Chemo-enzymatic synthesis of ester-linked taxol-oligosaccharide conjugates as potential prodrugs

7-Glycolylpaclitaxel 2″-O-α-glucooligosaccharides, novel taxol (paclitaxel) prodrugs of ester-linked oligosaccharide series compounds, were synthesized by chemo-enzymatic procedures, including enzymatic transglycosylations with α-glucosidase and cyclodextrin glucanotransferase. The water-solubility of 7-glycolylpaclitaxel 2″-O-α-glucopentaoside was 2.7 mM, which was 6.8 thousand-fold higher than that of paclitaxel. C-7 modification of paclitaxel with a longer oligosaccharide chain decreased the in vitro cytotoxicity of paclitaxel against KF human ovarian cancer cells.     

Synthesis and biological evaluation of lipid-soluble prodrugs of anethole dithiolthione

<正>16 ADT carboxylate esters were prepared by means of esterification and these compounds were expected to increase the bioavailability of 4-hydroxyanehole trithione.In vivo studies showed that ADT concentration of 3a in plasma was much higher than that of ATT during 120 min.Compound 3a could reach blood peak values of ADT at 660.6 ng/mL which was about 14 times of that by ATT.Additionally,the acute toxicity assay indicated high safety of compound 3a that the maximum tolerated dose was no less than 3.25 g/kg.     

Synthesis of conjugates of isobornylphenols and natural chlorins

A series of terpenophenol—chlorin conjugates containing terpenophenol and porphyrin fragments of various structure was synthesized. The terpenophenol fragment was added to the chlorin macrocycle using reactions of the exocyclic ester and the propionate substituent in the 17-position of methylpheophorbide a analogs. Translated from Khimiya Prirodnykh Soedinenii, No. 5, pp. 484–487, September-October, 2008.     

Nystatin—dextran conjugates: Synthesis and characterization

The coupling of nystatin (Nys), a water-insoluble antifungal agent, to dextran via an imine or amine bond was systematically investigated. Dextran was first oxidized to dialdehyde dextran using potassium periodate, purified from the oxidizing agent, and reacted with Nys to form the Schiff base. The Schiff base was reduced to the amine using borohydride. All reactions took place in water. The purification of the oxidized dextran from the oxidizing agent was essential to prevent oxidative degradation of Nys at the coupling step. The effects on the coupling yield of the following factors: dextran molecular weight, degree of oxidation (aldehyde content), Nys to dextran ratio, temperature, and reaction pH were studied. A 95% coupling yield was obtained at the optimized coupling conditions: pH 8.9 ± 0.1, 50% degree of oxidation, and initial ratio of Nys to dialdehyde dextran 1:2.5. In all experiments, dextran was decreased in molecular weight during the oxidation step. Both imine and amine forms of Nys-dextran conjugates were soluble in water and exhibited improved stability in aqueous solutions as compared to the unbound drug. The conjugates showed comparable minimum inhibitory concentration (MIC) values against Candida albicans and Cryptococcus neoformans. The conjugates were about 25 times less toxic than free Nys after a single injection in mice. © 1996 John Wiley & Sons, Inc.     

双喹啉-多胺缀合物的合成及生物活性测定

为了获得具有高活性的神经元保护药物,以1,3-丙二胺、1,4-丁二胺、1,6-己二胺等为原料,合成了4个新的双喹啉-多胺缀合物;利用核磁共振谱、质谱和元素分析确认了目标化合物的结构,同时评价了它们对神经元细胞的保护作用.结果表明,4个目标化合物对神经元细胞的保护作用均较差,说明多胺链并不能增强喹啉对神经元细胞的保护作用.     

A novel one-pot, two-step synthesis of N-acyl-1,3-thiazolidines and N-acyl-1,3-oxazolidines as potential double prodrugs of formaldehyde

A convenient and general one-pot, two-step protocol to prepare both N-acyl-1,3-thiazolidines and N-acyl-1,3-oxazolidines from formaldehyde, fatty acyl chlorides, and natural α-amino acids has been performed for the peculiar case of formaldehyde. In the presence of triethylamine to promote both the ring-forming process and the amide bond formation, subsequent addition of the acyl donor proved to be efficient to trap the preformed stable formaldehyde-derived 1,3-thiazolidine or the transient 1,3-oxazolidine using an appropriate ratio of formaldehyde.     

Synthesis and biological evaluation of new pyrrolopyrazinone compounds as potential antitumor agents

A series of pyrrolo[1,2-a]pyrazinone compounds(5a-9f) were synthesized,and their cytotoxic activity against SKOV-3,A549.HeLa cells in vitro were evaluated by the MTT method.Some of the compounds showed potential antitumor activity against three tumor cell lines.Among them,compounds 9c and 9d showed the most potent cytotoxic activity.The preliminary mechanism of action was discussed.     

Synthesis of 3-substituted 7-(3,3-dimethyl-1-triazeno)-10-methylphenothiazines as potential antitumor agents

A series of 3-substituted (chloro, bromo, fluoro or methyl) 7-(3,3-dimethyl-1-triazeno)-10-methylphenothiazines were synthesized as potential antitumor agents. Treatment of p-substituted anilines with ammonium thiocyanate in the presence of bromine gave 6-substituted 2-aminobenzthiazoles which, after methylation with methyl iodide were hydrolyzed in 50% potassium hydroxide to give 5-substituted 2-methylaminothiophenols in moderate yield. Condensation of methylaminothiophenols with 3,4-dichloronitrobenzene in ethanol under an atomsphere of nitrogen gave adducts which were cyclized in dimethylformamide under the catalysis of copper and cuprous iodide to give 3-substituted 7-nitro-10-methylphenothiazines. The nitro group was reduced to the amino function with stannous chloride. Diazotization of the amines followed by coupling with dimethylamine gave the corresponding triazenes.     

Regioselective protection of 10-deacetylbaccatin Ⅲ and semi-synthesis of paclitaxel

Semi-synthesis of paclitaxel was achieved in four steps from 10-deacetylbaccatin HI （10-DAB HI）. The key steps are the regioselective protection at the hydroxyl group at C-7 of 10-DAB HI, using 1,1′-thiocarbonyldiimidazole as a selective reagent, and the deprotection of the protected paclitaxel with a mixture of p-toluenesulfonic acid and 0.1 mol/L aqueous hydrochloride.     

Water-soluble dendrimer–poly(ethylene glycol) starlike conjugates as potential drug carriers

The design and synthesis of a new dendrimer–poly(ethylene glycol) (PEG) conjugate that may be used as a model drug carrier are described. The starting material is a polyether dendrimer with two different types of chain end functionalities. The dendritic assembly is made water soluble through attachment of short PEG chains to the dendrimer via one type of functionality. The remaining chain end functionalities then were used to incorporate model drug molecules of varying polarity into the modified dendrimer. Cholesterol and two amino acid derivatives were selected as model drugs for attachment through their respective hydroxyl, carboxylic acid, and amino functional groups to the dendrimer via carbonate, ester, and carbamate linkages. The resulting water-soluble dendrimer-model drug conjugates were characterized by matrix-assisted laser desorption ionization time of flight (MALDI-TOF) mass spectrometry. © 1999 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 37: 3492–3503, 1999     

Synthesis and antitumor activity of 7-azaindirubin

Twenty 7-azaindirubin derivatives were designed and synthesized.Their antitumor activities were evaluated in vitro against DU145 cell line.The pharmacological results showed that most of the prepared compounds displayed the excellent activity.Compound 18 exhibited the most potent antitumor activity among the tested compounds.     

Synthesis of PEG–iridium conjugates and their use as hydrogenation catalysts in a water/substrate two-phase medium

New syntheses of PEG-(OCH₂C₅H₄N)₂ and PEG-(OC₆H₄PPh₂)₂ (PEG: poly(ethylene glycol)) conjugates are reported. An iridium hydrogenation catalyst 1, is shown to catalyze hydrogenation in a water/substrate two-phase system. Attachment of 1 to PEG to make 2 and 3 succeeds in making the complex water-soluble and allows it to retain some of its catalytic ability, but leads to micelle formation that inhibits the separation of organic and aqueous phases.     

Synthesis of a (B12H11S) containing glucuronoside as potential prodrug for BNCT

A B₁₂H₁₁SH²⁻ containing glycoside of glucuronic acid has been prepared, for possible use as prodrug in BNCT. The synthesis was carried out by the Koenigs-Knorr reaction of the acetylated glucopyranosyluronate bromide with the nucleophile cyanoethylthioundecahydro-closo-dodecaborate(2−). After removal of the cyanoethyl-group, deacetylation and saponification of the reaction product tris(tetramethylammonium)-[S-(β-d-glucuronate)-thio] undecahydro-closo-dodecaborate(3−) could be prepared.     

Design, synthesis and in vitro evaluation of L-amino acid esters prodrugs of acyclic nucleoside phosphonates as anti-HBV agent

A series of novel L-amino acid esters prodrugs of acyclic nucleoside phosphonates was synthesized and their anti-HBVactivity was evaluated in HepG2 2.2.15 cells. Compound 1d exhibited more potent anti-HBV activity and lower cytotoxicity than those of adefovir dipivoxil with EC50 and CC50 values of 0.207 mmol/L and 2530 mmol/L, respectively.     

Fluorophilicity of alkyl and polyfluoroalkyl nicotinic acid ester prodrugs

The fluorophilicity of a series of hydrocarbon and fluorocarbon-functionalized nicotinic acid esters (nicotinates) is measured from their partitioning behavior (log K_p) in the biphasic solvent system of perfluoro(methylcyclohexane) (PFMC) and toluene. The chain length of the hydrocarbon or fluorocarbon alkyl group of the ester ranges from one to twelve carbon atoms. Knowledge of the fluorophilicity of these solutes is relevant to the design of these prodrugs for fluorocarbon-based drug delivery. The experimental log K_p values range from −1.72 to −3.40 for the hydrocarbon nicotinates and −1.64 to 0.13 for the fluorinated nicotinates, where only the prodrug with the longest fluorinated chain (2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-pentadecafluorooctyl nicotinic acid ester) partitions preferentially into the fluorinated phase (log K_p = 0.13). Predictions of the partition coefficients using solubility parameters calculated from group contribution techniques or molecular dynamics simulation are in reasonable agreement for the perhydrocarbon nicotinates and short chained perfluorinated nicotinates (≈0.3-39% deviation). Significant deviations from experimental partition coefficients (greater than 100%) are observed for the longest chain perfluoroalkyl nicotinates.     

Synthesis of adamantyl-containing cidofovir analogs as potential antiviral prodrugs with high bioavailability parameters

We report on preparation of potential nucleoside phosphonate prodrugs: 1-{3-hydroxy-2-[O-(adamantylalkyl)phosphorylmethoxy]propyl}cytosines containing two structural fragments providing antiviral activity, nucleoside phosphonate and adamantyl sites.

     

Synthesis and Antitumor Activity of a New 7-Azaindole Derivative

We designed and synthesized a 7-azaindole derivative（TH1082）, which was characterized by 1^H NMR and 13^C-NMR. We investigated its antitumor effects on human melanoma A375 cells, human liver cancer SMMC cells and human breast cancer MCF-7 cells in vitro via 3-（4,5-dimethyldiazol-2-yl）-2,5-diphenyl-tetrazolium bromide （MTT） assay and also explored the mechanism of antiproliferation of them. The results show that TH1082 significantly inhibited the proliferation of these cells to different extent. The IC50 values for A375 cells, SMMC cells and MCF-7 cells were 25.38, 48.70 and 76.94 μg/mL at 24 h, respectively. To observe cell morphological changes, acridine orange/ethidium bromide（AO/EB） staining and Hoechest33342/Pl staining were carried out. These results indicate that TH1082 could induced the apoptosis of A375 cells. The apoptotic rates were （9.5±2.09）%, （18.9±2.25）% and （39.5±2.02）%（5, 10 and 20 μg/mL） for A375, SMMC and MCF-7 cell lines, respectively. Further, we determined the activities of caspase-3 and caspase-9 in A375 cells treated with TH1082 at different concentrations（0, 5, 10 and 20 μg/mL） or Z-VAD-FMK（20 μmol/L）, a pan-caspase inhibitor for 24 h. The results show that TH1082 activated caspase-3 and caspase-9, and the activation could be blocked by Z-VAD-FMK. Taken together, these findings indicate that TH 1082 could inhibit the proliferation ofA375 cells via activating caspase-3 and caspase-9.     

Synthesis of uracil–coumarin conjugates as potential inhibitors of virus replication

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Synthesis and properties of vinyl monomer/enzyme conjugates

Monomer conjugation of an enzyme followed by copolymerization with free monomer is a useful method of enzyme immobilization. L-asparaginase was conjugated with N-succinimidyl acrylate. Analysis of the conjugated enzyme via isoelectric focusing showed that a molar ratio of 9.5 free monomers per enzyme was needed during the conjunction for each vinyl group bound. Only 3% of the enzyme activity was lost per vinyl group added, and conjugation of an average of four monomers per enzyme thermally destabilized the enzyme only at temperatures above 50‡C. Activity of the enzyme at physiological temperatures was relatively unaffected.     

Synthesis and Antitumor Activity of 7-Substituted Derivatives of Homocamptothecin

Camptotecin is the parent of an important class of anticancer agents which, can selectively poison the ubiquitous nuclear enzyme topoisomerase. Water soluble camptothecin analogues such as topotecan and irinotecan are already approved for clinical uses in…