Iodine (III)-mediated synthesis of some 2-aryl/hetarylbenzoxazoles as antibacterial/antifungal agents

Ten 2-aryl/hetarylbenzoxazoles (5a, 5b, and 6a–h) were synthesized via oxidative cyclization of Schiff bases (3a, 3b, and 4a–h) with 1.1 equivalent of iodobenzene diacetate (IBD) in methanol. All of these 2-aryl/hetarylbenzoxazoles (5a, 5b, and 6a–h) were tested in vitro for their antibacterial and antifungal activities against Bacillus subtilis, Bacillus stearothermophilus, Escherichia coli, and Pseudomonas putida. These compounds also were screened for their antifungal activity against Aspergillus flavus and Aspergillus niger. Biological activity of these compounds was compared with those of commercially available antibiotics, chloramphenicol and antifungal agent cycloheximide. Most of these compounds, 5a, 5b, 6a, 6b, 6d, 6e, 6g, 6h, were equipotent or more potent than these commercial drugs at concentration 100 μg/ml.     

Triazenoindazoles and triazenopyrazolopyridines: Design,synthesis, and cytotoxic activity

Several triazenoindazoles 3a–e and triazinopyrazolopyridines 6a–i were prepared through the reaction of the corresponding 3-amino-4-chloroindazole and 3-aminopyrazolopyridine diazonium salts 2 and 5 with a number of secondary amines. All compounds were evaluated for their in vitro cytotoxic activity on three cell lines, HepG2, MCF7, and HeLa. Most compounds inhibited cell growth with IC₅₀ less than 0.1 μM. Compound 6d was the most potent, with an IC₅₀ of 0.03 μM against HepG2 and 0.05 μM against MCF7 and HeLa cells.     

DNA binding,antiviral activities and cytotoxicity of new furochromone and benzofuran derivatives

Bromination of visnagin (1) afforded 9-bromovisnagin (2) which on its alkaline hydrolysis afforded the 3-acetyl benzofuran derivative (3). The condensation of (3) with hydrazine hydrate, phenylhydrazine and/or hydroxylamine hydrochloride afforded the corresponding pyrazole derivatives (4a, b) and isoxazole derivative (4c). On the other hand, when compound 3 was condensed with some aromatic aldehydes, this yielded corresponding α, β-unsaturated keto derivatives (5a–e). Furthermore, when 1 was subjected to chlorosulfonation, the visnaginsulfonylchloride derivative 6 was afforded, which on amidation using morpholine, a sulonamido derivative (7) was obtained. Alkaline hydrolysis of the latter compound yielded 7-N-morpholinosulsamidobenzofuran (8) which was condensed with some aromatic aldehydes to yield the corresponding chalcone compounds (9a–e). Demethylation of visnagin afforded norvisnagin (10). The reaction of 10 with ethylbromoacetate in dry acetone yielded the ester benzopyran derivative (11) which reacted with hydrazine hydrate to afford the corresponding hydrazide derivative (12) and this was condensed with 3,4,5-trimethoxybenzaldehyde to give the corresponding hydrazone (13). A thaizolidinone derivative (14) was obtained by condensation of (13) with thioglycolic acid. Chloromethylation of norvisnagin afforded a 4-chloromethyl derivative (15) which reacted with different primary and secondary amines to yield the corresponding ethylamino derivative (16a, b). Moreover, mannich bases (16a, b) and (17a–c) were obtained by reacting norvisnagin with different primary and secondary amines in the presence of formalin but benzoylation of (16a, b) and (17a–c) afforded 4-oxybenzoyl derivative (18a–e). The prepared compounds were tested for their interaction with DNA; bromovisnagin 2 showed the highest affinity and compounds 6, 15, 8a, > 14, > 16b, 17a, and 16a showed moderate activity in decreasing potency. Moreover, compound 2 also was the most active as antiviral agent toward HS-I virus and compounds 6, 7, 15, 14, 16a, and 18a were found to be moderately active. CD₅₀ of the active compounds were also measured.     

Synthesis and cytotoxicity of 1-phenylethanolamine carboxamide derivatives: effects on the cell cycle

Seven novel analogues of 1-phenylethanolamine carboxamide derivatives, 3a–3g, related to carboxamides isolated from Isodon excisus were synthesized and evaluated for their cytotoxic and apoptosis-induction properties against murine B16 and leukemia L1210 cell lines. Compounds containing no substitution at the 4′-position (3a–3d) or containing a 4′-amino (3e–3g) group were investigated. Generally, the amino-containing compounds were slightly more active than their unsubstituted congeners. Also, the indole-containing compounds 3c and 3f gave the strongest cytotoxic activity (IC₅₀ = 25–87 μM) against the growth of L1210 and B16 cancer cells. Compound 3f was subjected to flow cytometry studies and it was found to induce L1210 cells grown in culture to undergo apoptosis.     

Synthesis and biological evaluation of new Mannich and Schiff bases containing 1,2,4-triazole and 1,3,4-oxadiazole nucleus

5-(Pyridine-3-yl)-1,3,4-oxadiazole-2-thiole 2, obtaining starting from nicotinic acid hydrazide were converted to the corresponding Mannich bases (3a–c) by the reaction with several heterocyclic amines in the presence of formaldehyde. 1,2,4-Triazole-3-thiole, (4) prepared from 1,3,4-oxadiazole-2-thiole (2) was converted to the corresponding Mannich bases (5a–e) by several steps. The synthesis of Schiff bases (6a–d) was performed from the reaction of the corresponding triazol-3-thioles with various aromatic aldehydes. The treatment of Schiff bases containing 1,2,4-triazoles 6c and 6d with morpholine or thiomorpholine generated the corresponding Mannich bases 7a, b and 8a, b. The synthesized compounds were screened for their antimicrobial, antilipase, and antiurease activities. Some of them were found to possess good-moderate antimicrobial, antiurease, and/or antilipase activity.     

3,5-Disubstituted thiadiazine-2-thiones: New cell-cycle inhibitors

Two series, a and b, of 3-cyclopentyl or (3-cyclohexyl)-5-substituted-3,4,5,6-tetrahydro-2H-1,3,5-thiadiazine-2-thiones (THTT) 2a–9a and 3b, 4b, 6b–9b, were synthesized to develop new cell cycle inhibitors. Variable and promising in vitro antiproliferative activities were shown with the synthesized THTT derivatives. Compound 5a with a 5-cyclopentyl group on position-3 and a glutamine residue on position-5 of the THTT moiety showed maximum activity (IC₅₀ = 8.98 μM). Compound 5a possessed notable cell cycle disrupting and apoptotic activities with enhanced selectivity against cancer cells, suggesting the potential for the development of new selective cell cycle inhibitors. There is no evident relationship between the cytotoxic activity of the tested compounds and their lipophilicity. In addition, a pharmacophore based study was performed to explain the biological activity on structural bases. A successful model was generated with a good correlation with the observed activity.     

Synthesis,antioxidant and antimicrobial evaluation of simple aromatic esters of ferulic acid

Aromatic ester derivatives of ferulic acid where the phenolic hydroxyl is free (6a–d) or acetylated (5a–d) were evaluated for their antioxidant and antimicrobial properties. The superoxide radical scavenging capacity of compounds 5d and 6d–e (IC₅₀ of 0.19, 0.27 and 0.20 mM, respectively) was found to be twice as active as α-tocopherol (IC₅₀ = 0.51 mM). DPPH radical scavenging capacity was moderate and only found in compounds bearing free phenolic hydroxyl groups (6a–e). With regard to antimicrobial properties, compounds 6b and 6c displayed significant activity against Enterococcus faecalis (MICs = 16 μg/mL) and vancomycin-resistant E. faecalis (MIC for 6b, 32 and for 6c, 16 μg/mL). Compound 6c also demonstrated prominent activity against planktonic Staphylococcus aureus with a MIC value of <8 μg/mL and it inhibited bacterial biofilm formation by S. aureus with a MBEC value of <8 μg/mL, which was 64 and 128 times more potent than ofloxacin and vancomycin, respectively.     

Conventional and microwave-assisted synthesis of imidazole and guanidine derivatives and their biological evaluation

A number of imidazole derivatives 3a–f and 4a–f have been synthesized by the condensation of 3-methylthiophen-2-carboxaldehyde 1a, 5-methylthiophen-2-carboxaldehyde 1b, N-methylpyrrol-2-carboxaldehyde 1c, 1-naphthaldehyde 1d, 2-naphthaldehyde 1e, and 2-hydroxy-1-naphthaldehyde 1f with 1,2-diaminoanthraquinone 2a and 2,3-diaminophenazine 2b, respectively. Condensation of 2-guanidinobenzimidazole with functionalized aldehydes 1a–f leads to the formation of guanidine derivatives 5a–f. Both imidazole (3a–f, 4a–f) and guanidine derivatives (5a–f) were synthesized in good yields using conventional heating and microwave irradiation techniques. Structures assigned to compounds 3a–f, 4a–f and 5a–f are supported by correct spectral and analytic data. On screening for anti-inflammatory and anticancer activities, compounds 3e, 4a and 5a exhibited good anti-inflammatory and compounds 3d, 3f, 4d and 4f showed very good anticancer activity.     

Synthesis of pyrimidine and condensed pyrimidine derivatives and their evaluation for anti-inflammatory activity

Condensation of various amines (Ia–c) with 4-isothiocyanato-4-methyl-2-pentanone (2a) at room temperature gave tetrahydropyrimidinethiones (3a–c) whereas condensation of 1a–e with 3-isothiocyanatobutanal at room temperature gave tetrahydropyrimidinethiones (4a–e). Amines 1a, d, f–i on condensation with 4-isothiocyanato-4-methyl-2-pentanone (2a) by heating under reflux for 8 h at pH ~4 (for 1a, d) and at RT (for 1f–i) gave dihydropyrimidinethiones 5a–b and 5c–f, respectively. Condensation of 1f with 3-isothiocyanatobutanal gave dihydropyimidinethione 6. When isothiocyanate (2a) and phenylenediamine derivatives 1g, h were heated under reflux at pH ~4, tricyclic compounds 7a, b were obtained in good yields. Condensation of 3-isothiocyanatobutanal with o-phenylenediamines 1h and 1j at pH ~ 5 by refluxing in methanol for 8 h gave products 8 and 9. All these compounds were screened for anti-inflammatory activity. Compounds 3c, 4c and 7a exhibited anti-inflammatory activity comparable to standard drug ibuprofen.     

Inhibition of DNA topoisomerases I and II and cytotoxicity of compounds from <Emphasis Type="Italic">Ulmus davidiana</Emphasis> var. <Emphasis Type="Italic">japonica</Emphasis>

Twenty five compounds including ten triterpenes (1–3, 5–11), six flavonoids (12–15, 24, 25), five lignans (17, 18, 21–23), two butenyl clohexnone glycosides (19–20), one fructofuranoside (16) and one fatty acid (4) were isolated from the roots of Ulmus davidiana var. japonica. The structures of those compounds were identified by comparing their physicochemical and spectral data with those of published in literatures. All the compounds were evaluated for DNA topoisomerase inhibitory activities and cytotoxicities. Among the purified compounds, 4 and 19 showed more potent inhibitory acitivities (IC₅₀: 39 and 19 μM, respectively) than camptothecin, as the positive control (IC₅₀: 46 μM) against topoisomerase I. Compounds, 4, 10, 12, 19, 24 and 25 showed strong inhibitory activities toward DNA topoisomerase II (IC₅₀: 0.1, 0.52, 0.47, 0.42, 0.17 μM and 17 nM, respectively), which were more potent than that of etoposide as positive control (IC₅₀: 20 μM). In A549 cell line, 5 and 6 showed cytotoxicities (IC₅₀: 4 μM and 3 μM, respectively, with IC₅₀ of camptothecin as positive control: 10.3 μM). In the HepG2 cell line, 3, 5 and 7 showed cytotoxicity (IC₅₀: 4, 3 and 4 μM, respectively, with IC₅₀ of camptothecin: 0.3 μM). Compounds 6, 12 and 23 showed cytotoxicities in the HT-29 cell line (IC₅₀: 19, 19 and 15 μM, respectively, with IC₅₀ of camptothecin: 2 μM).     

Synthesis and biological activities of Schiff bases of gabapentin with different aldehydes and ketones: a structure–activity relationship study

A series of novel gabapentin derivatives 6a–k and 7a–f were synthesized, and their biological activities were determined. The chemical structures were confirmed by elemental analyses, UV–visible, FT-IR, and ¹H NMR spectral studies. The structure–activity relationships (SAR) for anticonvulsant and antioxidant activities were discussed. Compounds 7a–f were evaluated for their possible anticonvulsant activity by Maximal Electroshock Seizure (MES) test, and their neurotoxic effects were determined by rotorod test. Majority of the compounds were active in MES tests. Compounds 7b and 7e showed good protective effect from seizure when compared to standard drug, phenytoin (100 mg/kg). The same compounds showed no neurotoxicity at the maximum dose administered (100 mg/kg). Most of the novel compounds showed DPPH radical scavenging activity, where compounds 6f, 6j, and 7a were the best radical scavengers (IC₅₀ was about 60 μg/ml).     

Comparison of the cytotoxic effect of lapachol, α-lapachone and pentacyclic 1,4-naphthoquinones on human leukemic cells

The pentacyclic 1,4-naphthoquinones 1a–d were cytotoxic (IC₅₀ ∼ 2–7 μM) to human leukemic cell lines K562 (oxidative stress-resistant), Lucena-1 (MDR phenotype) and Daudi. Fresh leukemic cells obtained from patients, some with the MDR phenotype, were also sensitive to these compounds. The pentacyclic 1,4-naphthoquinones 1a and 1c induced apoptotic cell death in cells from leukemic patients as determined by flow cytometry. Conversely, the cell lines were highly insensitive to lapachol (2) and α-lapachone (3). Mitomycin-C inhibited cell proliferation at concentrations as low as 0.5 μM. The low toxicity against lymphocytes activated by phytohemagglutinin shows that these compounds are selective for the cancer cells studied. Previous data suggest that these compounds (1a–d) can be bioactivated in situ by reduction followed by rearrangement leading to enones, which are powerful alkylating agents. In contrast, lapachol (2) and β-lapachone (3), which cannot be bioactivated by reduction, showed little activity against the same cell lines.     

New thiazolidinedione-5-acetic acid amide derivatives: synthesis, characterization and investigation of antimicrobial and cytotoxic properties

The present work describes the synthesis, antimicrobial and cytotoxic activity of 2,4-thiazolidinedione-5-acetic acid amides 3a–n. The structures of the compounds were confirmed by IR, ¹H, ¹³C NMR and elemental analysis. All compounds were tested for antimicrobial activity by twofold serial dilution technique. The preliminary results revealed that the compound 3d exhibits promising antibacterial and antifungal activity. The cytotoxic (MTT) activity of 2,4-thiazolidinedione-5-acetic acid amides were tested in four tumour cell lines. We found that compound 3j inhibited proliferation of HeLa, HT29, A549 and MCF-7 cell lines with IC₅₀ values of 33, 35, 30 and 36 μM, respectively.     

Synthesis and Testing of New Antileukemic Schiff Bases of N-Hydroxy-N′ - Aminoguanidine Against CCRF-CEM/0 Human Leukemia Cells in Vitro and Synergism Studies with Cytarabine (Ara-C)

A series of eight new N-hydroxy-N-aminoguanidine (HAG) Schiff bases [ArCH = NNHC( = NH)NHOH · tosylate] was synthesized as potential antitumor agents through the inhibition of the enzyme ribonucleotide reductase (EC 1.17.4.1). Five of the HAG derivatives (LK02 through LK06) were designed to contain an orthohydroxy group on the phenyl ring of ArCH = to increase the stability of the Schiff base formed. In addition, two compounds with a substituted quinoline [LK10; ArCH = (4-hydroxy-7-trifluoromethylquinolin-3-yl)methylene] or isoquinoline (LK11; ArCH = (5-nitroisoquinolin-l-yl)methylene] moiety were synthesized through multiple-step reactions involving reduction and/or oxidation. The IC₅₀ values of the newly synthesized HAG Schiff bases were determined against human leukemic CCRF-CEM/0 cells in culture. The IC₅₀ values of two previously reported HAG derivatives [ATL25; ArCH = (5-nitro-isoquinolin-l-yl)methylene] and [LW02; ArCH = 2-hydroxy-3-allyl-benzylidene)] were also determined for the first time against CCRF-CEM/0 cells. Among the compounds tested, LK11 was found to be the most potent (IC₅₀, 2.95 ± 0.1 µM) and the 4-methoxy-2-hydroxy-phenyl derivative (LK02) to be the least potent (IC₅₀, 121 ± 16 µM). LK11 was about 15-fold more potent against CCRF-CEM/0 cells compared to the parent compound hydroxyguanidine sulfate (IC₅₀, 46 ± 7.1 µM) and was about 32 times more potent than LK10 (IC₅₀, 97.6 ± 0.9 µM). LK11 in combination was incubated in sequence with cytarabine (ara-C) at various molar ratios against CCRF-CEM/0 cells for 48 hr. The results were analyzed using both the isobologram and the median-effect methods. This combination at a 1:1 molar ratio was about 6-fold more potent (IC₅₀, 0.16 µM) compared to ara-C alone (IC₅₀, 1.05 µM) and about 18-fold more potent compared to LK11 alone (IC₅₀, 2.95 ± 0.1 µM). In summary, the antileukemic potency of certain HAG derivatives can be improved by the presence of orthohydroxy groups of the phenyl ring, and a 1:1 molar combination of an isoquinoline HAG compound and ara-C leads to significant synergistic antileukemic activity against CCRF-CEM/0 cells in vitro.     

Anthraquinones from the Roots of <Emphasis Type="Italic">Knoxia valerianoides</Emphasis> inhibit the formation of advanced glycation end products and rat lens aldose reductase <Emphasis Type="Italic">in vitro</Emphasis>

Eight known compounds, lucidin (1), lucidin-ω-methyl ether (2), rubiadin (3), damnacanthol (4), 1,3,6-trihydroxy-2-methoxymethylanthraquinone (5), 3,6-dihydroxy-2-hydroxymethyl-9,10-anthraquinone (6), 1,3,6-trihydroxy-2-hydroxymethyl-9,10-anthraquinone 3-O-β-primeveroside (7), and vanillic acid (8), were isolated from EtOAc- and n-BuOH-soluble fractions of the roots of Knoxia valerianoides. The structures of 1–8 were identified by analysis of spectroscopic data as well as by comparison with published values. All the isolates were subjected to in vitro bioassays to evaluate advanced glycation end products (AGEs) formation and rat lens aldose reductase (RLAR) inhibitory activity. Compound 5 showed the most potent inhibitory activity (IC₅₀ = 52.72 μM) against AGEs formation. Compounds 1, 2, and 8 also showed potent inhibitory activity on AGEs formation with IC₅₀ values of 79.28, 62.79, and 93.93 μM, respectively, compared with positive control, aminoguanidine (IC₅₀ = 962 μM). While, compounds 1 and 5–7 showed strong inhibitory activity against RLAR with IC₅₀ values of 3.35, 3.04, 6.39, and 2.05 μM, respectively.     

Potential antitumor α-methylene-γ-butyrolactone-bearing nucleic acid base. 3. Synthesis of 5′-Methyl-5′-[(6-substituted-9H-purin-9-yl)methyl]-2′-oxo-3′-methylenetetrahydrofurans

Search for a new α-methylene-γ-butyrolactone-bearing 6-substituted purine as a potental antitumor agent has led to synthesize seven, hitherto unreported, 5′-Methyl-5′-[(6-substituted-9H-purin-9-yl)methyl]-2′-oxo-3′ methylenetetrahydrofurans (H, Cl, I, CH₃, NH₂, SH, >C=O) (6a-g). These include 5′-Methyl-5′-[(9H-purin-9-yl)methyl]-2′-oxo-3′-methylenetetrahydrofurans (6a), 5′-Methyl-5′-[(6-chloro-9H-purin-9-yl)methyl]-2′-oxo-3′-methylenetetrahydrofurans (6b), 5′-Methyl-5′-[(6-iodo-9H-purin-9-yl) methyl]-2′-oxo-3′-methylenetetrahydrofurans (6c), 5′-Methyl-5′-[(6-methyl-9H-purin-9-yl) methyl]-2′-oxo-3′-methylenetetrahydrofurans (6d), 5′-Methyl-5′-[(9H-adenin-9-yl)methyl]-2′-oxo-3′-methylenetetrahydrofurans (6e), 5′-Methyl-5′-[(6-mercapto-9H-purin-9-yl) methyl]-2′-oxo-3′-methylenetetrahydrofurans (6f) and 5′-Methyl-5′-[(9H-hypoxanthin-9-yl)methyl]-2′-oxo-3′-methylenetetrahydrofurans (6g) which were made by the Reformatsky-type reaction of ethyl α-(bromomethyl) acrylate with the corresponding (6-substituted-9H-purin-9-yl)-2-propanone intermediates (5a-g). These ketone intermediates5a-g, 1-(9H-purin-9-yl)-2-propanone (5a), 1-(6-chloro-9H-purin-9-yl)-2-propanone, (5b), 1-(6-iodo-9H-purin-9-yl)-2-propanone (5c), 1-(6-methyl-9H-purin-9-yl)-2-propanone (5d), 1-(9H-adenin-9-yl)-2-propanone (5e), 1-(6-mercapto-9H-purin-9-yl)-2-propanone (5f), and 1-(9H-hypoxanthin-9-yl)-2-propanone (5g) were directly obtained by the alkylation of the 6-substituted purine bases with the chloroacetone in the presence of K₂CO₃ (or NaH) under DMF (or DMSO). The preliminary in vitro cytotoxcity assay for the synthetic α-methylene-γ-butyro-lactone compounds (6a-g) were determined against three cell lines (PM-3A, P-388, and K-562) and showed the moderate antitumor activity (IC₅₀ ranged from 1.4 to 4.3 μg/ml) with the compound 5′-methyl-5′-[(9H-hypoxanthin-9-yl)methyl]-2′-oxo-3′-methylenetetrahydrofuran (6g) showing the least antitumor activity.     

Synthesis and preliminary evaluation of selected 2-aryl-5(6)-nitro- 1<Emphasis Type="Italic">H</Emphasis>-benzimidazole derivatives as potential anticancer agents

In this study we report the synthesis and preliminary evaluation of a series of six 2-aryl-5(6)-nitro-1H-benzimidazole derivatives (1–6) as potential anticancer agents. Cytotoxicity was evaluated against seven human neoplastic cell lines using the MTT assay. Compound 6 [2-(4-chloro-3-nitrophenyl)-5(6)-nitro-1H-benzimidazole] was the most active of the series, showing an IC₅₀ of 28 nM against the A549 cell line. This compound displayed a selective in vitro cytotoxic activity index (>700) in non neoplastic HACAT cells (IC₅₀ = 22.2 μM). Compounds 3 and 6 induce arrest in the S phase of the cell cycle, and compounds 1–6 induce apoptosis in the K562 cell line. Compound 6 induces poly (ADP-ribose) polymerase (PARP) inhibition activity as a potential mechanism of action. These results suggest that compound 6 could be a potent anticancer agent. Compound 3 displayed the best inhibitory activity against PARP with an IC₅₀ value of 0.05 μM, compared to the activity shown by the positive control 3-aminobenzamide (IC₅₀ = 28.5 μM).     

Synthesis and antitumor evaluation ofcis-(1,2-diaminoethane) dichloroplatinum (II) complexes linked to 5- and 6-methyleneuracil and-uridine analogues

The search for platinum (II)-based compounds with improved therapeutic properties was prompted to design and synthesize a new family of water-soluble, third generation cis-diaminedichloroplatinum (II) complexes linked to uracil and uridine. Six heretofore unreported uracil and uridine-platinum (II) complexes are; [N-(uracil-5-yl-methyl)ethane-1,2-di-amine]dichloroplatinum (II) (3a), [N-(uracil-6-yl-methyl)ethane-1,2-diamine] dichloroplatinum (II) (3b), {[N-(2′,3′,5′-tri-O-acetyl)uridine-5-yl-methyl] ethane-1,2-diamine}dichloroplatinum (II) (6a), {[N-(2′,3′,5′-tri-O-acetyl) uridine-6-yl-methyl]ethane-1,2-diamine}dichloroplatinum (II) (6b), [N-(uridine-5-yl-methyl)ethane-1,2-diamine]dichloroplatinum (II) (7a), [N-(uridine-6-yl- methyl)ethane-1,2-diamine]dichloroplatinum (II) (7b). These analogues were prepared from the key starting materials, 5-chloromethyluracil (1a) and 6-chloromethyluracil (1b) which were reacted with ethylenediamine to afford the respective 5-[(2-aminoethyl)amino] methyluracil (2a) and 6-[(2-aminoethyl)amino]methyluracil (2b). The cis-platin complexes3a and3b were obtained through the reaction of the respective2a and2b with potassium tetrachloroplatiate (II). The heterocyclic nucleic acid bases1a and1b were efficiently introduced on the β-D-ribose ring via a Vorbruggen-type nucleoside coupling procedure with hexamethyldisilazane, trimethylchlorosilane and stannic chloride under anhydrous acetonitrile to yield the stereospecific β-anomeric 5-chloromethyl-2′,3′,5′-tri-O-acetyluridine (4a) and 6-chloromethyl-2′,3′,5′-tri-O-acetyluridine (4b), respectively. The nucleosides4a and4b were coupled with ethylenediamine to provide the respective 5-[(amino-ethyl)amino]methyl-2′,3′,5′-tri-O-acetyluridine (5a) and 6-[(aminoethyl)amino] methyl-2′,3′,5′-tri-O-acetyluridine (5b). The diamino-uridines5a and5b were reacted with potassium tetrachloroplatinate (II) to give the novel nucleoside complexes,6a and6b, respectively which were deacetylated into the free nucleosides,7a and7b by the treatment with CH₃ONa. The cytotoxic activities were evaluated against three cell lines (FM-3A, P-388 and J-82) and none of the synthesized compounds showed any significant activity.     

The novel amidocarbamate derivatives of ketoprofen: synthesis and biological activity

A series of novel ketoprofen derivatives 4a–j bearing both amide and carbamate functionalities were prepared using the benzotriazole method of carboxylic and hydroxy group activation. Selective reduction of ketoprofen produced hydroxy derivative 2, which in the reaction with one or two moles of 1-benzotriazole carboxylic acid chloride (1) gave benzotriazole derivatives 3a and 3b, respectively. Compounds 3a and 3b with various amines afforded amidocarbamates 4a–j. Antioxidative screenings revealed that the prepared compounds 3b and 4a–j possess excellent lipid peroxidation inhibition at 0.1 mM concentration, higher than 95% for the derivatives bearing aromatic, cycloalkyl or heterocyclic substituents. Two of the compounds, 3b and 4g, also show high soybean lipoxygenase inhibition activity (95 and 83.5%, respectively). On the other hand, the amidocarbamate derivatives of ketoprofen show only weak reducing activity against 1,1-diphenyl-2-picrylhydrazyl radicals. No selective antiviral effects were noted for the tested compounds against a broad variety of DNA and RNA viruses. Most compounds were endowed with a moderate (IC₅₀: 10–25 μM) cytostatic activity.     

Synthesis of piperine–amino acid ester conjugates and study of their cytotoxic activities against human cancer cell lines

Abstract  

A series of piperine–amino acid ester conjugates (4a–4r) were synthesized under mild conditions and screened for their cytotoxic activities against a panel of human cancer cell lines (IMR-32, MCF-7, PC-3, DU-145, Colo-205, and Hep-2). The parent compound piperine lacked significant activity but the analogues were effective to in all tested human cancer cell lines. The introduction of d- and l-amino acid side chain to piperine through peptide linkage significantly increased cytotoxic activity. Among the tested conjugates, 4p showed significant cytotoxic activity against DU-145 cell lines with IC₅₀ of 21 μM. The synthetic protocol is suitable for generating piperine derivatives with various structural motifs for exploring the desired activity.