Biological activity of two novel inhibitors of uridine phosphorylase.
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Antineoplastic Agents↗
Biomedical subjects
T S Lin
Publications and source records attributed to T S Lin.
Basic biochemical and pharmacological aspects of antiviral agents.
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Acyclovir↗
Synthesis of 1-[[2-hydroxy-1-(hydroxymethyl)ethoxy] methyl]-5-benzyluracil and its amino analogue, new potent uridine phosphorylase inhibitors with high water solubility.
Acyclic nucleosides 1-[[2-hydroxy-1-(hydroxymethyl)ethoxy] methyl]-5-benzyluracil (DHPBU) (1) and 1-[[2-hydroxy-1-(aminomethyl)ethoxy]methyl]-5-benzyluracil (AHPBU) (2) have been synthesized by direct coupling of bis(trimethylsilyl)-5-benzyluracil with the corresponding chloromethyl ether, followed by removal of the blocking groups. Compounds 1 and 2 were found to be very potent inhibitors of uridine phosphorylase isolated from Sarcoma 180 cells, with a Ki value of 0.098 and 0.020 microM, respectively, and exhibited no apparent cytotoxicity against Sarcoma 180 host cells. Furthermore, 1 and 2 have shown excellent water solubility (270 and greater than 300 mg/mL at 25 degrees C, respectively), which is a factor critical for the formulation that often limits the usefulness of a particular compound as a chemotherapeutic agent.
Animals↗
8-Substituted guanosine and 2'-deoxyguanosine derivatives as potential inducers of the differentiation of Friend erythroleukemia cells.
A variety of 8-substituted guanosine and 2'-deoxyguanosine derivatives were synthesized and tested as inducers of the differentiation of Friend murine erythroleukemia cells in culture. The most active agents in the guanosine series were 8-substituted-N(CH3)2, -NHCH3, -NH2, -OH, and -SO2CH3, which caused 68, 42, 34, 33, and 30% of erythroleukemia cells to attain benzidine positivity, a functional measure of maturation, at concentrations of 5, 1, 0.4, 5, and 5 mM, respectively. The 8-OH derivative of the 2'-deoxyguanosine series produced comparable activity, causing 62% benzidine-positive cells at a level of 0.2 mM. These findings indicate that 8-substituted analogues of guanosine and 2'-deoxyguanosine have the potential to terminate leukemia cell proliferation through conversion to end-stage differentiated cells.
Animals↗
Purine and 8-substituted purine arabinofuranosyl and ribofuranosyl nucleoside derivatives as potential inducers of the differentiation of the Friend erythroleukemia.
Several antimetabolites have been demonstrated to have the capacity to initiate differentiation in vitro of a variety of leukemic cell lines. To explore the structural requirements for this activity, a series of purine and 8-substituted purine arabinofuranosyl and ribofuranosyl nucleoside derivatives were synthesized and tested as inducers of the differentiation of Friend murine erythroleukemia cells. 9-(beta-D-Arabinofuranosyl)hypoxanthine and 6-(hydroxyamino)-9-(beta-D-arabinofuranosyl)purine were effective inducers of maturation, producing 82% and 74% benzidine-positive cells, a measure of the number of cells synthesizing hemoglobin. 6-Mercapto-9-(beta-D-ribofuranosyl)purine and 6-(methylmercapto)-9-(beta-D-ribofuranosyl)purine and their corresponding beta-D-arabinofuranosyl derivatives were also effective initiators of maturation, causing approximately 50% of the cell population to assume a differentiated phenotype.
Animals↗
Synthesis and in vitro antiviral activity of 3'-O-acyl derivatives of 5'-amino-5'-deoxythymidine: potential prodrugs for topical application.
A series of 3'-O-acyl derivatives of 5'-amino-5'-deoxythymidine (5'-NH2-TdR) (IIIa-j) was synthesized by acylation of 5'-azido-5'-deoxythymidine (I). The resulting acetoxy azides were reduced by catalytic hydrogenation to give the corresponding amines. The antiviral activity against herpes simplex virus type 1 (HSV-1) in vitro, the aqueous solubilities, and the octanol-water partition coefficients of these compounds were determined. All these derivatives have shown potency against HSV-1 virus similar to the parent compound, except the aromatic and highly branched aliphatic esters, IIIi and IIIj, which are less active. Because of their markedly improved lipophilicity, these compounds are believed to penetrate the biological membranes more easily, and thus, would be more effective for the topical treatment of cutaneous herpes virus infections.
Administration, Topical↗
Physical and biological consequences of incorporation of antiviral agents into virus DNA.
The molecular basis for the antiviral activity is discussed for a variety of nucleoside compounds approved for clinical use in the U.S.A. (5-iodo-2'-deoxyuridine, 5-trifluoromethyl-2'-deoxyuridine, 9-beta-D-arabinofuranosyladenine, 9-(2-hydroxyethoxymethyl)guanine), or in clinical trial (E-5-(2-bromovinyl)-2'-deoxyuridine, 1-(2-deoxy-2-fluoro-beta-D-arabinosyl)-5-iodocytosine, 1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide), or of specific interest to our laboratory (5-iodo-5'-amino-2',5'-dideoxyuridine, 5'-amino-5'-deoxythymidine). The consequence of incorporation of idoxuridine, the 5'-amino analog of thymidine or the 5'-amino analog of idoxuridine into the DNA of herpes simplex virus type 1 on transcription and translation is emphasized.
Acyclovir↗
2,3-Dimethyl-1,4-naphthoquinone derivatives as bioreductive alkylating agents with cross-linking potential.
Bioreducible 2,3-disubstituted 1,4-naphthoquinones have been synthesized and evaluated for anticancer activity by measuring their capacity to prolong the life span of Sarcoma 180 tumor bearing mice. The leaving group in the 2- and 3-positions of these agents significantly influenced the degree of antineoplastic activity, with the most active agents being the methyl sulfonate (5), the methyl carbamate (9), and the 2-chloroethyl carbamate (10) derivatives; when these quinones were administered daily for 6 consecutive days, they produced maximum T/C X 100 values of 232, 266, and 230, respectively.
Animals↗
Ribo- and deoxyribonucleoside effect on 3'-amino-2',3'-dideoxycytidine-induced cytotoxicity in cultured L1210 cells.
3'Amino-2',3'-dideoxycytidine (3'-NH2-dCyd) is a potent inhibitor of the replication of cultured L1210 cells, with an IC50 of 1 microM. When ribo- and deoxyribonucleosides were examined for their effects on 3'-NH2-dCyd-induced cytotoxicity, only dCyd could both prevent and reverse these effects. Furthermore, even when the maximum increase in modal cell volume was allowed to develop (24 hr) in the presence of 2.5 microM 3'-NH2-dCyd, the addition of 25 microM dCyd to the medium containing 3'-NH2-dCyd reduced the modal cell volume nearly to control levels within 24 hr. Examination of the viability of these cells by colony formation in soft agar, following as much as a 9.5-hr exposure of 1, 2.5 and 10 microM 3'-NH2-dCyd, revealed that the lethal effects of the 3'-NH2-dCyd treatment were not observed only when 25 microM dCyd was added to the medium during this time. However, the lethality of a 24-hr exposure of 2.5 and 10 microM 3'-NH2-dCyd could not be prevented either by removal of the drug from the medium or by a 24-hr exposure of the medium containing 3'-NH2-dCyd to 25 microM dCyd. When the effect of 3'-NH2-dCyd on DNA biosynthesis in L1210 cells was examined, it was found that radiolabeled dAdo incorporation decreased by approximately 60, 80 or 90% following a 2.5-hr exposure to 2.5, 10 or 20 microM 3'-NH2-dCyd respectively. The addition of 25 microM dCyd under the same conditions resulted in a greater amount of dAdo incorporation compared to the unrescued cultures. Deamination of 3'-NH2-dCyd by partially purified human cytidine-deoxycytidine deaminase was about 2.5% that of either Cyd or dCyd deamination. The deaminated derivative, 3'-amino-2',3'-dideoxyuridine, was significantly less cytotoxic even at 50 microM.
Animals↗
Synthesis and antineoplastic activity of 3'-azido and 3'-amino analogues of pyrimidine deoxyribonucleoside.
Several new 3'-azido and 3'-amino nucleosides (8, 9, 12, and 13) have been synthesized and their biological activities evaluated. Among them, 3'-amino-2',3'-dideoxycytidine (13) was found to exhibit potent cytotoxic activity against both L1210 and S-180 cells in vitro with an ID50 of 0.7 and 4.0 microM, respectively. Furthermore, 13 has also shown antitumor activity against L1210 tumor bearing mice with a T/C X 100 value of 283.
Animals↗
Synthesis and biological activity of 5-(trifluoromethyl)- and 5-(pentafluoroethyl)pyrimidine nucleoside analogues.
Various 5-substituted perfluoroalkylpyrimidine nucleoside analogues have been synthesized, and their biological activity against L1210, S-180, Vero cells, and herpes simplex virus type 1 (HSV-1) was evaluated. The 5-trifluoromethyl derivatives, 7 and 9, showed significant antiviral activity against HSV-1 with ED50 values of 7 and 5 microM, respectively. In addition, the unblocked nucleoside 9 was found to be about 64-fold less toxic to the host Vero cells and gave a favorable therapeutic index of 64 against HSV-1 in vitro.
Animals↗
Synthesis and biological activity of various 3'-azido and 3'-amino analogues of 5-substituted pyrimidine deoxyribonucleosides.
Various new 5-substituted 3'-azido- and 3'-amino derivatives of 2'-deoxyuridine and 2'-deoxycytidine have been synthesized and biologically evaluated. Among these compounds, 3'-amino-2',3'-dideoxy-5-fluorouridine (3), 3'-amino-2',3'-dideoxycytidine (7a), and 3'-amino-2',3'-dideoxy-5-fluorocytidine (7c) were found to be the most active against murine L1210 and sarcoma 180 neoplastic cells in vitro, with an ED50 of 15 and 1 microM, 0.7 and 4 microM, and 10 and 1 microM, respectively. The 3'-azido derivatives, 2 and 6c, were less active in comparison with their 3'-amino counterparts. In addition, the 5-fluoro-3'-amino nucleosides, 3 and 7c, were tested against L1210 leukemia bearing CDF1 mice. Our preliminary findings indicate that compound 7c (6 X 200 mg/kg) was as active as the positive control, 5-fluorouracil (6 X 20 mg/kg), yielding a T/C X 100 of 146 and 129, respectively. However, 3 was found to be inactive in this experiment.
Animals↗
Effect of 3'-amino-3'-deoxythymidine on L1210 and P388 leukemias in mice.
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Animals↗
Development of oral HSV-1 infection model in mice. Evaluation of efficacy of 5'-amino-5-iodo-2',5'-dideoxyuridine.
We developed a new model of oral HSV-1 infection in mice. After oral inoculation, 100 percent of mice developed the clinical lesions at the inoculated area and latent HVS infection in their trigeminal ganglia without mortality. The antiherpetic efficacy of AIdUrd, an agent specifically activated by herpesvirus-encoded enzyme, has been evaluated in this animal model. Early topical or systemic treatment of AIdUrd notably reduced the development of clinical lesions and the virus content in the inoculated lips. However, the establishment of latent HSV infection in the sensory ganglia was not influenced by AIdUrd treatment.
Animals↗
Comparative effects of 5'-amino-5'-deoxythymidine, a new antiviral agent, and 5-iodo-2'-deoxyuridine on the immune response of mice. No immunosuppression with 5'-amino-5'-deoxythymidine.
Immunological function was analyzed in mice that received daily inoculations of 5'-amino-5'-deoxythymidine (1000 mg/kg/day, i.p.) or 5-iodo-2'-deoxyuridine (100 mg/kg/day, i.p.) following antigenic stimulation. 5' Amino-5'-deoxythymidine did not suppress the development of: (1) delayed type hypersensitivity response to sheep red blood cells, (2) cell-mediated cytotoxicity response to allogeneic tumor cells, and (3) IgM and IgG antibody response to sheep red blood cells. In contrast 5-iodo-2'-deoxyuridine suppressed the development of all of these responses.
Animals↗
2- and 6-methyl-1,4-naphthoquinone derivatives and potential bioreductive alkylating agents.
A number of antineoplastic agents possess both the quinone nucleus and an appropriate substituent that permits them to function as bioreductive alkylating agents. To develop new compounds of this type with unique properties, we have synthesized a series of 2- and 6-methyl-1,4-naphthoquinone derivatives and have evaluated them for antineoplastic activity against Sarcoma 180 ascites cells. Several of these quinones showed antitumor activity, causing significant prolongation of the survival time of tumor-bearing mice. Among the most active agents were the mesylates, tosylates, and N-(chloroethyl)carbamates of 2- and 6-methyl-1,4-naphthoquinone. That bioreductive activation to a quinone methide might be involved in the mechanism of action of these agents was shown by the finding that compounds with the best leaving groups were the most efficacious as antineoplastic agents.
Alkylating Agents↗
Antitumor activity of the 3'-chloroethylnitrosourea analog of thymidine and the prevention by co-administered thymidine of lethality but not of anticancer activity.
The effect of the 3'-nitrosourea analog of thymidine (3'-[3-(2-chloroethyl)-3-nitrosoureido]-3'-deoxythymidine; 3'-CTNU) on the growth of the murine L1210 and P388 leukemias in mice was investigated. A single injection of 3'-CTNU (40 mg/kg) was minimally toxic to mice bearing the L1210 leukemia and produced 60-day survivors. The coadministration of thymidine did not prevent the initial loss of weight caused by 3'-CTNU but did prevent the lethality otherwise produced in non-tumor-bearing mice. A single dose of thymidine (2 g/kg) administered to L1210-bearing mice had no anticancer activity and when coadministered with 3'-CTNU had no detrimental effect on the potent antitumor effects of 3'-CTNU. Similar results were obtained against P388 leukemia. The hematopoietic toxicity produced by the administration of 3'-CTNU to non-tumor-bearing mice, as evidenced by changes in the white blood cells, neutrophil, and agar diffusion chamber precursor cell concentrations in the hematocrit and in bone marrow cellularity, could not be prevented by thymidine. Therefore, the lethality produced by 3'-CTNU is probably not related to hematopoietic toxicity since the coadministration of thymidine completely prevented any lethality.
Animals↗
Ac2IDU, BVDU, and thymine arabinoside therapy in experimental herpes keratitis.
The therapeutic efficacy of three new antiviral agents-5-iodo-3',5'-diacetyl-2'-deoxyuridine (diacetylidoxuridine, 1% Ac2IDU), E-5-(2-bromovinyl)-2'-deoxyuridine (0.25% BVDU), and 3% thymine arabinoside-is compared with available antivirals in an experimental model of herpes simplex virus type 1 (HSV-1) keratitis in New Zealand white rabbits. Compared with placebo, Ac2IDU significantly reduced ulcerative keratitis on days 4 through 8 after inoculation with virus and iritis on day 8 after inoculation. Compared with placebo, thymine arabinoside reduced ulcerative keratitis but not significantly. Thymine arabinoside caused significant iritis in all eyes. The epithelial disease in BVDU-treated eyes was significantly less than that in placebo-treated eyes on days 5 through 8 after inoculation. The results indicate that 1% Ac2IDU and 0.25% BVDU were effective in our ocular model of HSV-1 keratitis, whereas thymine arabinoside was not.
Animals↗