Synthesis and antiviral screening of some thieno[2,3-d]pyrimidine nucleosides

Some cyclic and acyclic nucleosides of thieno[2,3-d]-pyrimidine derivatives were synthesized via the reaction of compounds 1 and 2 or 3 and 4 with 2-chloroethyl methyl ether or 2,3,4, 6-tetra-O-acetyl-alpha-D-glucopyranosyl bromide. Nucleosides 9, 10, 15, and 16 were tested as antiviral agents against herpes simplex virus type-1 (HSV-1) and hepatitis-A virus (HAV). Compound 15 showed the highest effect on HSV-1 than the other three compounds, while the four tested compounds did not show any activity against HAV.     

Synthesis and antimicrobial activity of some cyclic and acyclic nucleosides of thieno[2,3-d]pyrimidines

The reaction of compounds 1, 2, 3, 4, or 13 with 2-chloroethyl methyl ether or 2,3,4,6-tetra-O-acetyl-alpha-D-glucopyranosyl bromide, afforded some acyclic and cyclic nucleosides of thieno[2,3-d]pyrimidine derivatives. Furthermore, cyclic C-nucleosides 24 and 25 were prepared from the reaction of 20, 21 or from 26, 27 with D-glucose. The antimicrobial evaluation of some prepared products showed promising antimicrobial activity.     

Concise synthesis and antiviral activity of novel unsaturated acyclic pyrimidine nucleosides

Novel acyclic nucleoside analogues were designed and synthesized as open-chain analogues of neplanocin A. The coupling of the allylic bromide with pyrimidine bases using cesium carbonate afforded a series of novel acyclic nucleosides. The synthesized compounds 15-22 were evaluated for their antiviral activity against various viruses such as HIV, HSV-1, HSV-2, and HCMV.     

Bicyclic furano-, pyrrolo-, and thiopheno[2,3-d] derivatives of pyrimidine nucleosides: Synthesis and antiviral properties

The methods of synthesis of furano-, thiopheno-, and pyrrolo[2,3-d]pyrimidine deoxyribonucleosides and their derivatives and studies of the relationship between the structure and the antiviral activity of these compounds towards the viruses of varicella zoster, hepatitis C, and others have been reviewed.     

Furano- and pyrrolo [2,3-d] pyrimidine nucleosides and their 5'-O-triphospates: synthesis and enzymatic activity

A series of bicyclic [2,3-d]furano- and pyrrolopyrimidine ribonucleosides were synthesized and converted chemically into corresponding 5'-O-triphosphates. Substrate properties of the triphosphates toward some RNA and DNA polymerases are reported.     

Synthesis and biological evaluation of some acyclic 4,6-disubstituted 1H-pyrazolo[3,4-d]pyrimidine nucleosides

The chemical synthesis and biological evaluation of some acyclic alpha-[6-(1'-carbamoylalkylthio)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]thioalkylamide nucleosides are described.     

Synthesis and evaluation of a classical 2,4-diamino-5-substituted-furo[2,3-d]pyrimidine and a 2-amino-4-oxo-6-substituted-pyrrolo[2,3-d]pyrimidine as antifolates

Two classical antifolates, a 2,4-diamino-5-substituted furo[2,3-d]pyrimidine and a 2-amino-4-oxo-6-substituted pyrrolo[2,3-d]pyrimidine, were synthesized as potential inhibitors of dihydrofolate reductase (DHFR) and thymidylate synthase (TS). The syntheses were accomplished by condensation of 2,6-diamino-3(H)-4-oxo-pyrimidine with alpha-chloro-ketone 21 to afford two key intermediates 23 and 24, followed by hydrolysis, coupling with l-glutamate diethyl ester and saponification of the diethyl ester to afford the classical antifolates 13 and 14. Compounds 13 and 14 with a single carbon atom bridge are both substrates for folylpoly-gamma-glutamate synthetase (FPGS), the enzyme responsible for forming critical poly-gamma-glutamate antifolate metabolites with increased potency and/or increased cell retention. Compound 14 is a highly efficient FPGS substrate demonstrating that 2,4-diamino-5-substituted furo[2,3-d]pyrimidines are important lead structures for the design of antifolates with FPGS substrate activity. It retains inhibitory potency for DHFR and TS compared to the two atom bridged analog 5. Compound 13 is a poor inhibitor of purified DHFR and TS, and both 13 and 14 are poor inhibitors of the growth of CCRF-CEM human leukemia cells in culture, indicating that single carbon bridged compounds in these series though conducive to FPGS substrate activity were not potent inhibitors.     

Discovery of novel c-Met kinase inhibitors bearing a thieno[2,3-d]pyrimidine or furo[2,3-d]pyrimidine scaffold

A series of thieno[2,3-d]pyrimidines and furo[2,3-d]pyrimidines were synthesized and evaluated for the c-Met inhibition. Thieno[2,3-d]pyrimidine 6b stood out as the most potent showing an IC(50) of 35.7 nM. This compound displayed high inhibitory effect on cell proliferation in BaF3-TPR-Met cells and showed high selectivity for c-Met family against other 14 tested kinases. However, compound 6b was found ineffective in the c-Met-dependent U-87MG human gliobastoma xenograft model that may be relevant to its poor PK profile.     

Synthesis and biological activity of 2'-deoxy-4'-thio-pyrazolo[3,4-d]pyrimidine nucleosides

The coupling of 4-aminopyrazolo [3, 4-d]pyrimidine with the appropriate thio sugar gave a 3:1 ratio of alpha,beta blocked 4-amino-1-(2-deoxy-4-thio-D-erythropentofuranosyl)-1H pyrazolo[3,4-d]pyrimidine nucleosides. The mixture was deblocked, both the anomers were separated, and the beta-anomer was readily deaminated by adenosine deaminase. The nucleosides have been characterized, and their anomeric configurations have been determined by proton NMR. All three nucleosides were evaluated against a panel of human tumor cell lines for cytotoxicity in vitro. The details of a convenient and high yielding synthesis of these nucleosides are described.     

Pyrrolo[2,3-d]pyrimidine nucleosides: synthesis and antitumor activity of 7-substituted 7-deaza-2'-deoxyadenosines

A one step synthesis, using the nucleoside 7-iodo-2'-deoxytubercidin (2b) in a Pd(0)/Cu(I)-catalyzed cross coupling reaction furnished a series of 7-alkynyl-2'-deoxytubercidin derivatives. The 7-iodo-, 7-chloro- or 7-bromo 2'-deoxytubercidins 2b-d as well as certain 7-alkynyl derivatives show significant activity against several tumor cell lines, with 7-iodo-2'-deoxytubercidin (2b) as the most effective compound.     

Synthesis and anti-HCMV activity of novel acyclic nucleosides

A series of novel acyclic nucleosides 10, 11, 21, and 22 were synthesized efficiently starting from D-lactose. The condensation of the mesylate 5 and 16 with an adenine and cytosine base under standard nucleophilic substitution conditions (K2CO3, 18-Crown-6, DMF) afforded a series of acyclic novel nucleosides. Compound 21 displayed moderate anti-HCMV activity in the AD-169 cells (EC50 = 18.5 microg/mL) without exhibiting any cytotoxicity up to 100 microM.     

Synthesis and anticancer activity of 4-amino-5-oxo-8-(beta-D-xylofuranosyl)pyrido[2,3-d]pyrimidine

4-Amino-5-oxo-8-(beta-D-xylofuranosyl)pyrido[2,3-d]pyrimidine (4) was recently synthesized and evaluated in our laboratories for anticancer activities. This compound showed potent in vitro inhibitory effects on the growth of HTB-81 prostate cancer cells and Daudi-lymphoma. In vivo studies showed that the compound could inhibit HTB-81 tumor growth in syngeneic mice by 93% at a daily dose of 8.5 mg/kg for 10 days.     

Nucleosides. 127. Synthesis of Pyrido[2,3-d]pyrimidine Nucleosides from 5-Cyanouridine

Abstract

7-Amino-6-substituted-1-(β-D-ribofuranosyl)pyrido [2,3–d]pyrimidine-2,4 (1H, 3H)-diones were prepared in good yields from 5-cyanouridine by application of a novel ring transformation reaction recently developed in our laboratory. Treatment of 3-benzyloxymethyl-2', 3'-O-isopropylidene-5'-O-trityl-5-cyanouridine with malononitrile, cyanoacetamide or ethyl cyanoacetate in base gave directly the pyridopyrimidine nucleosides bearing a CN, CONH₂ and CO₂ Et at C-6, respectively. The benzyloxymethyl and trityl protecting groups were removed by hydrogenolysis and the isopropylidene group by acid hydrolysis.     

Synthesis and anti-HSV activity of new N1-acyclic C4 and C6-disubstituted pyrazolo[3,4-d]pyrimidine nucleosides

Several N(1)-(2-hydroxyethoxy)methyl, (4-hydroxybutyl) and (2,3-dihydroxy-1-propoxy)methyl-C(4),C(6)-disubstituted-1H-pyrozolo[3,4-d]pyrimidines were synthesized. Some of them were evaluated against herpes simplex virus 1 and 2 replications in E(6)SM cells.     

Synthesis of pyrrolo[2,3-d]pyrimidine derivatives and their antiproliferative activity against melanoma cell line

Synthesis of a new series of diarylureas and amides having pyrrolo[2,3-d]pyrimidine scaffold is described. Their in vitro antiproliferative activities against A375 human melanoma cell line and HS 27 fibroblast cell line were tested and the effect of substituents on pyrrolo[2,3-d]pyrimidine was investigated. The newly synthesized compounds, except N-acetyl derivatives (Id, Ie, and Im), generally showed superior or similar activity against A375 to Sorafenib. Among all of these derivatives, compounds Iq and Ir having imidazole and morpholine moieties, respectively, showed the most potent antiproliferative activity against A375.     

Synthesis of 7-Glycopyranosyl-5-oxq-pyrrolo[2,3-d]Pyrimidine and 4-Glyco Pyranosylamino-Furo[2,3-d]Pyrimidine Derivatives

Abstract

The synthesis of some glycosyl derivatives of furo[2,3-d] and pyrrolo[2,3-d]pyrimidines is described.     

Synthesis of pyrrolo[2,3-d]pyrimidine nucleoside derivatives as potential anti-HCV agents

Several Toyocamycin (4) analogues were examined for their ability to inhibit HCV RNA in a replicon assay. Among the compounds examined 4-methylthio (18) and 5-carboxamide oxime derivatives (23 and 27) of Toyocamycin were found to have good activity and selectivity.     

Synthesis of new 2,4-Diaminopyrido[2,3-d]pyrimidine and 2,4-Diaminopyrrolo[2,3-d]pyrimidine inhibitors of Pneumocystis carinii,Toxoplasma gondii,and Mycobacterium avium dihydrofolate reductase

A concise new route allowing easy access to five previously unreported 2,4-diamino-6-(substituted benzyl)pyrido[2,3-d]pyrimidines (2a-e) was developed, involving condensation of 2,4-dipivaloylamino-5-bromopyrido[2,3-d]pyrimidine (6) with an organozinc halide in the presence of a catalytic amount of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II).CH(2)Cl(2), followed by removal of the pivaloyl groups with base. Also prepared via a scheme based on the Taylor ring expansion/ring annulation synthesis were three heretofore undescribed 2,4-diamino-5-(substituted benzyl)-7H-pyrrolo[2,3-d]pyrimidines (3b-c). Standard spectrophotometric assays were used to compare the ability of 2a-e and 3b-c to inhibit dihydrofolate reductase (DHFR) from Pneumocystis carinii, Toxoplasma gondii, and Mycobacterium avium, three examples of opportunistic pathogens to which AIDS patients are highly vulnerable because of their immunocompromised state. For comparison, 13 previously untested 2,4-diamino-6-(substituted benzyl)quinazolines (17a-m) were also evaluated as inhibitors of these enzymes, as well as the enzyme from rat liver. None of the quinazolines or pyridopyrimidines tested was more potent against the P. carinii enzyme than the structurally related reference compound piritrexim (1), and none showed selectivity for the P. carinii enzyme over the rat enzyme. One of the pyridopyrimidines (2c) showed 10-fold selectivity for T. gondii versus rat DHFR, and two of them (2b, 2c) showed selectivity for the M. avium enzyme. However, this gain in species selectivity was achieved at the cost of decreased in potency, as has been noted with many other lipophilic DHFR inhibitors.     

Solid-phase parallel synthesis of 4-beta-D-ribofuranosylpyrazolo[4,3-d]pyrimidine nucleosides

The synthesis of pyrazolo[4,3-d]pyrimidine nucleoside library using solid-phase parallel synthesis methodology is described. Glycosylation of the trimethylsilyl (TMS) derivative of 1- and 2-(methyl)-1H and 2H-pyrazolo[4,3-d]pyrimidine-5,7-(4H, 6H)-dione (5) with 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose in the presence of TMS triflate provided two novel protected nucleosides 6 and 7. The structures of 6 and 7 were assigned by 1H and 2D NMR experiments. Nucleosides 6 and 7 were then transformed to the key intermediates 12 and 15 respectively. Reaction of 12 and 15 with MMTCl resin in the presence of 2,6-lutidine afforded the necessary scaffolds B and C. Different amines (96) were introduced selectively by nucleophilic substitution on scaffolds B and C using solid-phase parallel semi-automated synthesizer. Cleavage of the products from the solid support with 30% HFIP in a parallel fashion yielded nucleoside libraries simultaneously, and they were analyzed and characterized by high-throughput LC-MS.     

Synthesis and anticancer activity of novel 4-morpholino-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine derivatives bearing chromone moiety

Herein, we designed and synthesized of a novel series of 7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine derivatives bearing chromone moiety (10a–j, 13a–j). All the compounds were evaluated for the IC₅₀ values against five cancer cell lines (A549, PC-3, MCF-7, Hela and HepG2). Seven of the target compounds exhibited moderate to excellent cytotoxicity. For these compounds, we tested their inhibitory activities against mTOR kinase, and four of them were tested their inhibitory activities against PI3Kα kinase in further. The results indicated that the optimized compound 10j showed excellent inhibitory activity and cytotoxicity against mTOR kinase, PI3Kα kinase and five cancer cell lines with IC₅₀ values of 1.1 μM, 0.92 μM and 8.77–14.3 μM. Structure–activity relationships (SARs) and docking studies indicated that the thiopyrano[4,3-d]pyrimidine scaffolds exerted little effect on antitumor activities of target compounds. Substitutions of chromone moiety at C-6 position with carboxyl were benefit to the antitumor activities.