Synthesis of some novel benzoxazole derivatives as anticancer, anti-HIV-1 and antimicrobial agents

In an effort to establish new candidates with improved antineoplastic, anti-HIV-1 and antimicrobial activities we report here the synthesis and in vitro biological evaluation of various series of 2-substituted benzoxazoles: 2-[(Arylhydrazono, arylidene, cycloalkylidene and N-substituted thiocarbamoyl)cyanomethyl]-benzoxazoles(2-4 and 7, respectively); 2-[(4- or 5-oxothiazoliden-2-yliden)benzoxazoles (5 and 6) and 2-(4-amino-3-substituted-2-thioxo-2,3-dihydrothiazol-5-yl)benzoxazoles (8), together with the synthesis of some substituted 3H-pyrido[2,1-b]benzoxazoles (9-11). The absolute configuration of compound 3b was determined by X-ray crystallography. The results of the in vitro anticancer screening revealed that some of the tested compounds exhibited broad spectrum antitumor activity. The most active compounds are 2a, 3b, 8a and 8d, their GI50 MG-MID values: 37.7, 19.1, 20.0 and 15.8 microM; TGI MG-MID values: 75.9, 53.7, 53.7, and 58.9 microM; and LC50 MG-MID values: 97.7, 93.3, 89.1 and 93.3 microM, respectively. The in vitro microbiological data showed that compound 7c was the most active against Staphylococcus aureus (minimal inhibitory concentration (MIC)<12.5 microg ml(-1). While compounds 5, 8a, and 8d were the most active against Bacillus subtilis (MIC values<12.5 microg ml(-1)). On the other hand, compounds 5 and 7c were the most active against Escherichia coli (MIC<25 microg ml(-1)), their activity is about half the activity of ampicillin and streptomycin . In addition, compound 4b and 7c were the most active against Pseudomonas aeruginosa (MIC<25, 50 microg ml(-1)). Compound 4b was two times as active as ampicillin and streptomycin while compound 7c was active as both. The results of antimycotic activity indicated that, Compound 7c showed mild activity against Candida albicans when compared with clotrimazole (MIC<100 microg ml(-1)). In vitro HIV-1 testing revealed that compound 7a displayed moderate anti-HIV-1 activity (maximum % cell protection, 36.6 at 2 x 10(-5) microM).     

Antimicrobial, antitumor and 5α-reductase inhibitor activities of some hydrazonoyl substituted pyrimidinones

A series of 2-[N-aryl-2-oxo-2-(4-chlorophenyl)ethanehydrazonoyl]-6-methyl-4(3H)-pyrimidinones 5 were prepared by coupling the diazonium salt of aniline derivatives with 2-(4-chlorobenzoylmethylene)-6-methyl-4(3H)-pyrimidinone 4 in sodium hydroxide solution. The structures of these newly synthesized compounds were confirmed by IR, NMR, mass spectrometry and elemental analyses and the tautomeric structure of these compounds was discussed. All the newly synthesized compounds were screened for their antibacterial and antifungal activities, some of which exhibited moderate activity. Also, the above compounds were evaluated for their antitumor activity against a panel of 60 human tumor cell lines by the National Cancer Institute (NCI), USA. Compounds 5b, 5d and 5i showed good cytotoxic activities against the tested cell lines. In addition, the newly synthesized compounds were screened for their 5α-reductase inhibitor activity and all the tested compounds showed activities in descending order as follows 5b, 5c, 5g, 5j, 5d, 5h, 5f, 5e and 5i.     

Synthesis and antitumor activity of cis-dichloroplatinum(II) complexes of 1-(2-aminophenyl)-1,2,3,4-tetrahydroisoquinolines

Fifteen cis-dichloroplatinum complexes (5a-5o) were synthesized by treatment of 1-(2-aminophenyl)-1,2,3,4-THIQs (4a-4o) with K(2)PtCl(4). The antitumor activity of these compounds was examined against four different human tumor cell lines. Their structure-activity relationships for antitumor activity are reported. All of these compounds exhibited activity against MCF-7 cell line and showed good activity against WiDr cell line except 5c and 5f. On the other hand, compounds 5j and 5o are more active than the other compounds against Hepa59T/VGH cell line. The electron-donating group at the 6-position of isoquinoline ring seems to decrease the antitumor activity and the chloro substituent at the C-4 position of the aniline ring shown the highest potency. The "trans influence" dominates the control of the stability of [1-(2-aminophenyl)-1,2,3,4-THIQ]dichloroplatinums(II).     

Novel 1,3,4-heterodiazole analogues: synthesis and in-vitro antitumor activity

The synthesis of some new heterodiazole and their annulated imidazo[2,1-b]1,3,4-oxa/thiadiazolone 6a-d, 7a-d; 1,3,4-oxa or thiadiazole[3,2-a]pyrimidine diamine 8a-d and 1,3,4-oxa or thiadiazole-3-piperidino-1-propamide 11a,b derivatives have been described. The obtained compounds were evaluated for their in-vitro antitumor activity. A single dose (10?μM) of the test compounds were used in the full National Cancer Institute (NCI) 60 cell lines panel assay. Compounds 6c and 6d displayed appreciable anticancer activity against leukemia, non-small cell lung, CNS and showed moderate activity against colon, melanoma, and breast cancer cells lines. Compound 6c possessed remarkable broad-spectrum antitumor activity which almost 4 fold more active than the known drug 5-FU with GI(50), TGI, and LC(50) values of 6.0, 17.4, and 55.1?μM, respectively.     

Structural variations of piritrexim, a lipophilic inhibitor of human dihydrofolate reductase: synthesis, antitumor activity and molecular modeling investigations

Piritrexim (PTX) (1), a lipophilic inhibitor of the human dihydrofolate reductase, has been evaluated as an anticancer agent. The synthesis of four structural variations (2-5) of PTX is reported. The PTX analogues 2-5 were obtained by reaction of suitable C3-building blocks with pyrimidine-2,4,6-triamine (14) or with cyanacetamide (7) and guanidine (10). The evaluation of 2-4 for antitumor activity against a panel of 60 human cancer cell lines showed inhibitory effects on the growth of the cell lines. These data are supported by molecular modeling and docking studies, which show that compounds 2-4 share the same binding mode within the DHFR active site. Moreover, the estimated ligand binding energies are in good agreement with the experimental activity data.     

Conformationally restrained analogues of sympathomimetic catecholamines. Synthesis and adrenergic activity of 5,6- and 6,7-dihydroxy-3,4-dihydrospiro[naphthalen-1(2H)-2',5'-morpholines

The 5,6- (10a) and 6,7-dihydroxy-3,4-dihydrospiro[naphthalen-1(2H)-)-2',5'-morpholine](11a) and their N-isopropyl derivatives (10b and 11b) (DDSNMs), which can be viewed as the result of the combination of the structure of the 2-(3,4-dihydroxyphenyl)morpholine 5a or 5b (DPMs) with the structure of the corresponding 1-(aminomethyl)-5,6-dihydroxy- (8a or 8b) or 1-(aminomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydro-1-naphthalen-ol (9a or 9b) (1-AMDTNs) were synthesised. The new compounds DDSNMs 10a,b and 11a,b were assayed for their alpha- and beta-adrenergic properties by means of binding experiments and functional tests and the results were compared with those obtained for catecholamines 1a, b and the previously described morpholine (5) and tetrahydronaphthalene (8, 9) derivatives. The affinity and activity indices thus obtained indicate in general a low ability of the new compounds 10 and 11 to interact with the alpha- and beta-adrenoceptors, which, in all cases, was lower than that of the corresponding morpholine (5) and tetrahydronaphthalene (8, 9) analogues.     

Synthesis and antimicrobial activities of some new 1-(5-phenylamino-[1,3,4]thiadiazol-2-yl)methyl-5-oxo-[1,2,4]triazole and 1-(4-phenyl-5-thioxo-[1,2,4]triazol-3-yl)methyl-5-oxo- [1,2,4]triazole derivatives

Acetic acid ethyl esters containing 5-oxo-[1,2,4]triazole ring (2) were synthesized by the condensation of compounds 1a-f with ethyl bromoacetate in basic media. The reaction of compounds 2a-f with hydrazine hydrate led to the formation of acid hydrazides (3a-f). The treatment of compounds 3 with two divers aromatic aldehydes resulted in the formation of arylidene hydrazides as cis-trans conformers (4a,c,e,f, 5a,e,f). The thiosemicarbazide derivatives (6a,c,d,f) were afforded by the reaction of corresponding compounds 3 with phenylisothiocyanate. The treatment of compounds 6a,c,d,f with sulfuric acidic caused the conversion of side-chain of compounds 6a,c,d,f into 1,3,4-thiadiazol ring; thus, compounds 7a,c,d,f were obtained. On the other hand, the cyclization of compounds 6a,c,d,f in the presence of 2 N NaOH resulted in the formation of compounds 8a,c,d,f containing two [1,2,4]triazole rings which are linked to each other via a methylene bridge. Compounds 4a, f, 5a, 7a, d, f, 8a and d have shown antimicrobial activity against one or more microorganism, but no antifungal activity has been observed against yeast like fungi. Also inhibitory effect on mycelial growth by compounds 4e, 7d and 8f has been observed. Compounds 4c and 5f were found to possess antitumor active towards breast cancer.     

Synergistic Effect of Squalene and Hydroxytyrosol on Highly Invasive MDA-MB-231 Breast Cancer Cells

Several studies relate Mediterranean diet and virgin olive oil (VOO) intake with lower risk of several chronic diseases, including breast cancer. Many of them described antitumor properties of isolated minor compounds present in VOO, but beneficial properties of VOO arise from the effects of all its compounds acting together. The aim of the present study was to test the antitumor effects of two minor compounds from VOO (hydroxytyrosol (HT) and squalene (SQ)) on highly metastatic human breast tumor cells (MDA-MB-231) when acting in combination. Both isolated compounds were previously analyzed without showing any antitumoral effect on highly invasive MDA-MB-231 breast cancer cells, but the present results show that HT at 100 µM, combined with different concentrations of SQ, could exert antitumor effects. When they are combined, HT and SQ are able to inhibit cell proliferation, promoting apoptosis and DNA damage in metastatic breast cancer cells. Therefore, our results suggest that the health-promoting properties of VOO may be due, at least in part, to the combined action of these two minor compounds.     

Synthesis and biological evaluation of some thiazolyl and thiadiazolyl derivatives of 1H-pyrazole as anti-inflammatory antimicrobial agents

Four series of pyrazolyl benzenesulfonamide derivatives have been synthesized. The first series was prepared by cyclization of the intermediate N,N-dimethylaminomethylene-4[3-phenyl-4-(substituted thiosemicarbamoyl hydrazonomethyl)-1H-pyrazol-1-yl]benzenesulfonamide 2a-c with ethyl bromoacetate to afford the corresponding thiazolidinyl derivatives 3a-c. The second series was prepared by cyclization of the key intermediates 2a-c with 4-bromophenacyl bromide giving rise to thiazolinyl derivatives 4a-c. Thiadiazolyl derivatives 5a-c were obtained by heating 2a-c with 2M FeCl(3) solution. Refluxing the intermediates 2a-c in acetic anhydride yielded the corresponding thiadiazolinyl derivatives 6a-c. All the target compounds showed anti-inflammatory activity and three of them 3b, 3c and 4c surpassed that of indomethacin both locally and systemically in the cotton pellet granuloma and rat paw edema bioassay. The active compounds showed selective inhibitory activity towards COX-2 enzyme as revealed by the in vitro enzymatic assay. All the tested compounds proved to have superior gastrointestinal (GI) safety profiles as compared to indomethacin, when tested for their ulcerogenic effects. The acute toxicity study of compounds having promising anti-inflammatory activity (3b, 3c and 4c) indicated that they are well tolerated both orally and parenterally. Antimicrobial activity tests expressed as minimal inhibitory concentrations (MIC), revealed that compounds 3b and 4a showed comparable antibacterial activity to that of ampicillin against Escherichia coli, while compounds 3a, 3c and 4a possessed about half the activity of ampicillin against Staphylococcus aureus. On the other hand, the results showed that all the tested compounds have weak or no antifungal activity against Candida albicans except for compounds 6b and 6c that showed half the activity of the control antifungal drug used (clotrimazole).     

Design, synthesis and biological study of novel pyrido[2,3-d]pyrimidine as anti-proliferative CDK2 inhibitors

The design and synthesis of a small library of 4-aminopyrido[2,3-d]pyrimidine derivatives is reported. The potential activity of these compounds as CDK2/Cyclin A, CDK4/Cyclin D, EGFR and anti-tumor was evaluated by cytotoxicity studies in A431a, SNU638b, HCT116 and inhibition of CDK2-Cyclin A, CDK4/Cyclin D and EGFR enzyme activity in vitro. The anti-proliferative and CDK2-Cyclin A inhibitory activity of compounds 4c and 11a was significantly more active than roscovotine with IC₅₀ 0.3 and 0.09 μM respectively. Molecular modeling study, including fitting to a 3D-pharmacophore model, docking into cyclin dependant kinase2 (CDK2) active site and binding energy calculations were carried out and these studies suggested the same binding orientation inside the CDK2 binding pocket for these analogs compared to ATP.     

Synthesis and primary cytotoxicity evaluation of 3-[[(3-phenyl-4(3H)-quinazolinone-2-yl)mercaptoacetyl]hydrazono]-1H-2-indolinones

New esters (2b and 2c) and hydrazides (3b and 3c) were synthesized from 6-methyl/fluoro-3-phenyl-4(1H, 3H)-quinazolinone-2-thiones (1b and 1c). Subsequent treatment of 3-phenyl-4(3H)-quinazolinone-2-yl)mercaptoacetic acid hydrazides (3a-e) with 1H-indole-2,3-diones (4a-e) furnished the corresponding 3-[[(3-phenyl-4(3H)-quinazolinone-2-yl)mercaptoacetyl]hydrazono]-1H-2-indolinones (5a-u). The structures of new compounds were determined by analytical and spectral (IR, 1H-NMR, (13)C-NMR, EIMS) methods. Previously reported 3-[[(3-phenyl-4(3H)-quinazolinone-2-yl)mercaptoacetyl]hydrazono]-5-bromo-1H-2-indolinone 5v and compounds 5b, 5d and 5o chosen as prototypes were evaluated against the full panel of 60 human tumour cell lines at a minimum of five concentrations at tenfold dilutions in the National Cancer Institute in vitro primary cytotoxicity assay. Sulforhodamine B protein assay was used to estimate cell stability or growth. 3-[[(6-Chloro-3-phenyl-4(3H)-quinazolinone-2-yl)mercaptoacetyl]hydrazono]-5-fluoro-1H-2-indolinone 5o showed the most favourable cytotoxicity against a renal cancer cell line UO-31 (log(10)GI(50) value -6.68). Compound 5v was also tested against human immunodeficiency virus 1 (HIV-1). Compound 5v was confirmed moderately active against HIV-1.     

Active hexose correlated compound potentiates the antitumor effects of low-dose 5-fluorouracil through modulation of immune function in hepatoma 22 tumor-bearing mice

BACKGROUND/OBJECTIVES

A variety of immunomodulators can improve the efficacy of low-dose chemotherapeutics. Active hexose correlated compound (AHCC), a mushroom mycelia extract, has been shown to be a strong immunomodulator. Whether AHCC could enhance the antitumor effect of low-dose 5-fluorouracil (5-FU) via regulation of host immunity is unknown.

MATERIALS/METHODS

In the current study Hepatoma 22 (H22) tumor-bearing mice were treated with PBS, 5-FU (10 mg·kg^-1·d^-1, i.p), or AHCC (360 mg·kg^-1·d^-1, i.g) plus 5-FU, respectively, for 5 d. CD3⁺, CD4⁺, CD8⁺, and NK in peripheral blood were detected by flow cytometry. ALT, AST, BUN, and Cr levels were measured by biochemical assay. IL-2 and TNFα in serum were measured using the RIA kit and apoptosis of tumor was detected by TUNEL staining. Bax, Bcl-2, and TS protein levels were measured by immunohistochemical staining and mRNA level was evaluated by RT-PCR.

RESULTS

Diet consumption and body weight showed that AHCC had no apparent toxicity. AHCC could reverse liver injury and myelosuppression induced by 5-FU (P < 0.05). Compared to mice treated with 5-FU, mice treated with AHCC plus 5-FU had higher thymus index, percentages of CD3⁺, CD4⁺, and NK cells (P < 0.01), and ratio of CD4⁺/CD8⁺ (P < 0.01) in peripheral blood. Radioimmunoassay showed that mice treated with AHCC plus 5-FU had the highest serum levels of IL-2 and TNFα compared with the vehicle group and 5-FU group. More importantly, the combination of AHCC and 5-FU produced a more potent antitumor effect (P < 0.05) and caused more severe apoptosis in tumor tissue (P < 0.05) compared with the 5-FU group. In addition, the combination of AHCC and 5-FU further up-regulated the expression of Bcl-2 associated X protein (Bax) (P < 0.01), while it down-regulated the expression of B cell lymphoma 2 (Bcl-2) (P < 0.01).

CONCLUSIONS

These results support the claim that AHCC might be beneficial for cancer patients receiving chemotherapy.     

Stereoselective synthesis and QSAR study of cytotoxic 2-(4-oxo-thiazolidin-2-ylidene)-2-cyano-N-arylacetamides

(2Z,5Z) 2-[(5-Arylidene-4-oxo-3-phenyl)-thiazolidin-2-ylidine]-2-cyano-N-arylacetamides 4a-l were stereoselectively prepared via condensation of aromatic aldehydes with 4-thiazolidinones 3a-c. The latters were obtained via electrophilic attack of phenylisothiocyanate on 2-cyano-N-arylacetamides 1a-c followed by reaction with chloroacetyl chloride under basic condition. Single crystal X-ray study of 3a allows good confirmation for the assigned structure. Additionally, 5-arylhydrazono analogs 5a-e were prepared via condensation of the appropriate diazonium salts with 4-thiazolidinones 3a,b. Many of the synthesized compounds exhibited promising antitumor properties against colon HCT116, breast MCF7 and liver HEPG2 cell lines. 3D-Pharmacophore modeling and QSAR analysis were combined to explain the observed antitumor properties.     

CoMFA and docking studies on triazolopyridine oxazole derivatives as p38 MAP kinase inhibitors

With the objective to design new chemical entities with enhanced inhibitory potencies against p38 MAP alpha kinase, the 3D-QSAR and Comparative Molecular Field Analysis (CoMFA) studies were carried out on triazolopyridine oxazole compounds as inhibitors of these kinase is presented here. The developed model gave q(2) value of 0.707 and r(2) value of 0.942 for CoMFA. The high leave-one-out (LOO) cross-validated correlation coefficient q(2) reveals that the model is a useful tool for the prediction of test set of 19 compounds that were not included in the training set of 55 compounds. The results not only lead to better understanding of structural requirements of p38 alpha inhibitors but also can help in the design of new potent inhibitors. The binding mode of the compounds at the active site of p38 MAP alpha kinase was explored using Glide docking program and hydrogen-bonding interactions were observed between the inhibitors and the target. The details of amino acid interactions of the active site are discussed briefly and correlated with the contour plots.     

Synthesis and biological evaluations of pyrazolo[3,4-d]pyrimidines as cyclin-dependent kinase 2 inhibitors

A series of 1,4,6-trisubstituted pyrazolo[3,4-d]pyrimidines 15-19, 30-38 capable of selectively inhibiting CDK2 activity were synthesized by derivatization at C-4, C-6 and N-1 with various amines and lower alkyl groups. For above synthetic compounds, biological evaluation was carried out and structure-activity relationship was examined. In our series, 4-anilino compounds exhibited better CDK2 inhibitory activity and antitumor activity compared to 4-benzyl compounds. The compounds 33a,b having a 3-fluoroaniline group at C-4 showed comparable or superior CDK2 inhibitory activity to those of olomoucine and roscovitine as reference compounds. In general, the unsubstituted compounds (30a,b, 33a,b, 36a,b) at N-1 possessed higher potency than the substituted compounds (32a,b, 34a,b) for the CDK2 inhibitory activity. As for EGFR inhibitory activity, most compounds didnot have a significant activity. The compounds 32a,b exhibited potent cell growth inhibitory activity against human cancer cell lines, but their CDK2 inhibitory activities were slightly poorer than olomoucine.     

Conformationally constrained diacylglycerol (DAG) analogs: 4-C-hydroxyethyl-5-O-acyl-2,3-dideoxy-D-glyceropentono-1,4-lactone analogs as protein kinase C (PKC) ligands

The (R)-DAG-lactones (5 and 7E/Z) are conformationally constrained diacylglycerol (DAG) analogs with high potency as protein kinase C (PKC) ligands. Here, we have prepared and characterized their one-carbon lengthened analogs (6 and 8E/Z). The target compounds were synthesized from 1,2-O-isopropylidene D-xylose through a key intermediate, 4-C-hydroxyethyl-2,3-dideoxy-D-glyceropentono-1,4-lactone (13); they were evaluated as competitive ligands to displace bound [(3)H]phorbol 12,13-dibutyrate (PDBU) from a recombinant single isozyme (PKC-alpha). The binding affinities of the synthesized compounds were K(i) = 2.623 microM for 6, K(i) = 1.080 microM for 8Z and K(i) = 0.92 microM for 8E, which were ca. 27, 90, and 70 times less potent than the corresponding parent compounds (5, 7Z and 7E). Molecular modeling indicated that the reduced binding affinity of the representative 3-alkylidene lactone 8Z, as compared to 7Z, may be explained by its poor fit in the sn-1 binding mode as well as by its entropic loss due to the relatively flexible hydroxyethyl group.     

Synthesis and in vitro antitumor activity of new quinoxaline derivatives

A series of novel 5,7-diamino-3-phenyl-2-benzylamino, 2-phenoxy, and 2-thiophenyl substituted quinoxalines has been designed, synthesized and evaluated for their in vitro antitumor activity towards cell lines of nine different types of human cancers. Some of these compounds exhibited inhibitory effects on the growth of a wide range of cancer cell lines generally at 10(-6) M, in some cases at 10(-7) M and 10(-8) M concentrations. Within this series the benzylamino quinoxaline derivatives 1b-7b were the most active, whereas compound 2c showed the highest MG_MD value (-5.66).     

Novel 5,7-disubstituted 6-amino-5H-pyrrolo[3,2-b]pyrazine-2,3-dicarbonitriles, the promising protein kinase inhibitors with antiproliferative activity

New derivatives of pyrrolo[2,3-b]pyrazine were synthesized and tested on a panel of cultured human tumor cell lines. It was found that 6-amino-5-(3-chlorophenylamino)-7-(1-methyl-1H-benzo[d]imidazol-2-yl)-5H-pyrrolo[3,2-b]pyrazine-2,3-dicarbonitrile (4j) exhibited a significant antiproliferative activity: GI50 for cell lines RXF 393 (renal cancer) and BT-549 (breast cancer) were 14 and 82 nM, respectively. To identify possible molecular targets, docking of the most active compounds into the active sites of cyclin-dependent kinases was performed. Molecular modeling of the inhibitor-enzyme complexes showed the differences in the binding poses of new pyrrolo[2,3-b]pyrazine derivatives in the kinase ATP-binding site compared with known pyrrolo[2,3-b]pyrazine inhibitors called aloisines. The patterns of drug kinase interactions correlated well with antiproliferative activities of novel derivatives. Key interactions and binding mode of docked compounds are discussed.     

Active conformation of some arylpiperazine postsynaptic 5-HT(1A) receptor antagonists

The synthesis and pharmacological properties of novel conformationally restricted arylpiperazine (2b-4b) or 1,2,3,4-tetrahydroisoquinoline (5b and 6b) derivatives of the known, flexible 5-HT(1A) receptor ligands 2a-6a (K(i)=0.95-7 nM) with different intrinsic activities are reported. Replacement of a tetramethylene chain with a 1e,4e-disubstituted cyclohexane ring in the structure of flexible ligands resulted in insignificant diminution of the 5-HT(1A) receptor affinity in the case of 2b-4b (K(i)=15-52 nM), whereas derivatives 5b and 6b were practically inactive (K(i)>1354 nM). The results of in vivo behavioural tests showed that 2a and 3a acted as postsynaptic 5-HT(1A) receptor partial agonists. Like the flexible 4a, the new rigid compounds 2b-4b showed features of postsynaptic 5-HT(1A) receptor antagonists. Since all possible conformations of the constrained compounds belong to an extended family--as indicated by molecular modelling studies--our hypothesis that such conformations are responsible for the blockade of postsynaptic 5-HT(1A) receptors has been confirmed. Determination of regions explored by terminal amide, or imide and hydrocarbon groups of the restricted compounds as well as the results of in vitro and in vivo studies allowed us to discuss the bioactive conformations of flexible ligands.     

Unsaturated fluoro-ketopyranosyl nucleosides: synthesis and biological evaluation of 3-fluoro-4-keto-beta-d-glucopyranosyl derivatives of N(4)-benzoyl cytosine and N(6)-benzoyl adenine

The protected beta-nucleosides 1-(2,4,6-tri-O-acetyl-3-deoxy-3-fluoro-beta-d-glucopyranosyl)-N(4)-benzoyl cytosine (2a) and 9-(2,4,6-tri-O-acetyl-3-deoxy-3-fluoro-beta-d-glucopyranosyl)-N(6)-benzoyl adenine (2b), were synthesized by the coupling of peracetylated 3-deoxy-3-fluoro-d-glucopyranose (1) with silylated N(4)-benzoyl cytosine and N(6)-benzoyl adenine, respectively. The nucleosides were deacetylated and several subsequent protection and deprotection steps afforded the partially acetylated nucleosides of cytosine 7a and adenine 7b, respectively. Finally, direct oxidation of the free hydroxyl group at 4'-position of 7a and 7b, and simultaneous elimination reaction of the beta-acetoxyl group, afforded the desired unsaturated 3-fluoro-4-keto-beta-d-glucopyranosyl derivatives. These newly synthesized compounds were evaluated for their potential antitumor and antiviral activities. Compared to 5FU, the newly synthesized derivatives showed to be more efficient as antitumor growth inhibitors and they exhibited direct antiviral effect toward rotavirus.