• Journal of Life Science
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• v.9 no.1
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• pp.58-62
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• 1999

Several nucleoside 5'-monophosphate analogues and lipophilic nucleoside 5'-(3-pyridinylcarbonyl)monophosphate analogues were synthesized. Antitumor activities of the synthesized nucleoside malogues against P338 mouse leukemia, FM3A murine mammary carcinoma, and U937 human histiocytic lymphoma cells were determined by MTT assay. Antitumor activities of the lipophilic uridine 5'-(3-pyridinylcarbonyl) monophosphate(7) and 2',3'-didehydro-3'-deoxy-thymidine-5'-(3-pyridinylcarbonyl) monophosphate(8) were stronger than those of uridine 5'-monophosphate(1) and 2',3'-didehydro-3'-deoxythymidine-5'-monophosphate(4). This preliminary experimental result suggests that nucleoside 5'-(3-pyridinylcar-bonyl)monophosphate analogues may be new prodrugs to overcome the clinical limit.

• Archives of Pharmacal Research
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• v.14 no.1
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• pp.48-51
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• 1991

Amides from amino acid ester and nalidixic acid were synthesized. The solubility characteristics and partition coefficient of the compounds were studied. The hydrolysis of the compounds was studied in the simulated gastric fluid and simulated intestinal fluid. Some compounds showed better antibacterial activity than nalidixic acid.

• Macromolecular Research
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• v.11 no.5
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• pp.317-321
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• 2003

In order to prepare a prodrug, poly(polyethylene glycol methacrylate-co-methacryloyloxymethyl-5-fluorouracil) (poly(PEGM-co-MAOFU)) prodrug particles were prepared by precipitation polymerization of MAOFU and PEGM in polyacrylic acid solution. The size of prodrug particles were 0.2-0.35 ${\mu}{\textrm}{m}$. The antitumor activity of prodrugs against sarcoma-l80 tumor cell in mice was demonstrated and the polymer particles themselves showed low toxicity and good biocompatibility when they were administrated into mice.

• Macromolecular Research
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• v.17 no.9
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• pp.709-713
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• 2009

The aim of this study was to develop novel intestinal specific drug delivery systems with pH sensitive swelling and drug release properties. The carboxyl group of ibuprofen was converted to a vinyl ester group by reacting ibuprofen and vinyl acetate as an acylating agent in the presence of catalyst. The glucose-6-acrylate-1, 2, 3, 4-tetraacetate (GATA) monomer was prepared under mild conditions. Cubane-1, 4-dicarboxylic acid (CDA) linked to two 2-hydroxyethyl methacrylate (HEMA) group was used as the crosslinking agent (CA). Methacrylic-type polymeric prodrugs were synthesized by the free radical copolymerization of methacrylic acid, vinyl ester derivative of ibuprofen (VIP) and GATA in the presence of cubane cross linking agent. The structure of VIP was characterized and confirmed by FTIR, $^1H$ NMR and $^{13}C$ NMR spectroscopy. The composition of the cross-linked three-dimensional polymers was determined by FTIR spectroscopy. The hydrolysis of drug polymer conjugates was carried out in cel-lophane membrane dialysis bags, and the in vitro release profiles were established separately in enzyme-free simulated gastric and intestinal fluids (SGF, pH 1 and SIF, pH 7.4). The detection of a hydrolysis solution by UV spectroscopy at selected intervals showed that the drug can be released by hydrolysis of the ester bond between the drug and polymer backbone at a low rate. Drug release studies showed that increasing the MAA content in the copolymer enhances the rate of hydrolysis in SIP. These results suggest that these polymeric prodrugs can be useful for the release of ibuprofen in controlled release systems.

• Korean Journal of Microbiology
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• v.29 no.6
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• pp.353-360
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• 1991

5-substituted uridine(I,Br,Cl), 5'-amino-5'-deoxyuridine conjugates of amino acid, peptide and penicillin G, 5'-monophosphate uridine derivatives and 5'-monophosphate-fatty acid detrivatives were chemically synthesized. Their biological activities were determined as MIC and IC/sub 50/ unit against various pathogenic microorganisms in vitro. 5'-amino-5'-deoxyuridine-cyclo(Phe-Asp)(23), 5-iodo-5'-amino-deoxyuridine-penicillin G(26) were the most efficient; their IC/sub 50/ against L5178Y murine lymphoma cell was 6.5 h/ml, MIC against S. aureus (+) and E. coli (-) was 6.25 g/ml. MIC of 5-bromo-2', 3'-O-isopropylideneuridine(6) against Trichophyton rubrum was 0.2 g/ml. And 5'-monophosphate derivatives are more active than simple uridine derivatives, suggesting other modified nucleoside 5'-phosphate may be worthwhile examing further as a new prodrugs.

• YAKHAK HOEJI
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• v.32 no.5
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• pp.334-339
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• 1988

AraC-5'-methylthioacetate (araC-MTA, 1) and araC-5'-butylthioacetate (araC-BTA, 2) were prepared and their physical and chemical properties and in vivo antitumor activities were examined. Both compounds were found to have higher partiton coefficients (n-hexanol/water) than their parent araC and to be hydrolyzed to araC within an hour in mouse plasma and ascitic fluid solutions. In in vivo antitumor activity test they showed similar potency to araC, which were assumed due to too quick hydrolyses of them to parent in the body fluid.

• The Korean Journal of Nuclear Medicine
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• v.36 no.2
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• pp.102-109
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• 2002

Purpose : In gene therapy, tumor cells expressing the herpes simplex virus thymidine kinase are sensitive to prodrugs. Potential prodrugs IVDU and IVFRU were synthesized and radiolabeled with radioiodine for noninvasive imaging of herpes simplex virus type 1 gene expression. Material and Methods : 5-(2-trimethysilyl) vinyl-2'-deoxyuridine and 5-(2-trimethylsilyl)vinyl-2'-fluoro-2'-deoxyuridine, precursors of 5-(2--iodo)viny l-2'-deoxy uridine(IVDU) and 5-(2-iodo)-2'-vinyl-2'-deoxy-2'-fluororibofuranosyl uracil(IVFRU), were synthesized from reaction of trans-1-trimethylsillyl-2-tri-n-butylstannylethylene with 5-iodo-2'-deoxyuridine and 5-iodo-2'-fluoro-2'-deoxyuridine, respectively, on the condition of Pd catalyst. These precursors were separated from reaction mixture by silica gel column chromatography method. Each precursor was radioiodinated with radioiodine by mixing with ICI oxidizing agent. These radioiodinated compounds were purified with HPLC. Radiohalogen exchange has been shown to be effective for the synthesis of products with lower specific activity. Similarly, carrier-added and high specific activity products have been isolated in respectable radiochemical yields using ICI method. Results : Synthetic yield of precursors, IVDU and IVFRU were 43% and 18%, respectively. Radiochemical purity of both compunds was over 98%. Conclusion : We synthesized precursors of IVDU and IVFRU for monitoring of HSV1-tk gene expression. Radiotracers were radioiodinated with high radiolabeling yield by ICI method.

• Natural Product Sciences
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• v.6 no.4
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• pp.165-169
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• 2000

In vitro cytotoxic activities of cisplatin combined with Chungpesagan-tang or puerarin, which were treated with or without human intestinal bacteria, were measured. When cisplatin was combined with Chungpesagan-tang and its ingredient treated without intestinal bacteria, they did not affect the in vitro cytotoxicity of cisplatin against tumor cell lines. However, when cisplatin was combined with intestinal bacteria-treated Chungpesagan-tang and its ingredients, the cytotoxicities against SNU C4, L1210, A549 and P388 tumor cell lines were synergistically increased. Puerarin, which was isolated from Puerariae Radix, did not show in vitro cytotoxicity. However, its metabolite, daidzein, showed potent cytotoxicity against tumor cell lines and was synergistic by the combined usage of cisplatin. These results suggest that natural glycosides are not only prodrugs which can be transformed to active compounds by intestinal microflora, but the combined usage of cisplatin with natural components, such as daidzein, and herbal medicinal polyprescriptions, such as Chungpesagan-tang, may be a new method for prevention and minimization of the toxicity of cisplatin.

• Journal of Pharmaceutical Investigation
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• v.38 no.4
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• pp.255-259
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• 2008

The present study aimed to investigate the in-vitro characteristics of N4-amino acid derivatives of cytarabine for the oral delivery of cytarabine. After the synthesis of L-Ile-cytarabine, L-Leu-cytarabine and L-Arg-cytarabine, the gastrointestinal stability of each prodrug was examined using artificial gastric juice and intestinal fluids. The cellular uptake characteristics of prodrugs were also examined in Caco-2 cells. While L-Ile-cytarabine and L-Leu-cytarabine appeared to be stable in all the tested biological media during 4-hr incubation, L-Arg-cytarabine was rapidly disappeared within 5 min. Accordingly, the cellular uptake of L-Ile-cytarabine and L-Leu-cytarabine was significantly higher than that of its parent drug, cytarabine in Caco-2 cells but the cellular uptake of L-Arg-cytarabine was similar to that from its parent drug. The cellular uptake of L-Ile-cytarabine and L-Leu-cytarabine appeared to be saturable as drug concentration increased from 0.4 to 4 mM. Collectively, L-Ile-cytarabine and L-Leu-cytarabine could be promising candidates to improve the oral absorption of cytarabine via a saturable transport pathway.

• Archives of Pharmacal Research
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• v.27 no.8
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• pp.878-883
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• 2004

Tacrolimus (FK506), which is isolated from Streptomyces tsukubaensis, is a new potent immu-nosuppressant. Because of poor solubility in water, the conventional intravenous dosage forms of tacrolimus contain surfactants such as cremophor EL (BASF Wyandotte Co.) or hydroge-nated polyoxy 60 castor oil (HCO-60) which may cause adverse effects. This study relates to a polymer-tacrolimus conjugate, which can be dissolved in water, formed by chemically binding the sparingly soluble drug, tacrolimus, with the water soluble polymer, methoxypoly(ethylene glycol) (mPEG). Water soluble tacrolimus-mPEG conjugates have been synthesized and shown to be function in vitro as prodrugs. These conjugates are in the form of an ester wherein the 24-, 32- or 24,32-positions are esterified. The desired 24-, 32- or 24,32-esterified com-pounds were obtained by initially acylating of tacrolimus with iodoacetic acid at the 24-,32-, or 24,32-positions and then reacting the resulting acylated tacrolimus with a mPEG in the pres-ence of a base such as sodium bicarbonate. These conjugates were converted again into tac-rolimus by the action of enzymes in human liver homogenate, and the half-lives of the conjugates are approximately 10 min in the homogenate, indicating that the esterified tacroli-mus derivatives may be practically applicable as a prod rug for the immunosuppressant.