized. The cyclopentyl groups in these nucleosides are (±)-{(1β,3α,4β)-3-hydroxy-4-(hydroxyrnethyl)cyclopentyl} (see 31), (±)-{(1β,2α,4β)-2-hydroxy-4-(hydroxymethyl)cyclopentyl} (see 32), and (±)-{(1β,2α,3α,4β)-2,3-dihydroxy-4-(hydroxymethyl)cyclopentyl} (see 33). The nucleosides were prepared by coupling the appropriate hydroxy derivatives of cis-3-aminocyclopentanemethanol with 3-ethoxypropenoyl isothiocyanate (21) followed by cyclization in 15 N aqueous ammonia to give the 2-thiouracil nucleosides. In addition a modified and shortened synthetic route is described for the synthesis of (±)-(1β,2α,3α,4β)-4-amino-2,3-dihydroxy-cyclopentanemethanol (19). The 1H nmr spectra at 200 MHz of all of the synthetic intermediates, the 2-thiouracil nucleosides, and of the corresponding carbocyclic analogs of uracil nucleosides are discussed. It is shown that each nucleoside has a characteristically unique 1H nmr spectrum and that in general the protons in the sulfur-containing compounds resonate at lower fields than those in the corresponding oxygen-containing compounds. The magnitude of this downfield shift is inversely related to the number of bonds separating a particular proton from the sulfur atom.

A novel approach to carbocyclic analogues of nucleosides

(±)-1-[(1α,3α,4α)-3-Hydroxy-4-hydroxymethlcyclopentyl]- (1H,3H-pyrimidin-2,4-dione (6) was synthesized starting from endo-5-norbornen-2-yl acetate via the urea derivative 5 in 32% overall yield.

Conformational studies of some carbocyclic nucleoside analogues

Proton NMR spectra of some carbocyclic nucleoside analogs of tuberculin have been analyzed at 100 MHz in DMSO-d 6. The spectral characteristics and nuclear Overhauser effects indicate a preferential syn conformation about the glycosidic bond when a hydroxyl group, oriented toward the base, is available for intramolecular hydrogen bond formation.

Carbocyclic analogues of 5-substituted uracil nucleosides: synthesis and antiviral activity.

Carbocyclic analogues of 3'-deoxyuridines, 3'-deoxyuridines, and uridines with substituents at position 5 of the uracil moiety were prepared by direct halogenation (5-bromo and 5-iodo groups) and by displacement of the 5-bromo group by amino and substituted-amino groups. The analogue of 5-(hydroxymethyl)uridine was prepared via reaction of the isopropylidene derivative of the uridine analogue with paraformaldehyde. The carbocyclic analogues of thymidine and of 5-bromo-, 5-iodo-, and 5-(methylamino)-2'-deoxyuridine were highly active in vitro against herpes simplex virus, types 1 and 2. The corresponding analogues of 5-substituted 3'-deoxyuridines and of 5-substituted uridines were not active in this assay.

Evaluation of carbodine, the carbocyclic analog of cytidine, and related carbocyclic analogs of pyrimidine nucleosides for antiviral activity against human influenza Type A viruses.

Carbodine, the carbocyclic analog of cytidine, was found to possess significant antiviral activity against influenza virus types A0/PR-8/34 and A2/Aichi/2/68 (Hong Kong) in vitro. The compound selectively inhibited PR-8 influenza virus-induced cytopathogenic effects in Madin-Darby canine kidney and inhibited Hong Kong influenza virus replication in primary rhesus monkey kidney cell cultures. The 50% minimum inhibitory concentration for inhibition of human influenza type A viruses by carbodine was approximately 2.6 microgram/ml (i.e., in the range of antiviral potency of ribavirin, but less potent than amantadine hydrochloride in concomitant assays). The fact that carbodine is metabolized to carbodine triphosphate in mammalian cells makes interference with the viral ribonucleic acid-dependent ribonucleic acid polymerase reaction a likely possibility for its principal mode of action. The carbocyclic analogs of uridine (the deamination product of carbodine), 2'-deoxycytidine, 3'-deoxycytidine, N,N-dimethylcytidine, N-methylcytidine, and some related carbocyclic analogs of pyrimidine nucleosides were inactive against PR-8 influenza virus in vitro. The combination of carbodine plus tetrahydrouridine was no more effective in vitro than carbodine alone, thus indirectly indicating that deamination of carbodine probably did not occur to a significant degree during the cell culture experiments. Although reproducibly active in vitro, carbodine did not exhibit any efficacy against lethal influenza virus infections in mice when administered by either the intraperitoneal or intranasal routes up to dose-limiting toxic levels.

Carbocyclic analogues of 5-fluorouracil nucleosides.

The carbocyclic analogues of 5-fluoro-2'-deoxyuridine (5-FdUrd, 1), 5-fluorouridine, and 5-fluoro-3 alpha-deoxyuridine were prepared by fluorination of the uracil nucleoside analogues with elemental fluorine. The 5-FdUrd analogue (C-5-F-2'-dUrd, 6) was enzymatically phosphorylated to the analogue of 5-FdUrd 5'-phosphate and inhibited the incorporation of 2'-deoxyuridine into DNA of murine colon 26 tumor cells and L-1210 cells in culture. Biochemical studies also indicated that C-5-F-2'-Urd (6) was a less potent inhibitor of DNA synthesis in tumor cells than was 5-FdUrd (1). C-5-F-2'-dUrd was cytotoxic (ED50 = 2.5 mcg/mL) to L-1210 cells in culture; the other two analogues were less cytotoxic. C-5-F-2'-dUrd was inactive--or, at best, borderline active--in tests against P-388 leukemia in vivo.

ChemInform Abstract: CARBOCYCLIC ANALOGS OF ARABINOSYLPURINE NUCLEOSIDES

AbstractAus dem Aminoalkohol (I) und dem Pyrimidin (II) wird auf dem im Formelschema gezeigten Weg das Chlorpurin‐Derivat (VIII) hergestellt.

Carbocyclic analogs of thymine nucleosides and related 1‐substituted thymines

AbstractThe carbocyclic analogs of thymidine (IXf), 1‐β‐ribofuranosylthymine (IXg), and 1‐β‐3′‐deoxyribofuranosyl‐thymine (IXe) were synthesized by incorporating modifications into the Shaw method of synthesizing 2,4‐(1H,3H)pyrimidinediones via acryloylureas. Simpler analogs of thymine nucleosides were also prepared by this method. The carbocyclic analog of thymidine displayed modest activity against Leukemia L1210 in vivo. It differs from a compound prepared previously by a Prins reaction.

Carbocyclic Analogs of Arabinosylpurine Nucleosides

Carbocyclic analogs of arabinofuranosylguanine (VII) and 2,6-diamino-9-β-arabinofuranosylpurine (VIII) and the corresponding 8-azapurine analogs, 5-amino-7-hydroxy-3-[2α,3β-dihydroxy-4α-(hydroxymethyl)cyclopent-1α-yl]-v-triazolo[4,5-d]pyrimidine (X) and 5,7-diamino-3-[2α,3β-dihydroxy-4α-(hydroxymethyl)cyclopent-1α-yl]-v-triazolo[4,5-d]pyrimidine (XI), were prepared. Carbocyclic nucleoside analogs VII and × exhibited significant cytotoxicity against P-388 mouse leukemia cells in culture. In vitro testing against herpes simplex type 1 (strain HF) indicated that only VIII exhibited significant antiviral activity.

Carbocyclic analogs of cytosine nucleosides

AbstractThe carbocyclic analogs of cytidine, 2′‐deoxycytidine, and 3′‐deoxycytidine were synthesized from the analogous uracil derivatives. The route consists of complete benzoylation of the uracil derivative, selective removal of a benzoyl group attached to the pyrimidine ring, conversion of the 4‐oxo to a 4‐chloro group with the dimethylformamide‐thionyl chloride reagent, and replacement of the chloro group with an amino group in methanolic ammonia. When the total products of the deoxychlorination reaction were employed, the desired cytosine derivatives were frequently accompanied by small amounts of the corresponding N,N‐dimethylcytosine derivatives, which could be removed by ion‐exchange chromatography. Carbodine (VIa), the carbocyclic analog of cytidine, was obtained in 84% yield from the pure 4‐chloropyrimidinone intermediate, after the latter was prepared by deoxychlorination in carbon tetrachloride. Carbodine has antileukemic, antiviral, and antibacterial activity.

A convenient route to carbocyclic analogs of nucleosides: (±) aristeromycin

Stereocontrolled elaboration of cyclopentadiene-azomethine adducts 1 6 and 2 7 led to a short total synthesis of (±) aristeromycin. In the course of this work a novel zinc reduction ( 6 / 7 + 9 ) was observed. Also, ozonolysis of the gem -dihalo olefin 10 in methanol directly gave the methyl ester 12 .

Synthesis of the carbocyclic analogs of uracil nucleosides

AbstractTreatment of the required hydroxyl derivatives of cis‐3‐aminocyclopentanemethanol with 3‐ethoxyacryloyl isocyanate gave N‐(3‐ethoxyacryloyl)‐N′‐[hydroxy‐ or dihydroxy(hydroxy‐methyl)cyclopentyl]ureas. Cyclization of the ureas in dilute sulfuric acid afforded high yields of the carbocyclic analogs of uridine, 2′‐deoxyuridine, and 3′‐deoxyuridine. The uridine and 3′‐deoxyuridine analogs were also obtained in good yields by cyclizing the ureas in concentrated aqueous ammonia. None of the three analogs showed activity in tests versus KB cells in culture or L1210 leukemia in vivo.

Carbocyclic Analog of Purine Ribonucleosides with Antileukemic Activity

Carbocyclic analogs of several naturally occurring and biologically active purine nucleosides have been synthesized (1–4). In these analogs a methylene group occupies the position of the ring oxygen atom of the ribo- or deoxyribofuranosides. Because of the presence of a stable carbon-nitrogen bond at position 9 of the purine moiety, these analogs are not subject to cleavage by enzymes that remove or transfer the ribofuranosyl moiety of the nucleosides or nucleotides. Biochemical studies (5–7) have shown that the racemic analog (III) of adenosine can serve either as a substrate for or as an inhibitor of some of the enzymes involved in purine nucleotide metabolism, one of the more interesting findings being the inhibition of guanylic acid kinase by the phosphate (7). The antibiotic aristeromycin (8). the optically active form (9, 10) of the adenosine analog, inhibits certain plant pathogens (8, 11). Several racemic carbocyclic analogs of purine nucleosides are cytotoxic to neoplastic cells growing in culture (4). In this communication, antileukemic activity in vivo by a carbocyclic analog, the 8-azaadenosine analog (II), is reported. Carbocyclic analogs of several naturally occurring and biologically active purine nucleosides have been synthesized (1–4). In these analogs a methylene group occupies the position of the ring oxygen atom of the ribo- or deoxyribofuranosides. Because of the presence of a stable carbon-nitrogen bond at position 9 of the purine moiety, these analogs are not subject to cleavage by enzymes that remove or transfer the ribofuranosyl moiety of the nucleosides or nucleotides. Biochemical studies (5–7) have shown that the racemic analog (III) of adenosine can serve either as a substrate for or as an inhibitor of some of the enzymes involved in purine nucleotide metabolism, one of the more interesting findings being the inhibition of guanylic acid kinase by the phosphate (7). The antibiotic aristeromycin (8). the optically active form (9, 10) of the adenosine analog, inhibits certain plant pathogens (8, 11). Several racemic carbocyclic analogs of purine nucleosides are cytotoxic to neoplastic cells growing in culture (4). In this communication, antileukemic activity in vivo by a carbocyclic analog, the 8-azaadenosine analog (II), is reported.