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T S Lin

Publications and source records attributed to T S Lin.

At least 127 records · Page 7Linked to original sources
PubMed1988

Specific inhibition of DNA biosynthesis induced by 3'-amino-2',3'-dideoxycytidine.

3'-Amino-2',3'-dideoxycytidine (3'-NH2-dCyd) produced an S-phase-specific block in exponentially growing L1210 leukemia cells. The monophosphate and triphosphate forms of the drug were detected within a few hours of 3'-NH2-dCyd treatment of intact cells. No significant change in the deoxynucleoside triphosphate levels was observed during the early stages of treatment. However, by 24 h a 2-fold increase in the amount of the deoxynucleoside triphosphates was seen. The triphosphate form of the drug competitively inhibited dCTP incorporation into calf thymus DNA using highly purified DNA polymerase alpha. The Ki was determined to be 9.6 microM with respect to dCTP. Incorporation of the analogue into DNA was not detected. On the other hand, sucrose gradient analysis suggested that incorporation of the analogue into actively synthesized DNA may account for the biological activity of this compound. Treatment with 3'-NH2-dCyd induced single-strand breaks in actively synthesized DNA, but no double-strand breaks were observed in the presence of the analogue. The data indicate that 3'-amino-2',3'-dideoxycytidine specifically interferes with DNA replication at the level of DNA polymerase by inhibiting chain elongation.

Animals↗
PubMed1988

Structure-activity analysis of antagonism of the feedback inhibition of thymidine kinase.

The effects of a variety of 5-, 5'-, and 3'-substituted deoxyuridine derivatives on the cytoplasmic thymidine kinase (EC 2.7.1.21) purified from a human colon carcinoma cell line, HCT 116, were determined. Of particular interest was elucidation of the structural features important for antagonism of the feedback inhibition of thymidine kinase exerted by thymidine triphosphate. Substitutions at the 5-position altered the potency of the 5'-modified compounds. The replacement of the 5-hydrogen with a methyl group or an iodine greatly increased the affinity of compounds for the thymidine kinase. This was evident for enzyme substrates with 5'-hydroxyl groups [2'-deoxyuridine (dUrd), 2'-deoxythymidine (dThd) and 5-iodo-2'-deoxyuridine (IdUrd)], feedback inhibitors with 5'-triphosphate substitutions (dUTP, dTTP and IdUTP), and for 5'-amino derivatives [5'-amino-2',5'-dideoxyuridine (5'-AdUrd), 5'-amino-2'-5'-dideoxythymidine (5'-AdThd) and 5-iodo-5'-amino-2',5'-dideoxyuridine (5'-AIdUrd)]. Qualitatively, however, the 5-substitutions did not affect the nature of the interactions with dThd kinase. For example, in the presence of dTTP, 5'-AdUrd stimulated dThd kinase activity as much as 5'-AdThd, but approximately a 100-fold greater concentration of 5'-AdUrd was required. Similar results were obtained using intact cells in which substitutions at the 5-position affected the potency, but not the efficacy, of the 5'-amino derivatives to stimulate dThd phosphorylation. In contrast, substitutions at the 5'-position did alter the nature of the interaction with dThd kinase. Thus, the 5'-hydroxyl compounds, dUrd, dThd and IdUrd, did not reverse the enzyme inhibition produced by dTTP nor did they stimulate dThd uptake in intact cells. 5'-Deoxy-5'-(ethylthio)thymidine, 5'-deoxy-5'-[(2-hydroxyethyl)thio]thymidine, and dTMP, but not dTDP, also antagonized the inhibition of dThd kinase produced by dTTP. In comparison to 5'-AdThd, the 3'-amino derivatives, 3'-AdThd and 3'-5'-diAdThd, were much less potent, but still efficacious, antagonists of feedback inhibition. These results indicate that a wide range of dUrd derivatives can disrupt the regulation of dThd kinase and provide leads for the development of new nucleotide analogues.

Deoxyuridine↗
PubMed1988

Unusual structural features of 2',3'-dideoxycytidine, an inhibitor of the HIV (AIDS) virus.

The structure and conformation of 2',3'-dideoxycytidine, a potent inhibitor of the human immunodeficiency virus, was determined by X-ray crystallography. The nucleoside crystallizes in the tetragonal space group P4(1)2(1)2 with cell dimensions a = b = 8.698(4) and c = 26.155(9) A. Atomic parameters were refined by full-matrix least squares to a final value of R = 0.037 for 1926 observed reflections. The conformation of the furanose ring corresponds to the unusual C3'exo/C4'endo (3T4) pucker, similar to that found in one of the molecules of 3'-azidothymidine (AZT). The glycosidic torsion angle is also smaller than expected. The relevance of these unusual structural features to anti-AIDS activity is assessed.

Acquired Immunodeficiency Syndrome↗
PubMed1988

Synthesis and antiviral activity of various 3'-azido analogues of pyrimidine deoxyribonucleosides against human immunodeficiency virus (HIV-1, HTLV-III/LAV).

Various 3'-azido analogues of pyrimidine deoxyribonucleosides have been synthesized and tested against human immunodeficiency virus (HIV-1, HTLV-III/LAV) in human peripheral blood mononuclear cells. Among these compounds, the 3'-azido analogues of thymidine (2), 3-(3-oxo-1-propenyl)thymidine (21), 2'-deoxyuridine (1), 2'-deoxy-5-bromouridine(5), 2'-deoxy-5-fluorocytidine (19), 2'-deoxy-5-iodouridine (6), 2'-deoxycytidine (18), 2'-deoxy-5-fluorouridine (4), 2'-deoxy-5-thiocyoanatouridine (16), 2'-deoxy-5-methylcytidine (20), 2'-deoxy-5-aminouridine (7), and 2'-deoxy-5-hydroxyuridine (10) were found to have significant antiviral activity, with EC50 values of 0.002, 0.01, 0.2, 1.0, 1.0, 1.1, 1.2, 4.8, 5.1, 5.1, 6.2, and 10 microM, respectively. The structure-activity relationships are discussed.

Antiviral Agents↗
PubMed1988

Synthesis and antiviral evaluation of carbocyclic analogues of 2'-azido- and 2'-amino-2'-deoxycytidine.

Carbocyclic analogues of 2'-azido- and 2'-amino-2'-deoxycytidine, compounds 8 and 9, were synthesized by an eight-step synthesis from (+/-)-(1 alpha,2 alpha,3 beta,5 beta)-3-amino-5-(hydroxymethyl)-1,2- cyclopentanediol (1), which was prepared from cyclopentadiene via an eight-step route. These compounds were tested in vitro against herpes simplex virus type 1 (HSV-1). The 2'-amino analogue was found to show moderate antiviral activity, with an ED50 of 50 microM. However, the 2'-azido analogue was not active at a concentration up to 400 microM.

Antiviral Agents↗
PubMed1987

Enhancement of the anticancer activity of bis(2-chloroethyl)nitrosourea in mice by coadministration of 2'-deoxyuridine, 2'-deoxycytidine, or thymidine.

The previous observation that the coadministration of a single dose of thymidine with the 3'-chloroethylnitrosourea analog of thymidine (3'-[3-(2-chloroethyl-3-nitrosoureido]-3'-deoxythymidine, 3'-CTNU) to mice bearing the L1210 or P388 leukemia enhanced the antitumor activity of 3'-CTNU, has led to a similar study of the potential effect on antitumor activity where thymidine, 2'-deoxyuridine, or 2'-deoxycytidine is coadministered with 1,3-bis(2-chloroethyl)-1-nitrosourea. Three levels of 1,3-bis(2-chloroethyl)-1-nitrosourea (10, 15, and 20 mg/kg) were coadministered to mice bearing the L1210 leukemia or the B16/F10 melanoma with each of the deoxyribonucleosides (2 g/kg). There was not only an increase in average days of survival of those that perished, but also a marked increase in the number of greater than 60-day survivors. The present report is a result of a determination of whether the augmented anticancer activity produced by a single injection of thymidine with 3'-CTNU was restricted to nitrosourea analogs of thymidine. The present study reveals not only that the phenomena of enhanced anticancer activity by the coadministration of thymidine can be extended to non-thymidine-containing nitrosoureas, but also that the coadministration of thymidine with 1,3-bis(2-chloroethyl)-1-nitrosourea produced an even more marked enhancement of antitumor activity than that previously observed when thymidine was coadministered with 3'-CTNU.

Animals↗
PubMed1987

Reactivity of thiols towards derivatives of 2- and 6-methyl-1,4-naphthoquinone bioreductive alkylating agents.

The stoichiometry and kinetics of the anaerobic reactions between some thiols and derivatives of 2- and 6-methyl-1,4-naphthoquinones in water were measured using stopped flow spectrophotometry. The stoichiometry of the reaction with representative compounds was 1:2 thiol:quinone, a finding consistent with the formation of a hydroquinone as well as a thioether in the reaction. The first-order dependence of rate on thiol concentration, and the pH-dependent rate constants indicated that the thiolate anion was involved in the rate-limiting step, with rate constants at pH 7.6 generally increasing in the order glutathione (GSH) less than cysteamine less than dithiothreitol (DTT) less than cysteine. Despite the lower reactivity of GSH, the half-lives of the uncatalyzed conjugation reaction of these quinones at typical biological concentrations of GSH (e.g. 2 mM) ranged from about 2.0 to 20 s at pH 7.6 and 25 degrees C. The implications of these reactions in the use of naphthoquinones as potential bioreductive alkylating agents and as hypoxic cell radiosensitizers are discussed.

Alkylating Agents↗
PubMed1987

Synthesis and antiviral activity of various 3'-azido, 3'-amino, 2',3'-unsaturated, and 2',3'-dideoxy analogues of pyrimidine deoxyribonucleosides against retroviruses.

Various 3'-azido, 3'-amino, 2',3'-unsaturated, 2',3'-dideoxy, and 5-substituted analogues of pyrimidine deoxyribonucleosides have been prepared and tested against Moloney-murine leukemia virus (M-MULV), a mammalian T-lymphotropic retrovirus in vitro. Among these compounds, the 3'-azido analogues of thymidine, 2'-deoxy-5-bromouridine, and 2'-deoxy-5-iodouridine, the 2',3'-unsaturated analogue of thymidine and and 2'-deoxycytidine, and 2',3'-dideoxycytidine were found to be most active, with ED50 values of 0.02, 1.5, 3.0, 2.5, 3.7, and 4.0 microM, respectively. These active compounds were nontoxic to the host SC-1 cells up to 100 microM concentration. The 3'-azido analogues of thymidine and 2'-deoxy-5-bromouridine were also tested in vitro against HTLV-III/LAV/AAV ("AIDS" virus) and found to be significantly active, with ED50 values of 0.23 and 2.3 microM, respectively. The structure-activity relationships are discussed.

Antiviral Agents↗
PubMed1986

Potential targets for antiviral chemotherapy.

Serendipity and random screening have been successful in producing effective antiviral agents. The increase in our knowledge of the basic biochemistry of viral replication and of virus-host interrelationships has revealed not only an understanding of the targets upon which existing antiviral agents exert their inhibitory effect, but also has uncovered new potential targets. The hope is that such molecular understanding will afford the synthesis of compounds with selective antiviral activity. A review of various viral targets which are potentially susceptible to attack, and a few approaches for development of antiviral agents are presented.

Antiviral Agents↗
PubMed1986

(o- and p-Nitrobenzyloxycarbonyl)-5-fluorouracil derivatives as potential conjugated bioreductive alkylating agents.

A series of (o- and p-nitrobenzyloxycarbonyl)-5-fluorouracil derivatives were synthesized by reacting o- or p-nitrobenzyl chloroformate with 5-fluorouracil in the presence of triethylamine in DMF or Me2SO. The reductive activation of these agents was hypothesized to generate a reactive methide and 5-fluorouracil, two components that are capable of synergistic interaction through complementary inhibition. Measurement of the surviving fractions of EMT6 tumor cells treated with these agents in culture under conditions of hypoxia and aerobiosis resulted in equal cell kill regardless of the state of oxygenation. One of the synthesized agents, 3-(p-nitrobenzyloxycarbonyl)-5-fluorouracil (4), appeared to be superior to 5-fluorouracil in prolonging the survival time of mice bearing intraperitoneal implants of the P388 leukemia and Sarcoma 180.

Animals↗
PubMed1986

Synthesis and biological activity of several amino nucleoside-platinum(II) complexes.

Several platinum(II) complexes of 3',5'-diamino-3',5'-dideoxythymidine (compound 1), 5'-amino-5'-deoxythymidine (compound 2), and 3'-amino-3'-deoxythymidine (compound 3) and the respective 2'-deoxyuridine amino nucleoside complexes, 4-6, have been synthesized. Whereas compounds 1, 2, and 4-6 had no inhibitory effect on the replication of murine L1210 cells in cell culture, compound 3 [(3'-AdThd)2PtCl2] inhibited these cells with an ED50 of 0.8 microM. Incubation of L1210 cells with 10-20 microM compound 3 for 2 h produced less than 18% inhibition of RNA, DNA, or protein synthesis, which is of questionable significance. However a 16-h incubation resulted in an increased uptake of labeled thymidine into DNA (77%), labeled uridine into RNA (17%), and labeled amino acids into protein (100%). These unexpected results indicate that inhibition of macromolecules may not be involved in the inhibition of the replication of L1210 cells. The increased incorporation of labeled metabolites into macromolecules may be related to the increase in cell volume after a 2-h incubation of L1210 cells with compound 3 plus a marked increase after 2 h in the proportion of cells in their S phase. Compound 3 appears to delay the progression of cells through their cell cycle. A marked inhibitory effect on the transport of methionine or aminoisobutyric acid into L1210 cells was found with compound 3, which was slightly greater than that produced with cisplatin. Compound 3 had a dose-dependent effect on the survival of mice bearing the L1210 ascites neoplasm, with a T/C X 100 of 175 at a dose of 320 mg/kg. Investigation of the kinetics of decomposition in aqueous systems demonstrated that the primary UV-absorbing decomposition product is 3'-amino-3'-deoxythymidine and that only a limited amount of the compound is formed (less than 8%). Although 3'-amino-3'-deoxythymidine could account for a part of the inhibition of the replication of L1210 cells in culture, it cannot account for the inhibition of amino acid transport by compound 3, the platinum complex of 3'-amino-3'-deoxythymidine. Compound 3 has been shown to limit part of the amino acid uptake into L1210 cells in a similar manner to cisplatin.

Amino Acids↗
PubMed1986

Antineoplastic activity of 3'-(chloroethyl)nitrosourea analogues of 2'-deoxyuridine and 2'-deoxy-5-fluorouridine.

The (chloroethyl)nitrosourea analogues of 2'-deoxyuridine and 2'-deoxy-5-fluorouridine, 3'-[3-(2-chloroethyl)-3-nitrosoureido]-2',3'-dideoxyuridine (3'-CdUNU, 7) and 3'-[3-(2-chloroethyl)-3-nitrosoureido]-2,3'-dideoxy-5-fluorouridine (3'-CFdUNU, 8), have been synthesized by treatment of the corresponding 3'-amino nucleosides with chloroethyl isocyanate, followed by nitrosation of the resulting ureas. Nucleoside nitrosoureas 7 and 8 exhibited marked anticancer activity against L1210 leukemia in tumor-bearing mice. At an optimum dosage level of 40 mg/kg, 7 and 8 produced 90% and 60% "cures" (greater than 60-day survivors), respectively. The structure-activity relationships are discussed.

Alkylation↗
PubMed1986

One-electron reduction of 2- and 6-methyl-1,4-naphthoquinone bioreductive alkylating agents.

The semiquinones, Q.-, of derivatives of 2- and 6-methyl-1,4-naphthoquinones, some incorporating leaving groups with substituents such as CH2Br or CH2OCONHCH3, have been produced by radiolytic reduction of Q by (CH3)2COH radicals. The absorption spectra and decay kinetics of Q.- were all closely similar to that produced from 2-methyl-1,4-naphthoquinone, with no evidence for unimolecular elimination of a leaving group in the semiquinone form, but immediate loss of leaving group upon two-electron reduction of Q to the hydroquinone. The redox equilibria between Q/Q.- and O2/O2.- were characterized, and reduction potentials of the couples Q/Q.- in water at pH 7.6 were calculated. The implications of these observations for the use of these compounds as bioreductive alkylating agents or as radiosensitizers with potential selective activity toward hypoxic cells are discussed.

Alkylating Agents↗