Synthesis of the carbocyclic analogs of uracil nucleosides

Treatment 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 analogs of thymine nucleosides and related 1-substituted thymines

The 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.     

Nucleosides. CIX. 2′-Deoxy-ψ-isocytidine, 2 -deoxy-ψ-uridine,and 2′-deoxy-l-methyl-ψ-uridine. Isosteres of deoxycytidine,deoxyuridine and thymidine

2′-Deoxy-ψ-isocytidine (VIIβ), a 2′-deoxy analog of antileukemic ψ-isocytidine and also a C-nucleoside analog of deoxycytidine, was synthesized from ψ-uridine by making use of the newly discovered pyrimidine to pyrimidine transformation reaction [J. Chem. Soc., 14, 537 (1977)]. 2′-Deoxy-ψ-uridine (IIβ) and 2′-deoxy-l-methyl-ψ-uridine (V), both C-nucleoside analogs of deoxyuridine and thymidine, were also synthesized. ψ-Uridine was converted into the 2′-chloro analogs (I) which was reduced with tributyltin hydride to give an α,β-mixture of 2′-deoxy-ψ-uridines. The β-isomer (11β was trimethylsilylated and the product (III) treated with methyl iodide to afford the 1-methyl derivative (IV). After hydrolytic removal of the trimethylsilyl groups from IV, the thymidine analog (V) was obtained in good yield. A crude mixture of II was converted in good yield into an α,β-mixture of 1,3-dimethyl-2 -deoxy-ψ-uridines (VI) by treatment with DMF dimethyl acetal in DMF. Treatment of the β-isomer (VIβ) with guanidine, however, gave the α,β-mixture of 2 -deoxy-ψ-isocytidines (VII). The pure β-isomer (VIIβ) was obtained by thick layer chromatography. The pure α-isomer (VIIα) was obtained when VIα was treated with guanidine. 2 -Deoxy-ψ-isocytidine (VIIβ) and 2 -deoxy-l-methyl-ψ-uridine (V) exhibited inhibitory activity against P815 cells (ID_{5 0} 1.2 μg./ml. and 4.9 μg./ml., respectively) and the thymidine analog V was found to be active against Streptococcus faecium var. duran. J. Heterocyclic Chem., 14, 1119 (1977)     

Nucleosides and nucleotides. 186. Synthesis and biological activities of pyrimidine carbocyclic nucleosides with a hydroxyamino group instead of a hydroxymethyl group at the 4'-position of the sugar moiety.

Pyrimidine carbocyclic nucleosides with a hydroxyamino group instead of a hydroxymethyl group at the 4'-position of the sugar moiety were designed as potential antitumor and/or antiviral agents. Pd (O)-catalyzed reactions of enantiomerically pure (+)-(1R,4S)-4-[(tert-butyldiphenylsilyl)oxy]-1-(ethoxycarbonylo xy)-2- cyclopentene (9) with N3-benzoylthymine and -uracil gave carbocyclic nucleosides 10 and 11. Subsequent Pd (O)-catalyzed reactions of N3-benzoyl-1-[(1R,4S)-4-(ethoxycarbonyloxy)-2-cyclopenten-1- yl]thymine (14) and -uracil (15) with O-benzylhydroxylamine smoothly gave the hydroxyamino-substituted carbocyclic nucleosides 16 and 17. From these nucleosides, the target compounds were prepared after deprotection or further reactions. The 2',3'-didehydro-2',3'-dideoxythymidine (D4T) analogue 20 was the most effective compound, with IC50 values of 27.3 and 34.5 microM against KB and L1210 cells in vitro. Carbocyclic analogues of uridine and cytidine (29 and 32) were less effective than 20 against both cell lines.     

Carbocyclic analogs of cytosine nucleosides

The 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.     

Design, synthesis, conformational analysis and biological activities of purine-based 1,2-di-substituted carbocyclic nucleosides

New 1,2-di-substituted carbocyclic nucleosides with 6-chloropurine, adenine and hypoxanthine bases were synthesized by construction of purine on the primary amino group of (+/-)-trans-2-aminocyclopentylmethanol. AM1 calculations showed close correspondence between the positions of the heteroatoms in the adenine derivative and dideoxyadenosine. The most active of the new compounds in antiviral assays and antitumoral assays against L1210/0, MOLT4/C8 and CEM/0 cells was the 6-chloropurine derivative.     

Carbocyclic analogs of anhydrothymidines

The carbocyclic analog of thymidine (C-Thymidine, 2 ) was converted to the analog of 3′-(O-methanesulfonyl)-5′-O-tritylthymidine, which was cyclized in alkaline solution or with 1,5-diazabicyclo[5.4.0]undec-5-ene (DBU) to the carbocyclic analog of 5′-O-trityl-2,3′-anhydrothymidine ( 6 ). Hydrolysis of the latter compound produced the carbocyclic analog of all-cis-thymidine. C-Thymidine was also converted to the carbocyclic analog of 3′-O-acetyl-2,5′-anhydrothymidine ( 12 ) by treating the 5′-O-methanesulfonyl analog with DBU. Hydrolysis of the anhydro derivative gave back C-Thymidine. The carbocyclic analog ( 3 ) of 3′-deoxy-2′-hydroxythymidine was converted similarly to the corresponding 2,2′-anhydrothymidine ( 15 ) and 2,5′-anhydrothymidine ( 21 ) analogs. As expected, C-5′-O-trityl-2,2′-anhydrothymidine formed more readily than did the 2,3′-anhydrothymidine analog. Hydrolysis of these 2,2′- and 2,5′-anhydrothymidine analogs gave, respectively, the carbocyclic analog of all-cis-3′-deoxy-2′-hydroxythymidine and 3 .     

Folic acid analogs. III. N-(2-[2-(2,4-diarnino-6-quinazolinyl)ethyl]benzoyl)-l-glutamic acid

A trideaza analog of aminopterin, N-(4[2-(2,4-diamino-6-quinazolinyl)ethyl]benzoyl)-L-glutamic acid, was prepared by a Wittig condensation of 2,4-diaminoquinazoline-6-carboxaldehyde and [P-(N-[1,3-bis(ethoxycarbonyl)propan-1-yl]aminocarbonyl)phenylmethyl]triphenylphosphonium bromide followed by catalytic reduction and mild hydrolysis. This compound was found to have confirmed inhibitory activity against leukemia L1210 in mice.     

Synthesis of 1,2‐Disubstituted Carbocyclic Nucleoside Analogues of Cytidine

The synthesis of new 1,2‐disubstituted, five‐ or six‐ring‐carbocyclic nucleoside analogues of cytidine, compounds 1 and 2a – d , are described. These compounds were obtained by aminolysis, starting from the corresponding uracil derivative, via nucleophilic displacement of a triazolyl (Scheme 1) or a (2,4,6‐triisopropylphenyl)sulfonyl (TPS) group (Scheme 2) at 4‐position of the pyrimidine ring.     

Synthesis and single-crystal X-ray diffraction analysis of 2-sulfamoyladenosine (6-amino-9-β-D-ribofuranosylpurine-2-sulfonamide)

2-Amino-9-β-D-ribofuranosylpurine-2-sulfonamide (2-sulfamoyladenosine, 4 ), a congener of sulfonosine ( 3 ), was synthesized by four different routes. Acid catalyzed fusion of 6-chloropurine-2-sulfonyl fluoride ( 5 ) with 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose ( 8 ) gave a good yield of 6-chloro-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine-2-sulfonyl fluoride ( 9 ). Ammonolysis of 9 furnished 4 . Lewis acid catalyzed glycosylation of the trimethylsilyl derivative of either 6-chloropurine-2-sulfonamide ( 6 ) or 6-aminopurine-2-sulfonamide ( 7 ) with 8 gave the corresponding N9-glycosylated products, 10 and 11 , respectively, which on ammonolysis gave 4 . Amination of 2-thioadenosine ( 12 ) with chloramine solution gave the sulfenamide derivative 13 , which on subsequent oxidation with m-chloroperoxybenzoic acid furnished an alternate route to 4 . The structure of 4 was established by single-crystal X-ray diffraction studies. 2-Sulfamoyladenosine ( 4 ) is devoid of significant inhibitory activity against L1210 leukemia in mice.     

Synthesis and Properties of 10-Benzylaminopterin

Substitution of a benzyl group for the methyl at N-10 of Methotrexate caused only a slight decrease in the inhibitory properties of the folate analog against L1210 leukemia in cell culture.     

5-Fluorouracil derivative. XVII. Synthesis and antitumor activity of 5'-O-acyl-5-fluorouridines

With the aim of diminishing the toxicity of 5-fluorouridine (1) and obtaining biologically active derivatives of 1, various kinds of 5'-O-acyl-5-fluorouridines 2 were synthesized. The antitumor activity of the compounds against L-1210 leukemia in mice was examined. The 5'-O-heptanoyl derivative 2h showed the highest antitumor activity.     

Anticancer anthrapyrazoles. The synthesis of 2-substituted 5-nitro and 5-aminoanthra[1,9-cd]pyrazol-6(2H)-ones

Synthetic methodologies for the preparation of substituted 5-nitro- and 5-aminoanthra[1,9-cd]-pyrazol-6(2H)-ones, 4 and 5 respectively, substituted with a basic side at N-2 and dioxy substitution in the A-ring, are reported. These compounds are essentially devoid of activity against in vitro L1210 leukemia and in vivo murine P388 leukemia.     

Syntheses and biological evaluation of vinblastine congeners

Sixty-two congeners of vinblastine (VLB), primarily with modifications of the piperidine ring in the carbomethoxycleavamine moiety of the binary alkaloid, were synthesized and evaluated for cytotoxicity against murine L1210 leukemia and RCC-2 rat colon cancer cells, and for their ability to inhibit polymerization of microtubular protein at < 10(-6) M, and for induction of spiralization of microtubular protein, and for microtubular disassembly at 10(-4) M concentrations. An ID50 range of >10(7) M concentrations was found for L1210 inhibition by these compounds, with the most active 1000x as potent as vinblastine.     

Synthesis and antifolate activity of 8,10-dideazaminopterin

A synthesis of 8,10-dideazaminopterin, using 2,4-diamino-6-bromomethyl-8-deazapteridine ( 2 ) as a key intermediate, is described. Condensation of the triphenylphosphinylide derived from 2 with p-formylbenzoyl-L-glutamate afforded a 9,10-dehydro-8,10-dideazaminopterin ester intermediate 5 . Hydrogenation of the olefinic linkage and subsequent hydrolysis of the glutamate ester gave the title compound. 8,10-Dideazaminopterin was a potent growth inhibitor of folate dependent bacteria. It was 16 times more potent then methotrexate as an inhibitor of dihydrofolate reductase derived from L1210 leukemia cells, and showed strong activity against L1210 in mice.     

On the formation of homo-azasteroidal esters of N,N-bis(2-chloroethyl)aminobenzoic acid isomers and their antitumor activity

The N, N-bis(2-chloroethyl)aminobenzoate isomers and the 4-methyl-3-N, N-bis(2-chloro-ethyl)aminobenzoate of 3β-hydroxy-13α-amino-13,17-seco-5α-androstan-17-oic-13,17-lactam, 3α-hydroxy-13α-amino-13,17-seco-5α-androstan-17-oic-13,17-lactam, 3α-hydroxy-13α-amino-13,17-seco-5-androsten-17-oic-13,17-lactam and 17β-hydroxy-3-aza-A-homo-4α-androsten-4-one, have been prepared and their biological activity evaluated against P388 leukemia in vivo and Ehrlich Ascites tumor (EAT), P388 and L1210 leukemias and Baby Hamster cells (BHK) in vitro. The esters in which the alkylating congener is linked to the lactam alcohol in the axial position are inactive in vivo in P388 leukemia, while compounds 1, 4, 6, 13, 14 and the alkylating congeners 17, 18 and 20 are active. The effect of the homo-azasteroidal of N, N-bis(2-chloroethyl)aminobenzoic acid isomers and of 4-methyl-3-N, N-bis(2-chloroethyl)aminobenzoic acid on the incorporation of the radioactive precursor into the DNA of L1210, P388 leukemias, Ehrlich ascites tumor and, baby Hamster kidney cells was investigated. Higher inhibitory effects on the incorporation of the radioactive precursor was obtained with the ortho derivatives, yielding <70% inhibition of thymidine incorporation in all tumor lines tested.     

Carbocyclic Analogs of Nucleosides. Part 3. Synthesis of a new sulfone analog of cyclic adenosine 3′,5′-monophosphate

The novel uncharged analog 2 of adenosine 3′,5′ -monophosphate (1) was prepared in its racemic form. To increase membrane permeability, the phosphate diester monoanion group of 1 was replaced by a dimethylene sulfone unit ( = methanosulfonylmethano group), and the 2′-OH group was removed. To decrease lability against acid-catalyzed depurination, the ring O-atom was replaced by a CH₂ group. All three modifications are also expected to increase the stability of analog 2 towards enzymatic degradation. The carbocyclic skeleton of 2 was constructed from trinorbornenecarbaldehyde 3 (see Scheme 1–3), and the adenine precursor 6-chloropurine was introduced in the carbocyclic unit via an S_N2 reaction based on Mitsunobu chemistry (Schemes 4 and 5).     

A new entry to carbocyclic nucleosides: oxidative coupling reaction of cycloalkenylsilanes with a nucleobase mediated by hypervalent iodine reagent

A novel method for synthesizing carbocyclic nucleosides was developed. The new synthesis includes a direct coupling reaction of cycloalkenylsilanes with a silylated nucleobase catalyzed by a hypervalent iodine reagent. By applying the method, a novel carbocyclic cytidine derivative having bis(hydroxymethyl)cyclohexene as a pseudosugar moiety, designed as a potential anti-HIV agent, was successfully synthesized.     

Synthesis of some 1,3,8-trisubstituted pyrimido[4,5-c][2,7]-naphthyridin-6-ones as potential antitumor agents

Condensation of three 2,4-disubstituted 6-aminopyrimidines with methyl 1-benzyl-4-oxo-3-piperidinecarboxylate afforded, in each case, new tricyclic, angular 1,3,8-trisubstituted pyrimido[4,5-c][2,7]naphthyridin-6-ones. 2,4,6-Triaminopyrimidine gave the 7,8,9,10-tetrahydrocyclo condensed product 5 as anticipated. However, the use of 2-amino-4-oxo- or 2,4-dioxo-6-aminopyrimidine afforded the dehydrogenated, 9,10-dihydrotricyclic products 11 and 12 . The growth of leukemia L1210 cells in culture were inhibited 50% by the 1,3-diamino analog 5 at 2 × 10⁻⁶M and by the 1,3-dioxo analog 12 at 10⁻⁵M.     

Synthesis of 5'-amino-5'-phosphonate analogues of pyrimidine nucleoside monophosphates

The 5'-amino-5'-phosphono derivatives of cytidine, cytosine arabinoside (ara-C), and uridine have been prepared via the corresponding nucleoside aldehydes. Phosphite addition to imines derived from the nucleoside aldehydes and p-methoxybenzylamine was efficient, and use of this amine allowed cleavage of the products to the parent amino phosphonic acids. The phosphite additions proved to be diastereoselective, with the cytidine and uridine derivatives favoring the 5'S stereochemistry and the ara-C derivative favoring the 5'R isomer. The stereochemistry of one cytidine derivative was established by single-crystal diffraction analysis, and detailed comparisons of the (13)C NMR data allowed assignments of the other amino phosphonates.