Biomedical subjects
Publications and source records attributed to M Saneyoshi.
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3'-Deoxycytidine 5'-triphosphate and 3'-deoxyuridine 5'-triphosphate were synthesized starting from cordycepin in good yield. The inhibitory effects of these nucleotides were examined in comparison with that of cordycepin 5'-triphosphate (3'-dATP) using purified DNA-dependent RNA polymerases I and II from Dictyostelium discoideum cells. Both nucleotide analogues strongly and competitively inhibited the incorporations of CTP and UTP into RNA by the RNA polymerases. The Km and Ki values for CTP and 3'-dCTP were 6.3 micro M and 3.0 micro M, respectively, and those for UTP and 3'-dUTP were 6.3 micro M and 2.0 micro M, respectively. These two analogues will be useful in studies at the molecular level on the relationship of template and substrate in RNA synthesis with chromatin, isolated nuclei or permeable cells, because they do not have any effect on poly (rA) synthesis.
Antitumor activity of several 3',5'-diesters of 5-fluoro-2'-deoxyuridine (FUdR) against L1210 leukemia cells following intraperitoneal administration was examined. Esters of FUdR with aromatic acid or aliphatic acid of longer chain length were markedly active. Their activities, with respect to ILS30, were as much as 100 times that of unesterified FUdR. 3',5'-ditoluoyl FUdR also had an improved therapeutic effect: its therapeutic ratio was increased to 8.1, as against 2.0 for FUdR. On the other hand, 3',5'-diesters of FUdR with aliphatic acid of shorter chain length do not appear to be as active as FUdR. The relationship between the antitumor activity and plasma levels has also been examined. After 3',5'-diacetyl FUdR, which is one of the drug group showing low cytotoxicity, the plasma concentration rapidly decreased to an unmeasurable level 3 h after dosing. This tendency is similar to that shown in FUdR. On the other hand, with 3',5'-dipalmitoyl FUdR and 3',5'-dibenzoyl FUdR, each of which has a marked antitumor effect, plasma concentrations decreased slowly and were maintained for as long as 48 h after dosing. The results show that the cytotoxicity of diesters of FUdR is correlated with the duration of a high plasma level of FUdR.
A number of 1-(5-phospho-beta-D-arabinosyl)-5-substituted-uracils (ara-UMP's) have been examined as inhibitors of dTMP synthetase. As reversible inhibitors, all were substantially less potent than their 2'-deoxyribosyl counterparts. In the presence of 5,10-methylenetetrahydrofolate (CH2-H4folate), ara-FUMP caused a first-order, time-dependent inactivation of the enzyme. At 0 degrees C, kinetic studies indicated a reversible Kd of 3.6 micro M for the ara-FUMP-CH2-H4folate complex, and k = 0.22 min-1 for the subsequent inactivation. Spectral studies of the complex and its behavior toward protein denaturants demonstrate that its structure and stoichiometry are directly analogous to those which have previously been described for FdUMP. The significance of this finding with regard to prodrugs of ara-FU and the potential of ara-FU as a chemotherapeutic agent are discussed.
Antitumor activity and toxicity to host of newly synthesized disulfide derivatives of 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) were examined in murine ascites sarcoma-180 system (total packed cell volume method) by parenteral administration. The compounds tested were 6-alkyl disulfides (carbon number of alkyl group: 2, 3, 4, 5, 6, 7, 8, 10, and 14), 6-branched-alkyl disulfides (iso-propyl, sec-butyl, and tert-butyl), and 6-aralkyl disulfide (naphthyryl). Most disulfide derivatives of 6-MP and 6-TG showed higher antitumor activity (lower ED50) and higher toxicity to host (lower LD50) than parent compounds, but ratios of increase in activity and toxicity were different with each other. The compounds with higher chemotherapeutic index (LD50/ED50) than parent compounds were alpha-naphthyryl (8.7) disulfide in a series of 6-MP (7.5) derivatives; and sec-butyl (27), tert-butyl (24), octyl (23), decyl (26), and alpha-naphthyryl (28) disulfides in a series of 6-TG (14) derivatives. These 6-TG derivatives were promising for antitumor agents.
Antitumor activity of twenty seven 6-alkyl disulfide derivatives of 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) were examined in the system of murine L-1210 leukemia. When given by intraperitoneal administration, maximum increase in life span produced by iso-pentyl (75%) and heptyl (68%) disulfides of 6-MP and sec-butyl (83%), pentyl (78%), and naphthyryl (90%) disulfides of 6-TG were higher than that of parent compounds (6-MP: 53%, 6-TG: 64%). Compounds with higher therapeutic ratio than respective parent compound were decyl and naphthyryl disulfide derivatives of 6-MP and almost all the derivatives of 6-TG tested (propyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, decyl, benzyl, and naphthyryl disulfides of 6-TG). Among them, decyl derivatives of both 6-MP and 6-TG showed the highest therapeutic ratio as high as 50 and 48, while those of parent compounds were 6.2 and 5.0, respectively. The improvement of therapeutic effect by the modification to decyl disulfide of 6-MP was demonstrated inthe L-1210 system, but it was not found in the Sarcoma-180 system reported previously. By oral administration, these derivatives were active against the leukemia but they were not superior to the parent compounds.
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Chemically synthesized 5-fluoro-2'-deoxyuridine 5'-triphosphate and 5-fluoro-2'-deoxycytidine 5'-triphosphate were used efficiently as substitutes for DNA synthesis catalyzed by DNA polymerases alpha or beta from calf thymus. 5-fluoro-2'-deoxyuridine 5'-triphosphate and 5'-fluoro-2'-deoxycytidine 5'-triphosphate were incorporated into DNA in place of deoxythymidine 5'-triphosphate and deoxycytidine 5'-triphosphate, respectively. The incorporated pyrimidine analogs supported further elongation of DNA. The apparent Km's for 5-fluorodeoxyuridine 5'-triphosphate in the reaction of DNA polymerases alpha and beta were 4.3 and 15.4 microM, while those of 5-fluorodeoxycytidine 5'-triphosphate with DNA polymerases alpha and beta were 7.7 and 8.8 microM, respectively, which are comparable to Km's for natural substrates. These results suggest the new possibility that the fluorinated pyrimidines are incorporated into DNA via their triphosphate forms to exhibit their cytostatic actions.
Various 1-beta-D-xylofuranosyl-5-substituted uracil 5'-triphosphates were synthesized and their inhibitory effects on DNA-dependent RNA polymerase I and II, which were purified from cherry salmon (Onchorhynchus masou) liver, were examined. The results were as follows: 1) Xylo UTP and xylo TTP were strongly inhibited for both RNA polymerase I and II. 2) 5-Ethyl, 5-n-propyl and 5-n-butyl derivatives showed little inhibitory effect on RNA polymerase I while RNA polymerase II activity was strongly affected by these derivatives. 3) Four kinds of 5-halogenated derivatives including fluoro, chloro, bromo and iodo substituent inhibited both RNA polymerase I and II in almost same extent. 4) The mode of inhibition was, in all cases, competitive with UTP.
It has been shown that beta-2'-deoxy-6-thioguanosine is incorporated into mammalian DNA via its triphosphate form. The newly synthesized DNA of HeLa cells containing thioguanosine, adsorbed specifically on an organomercurial agarose column and was eluted with 2-mercaptoethanol. By recycling this affinity chromatography, the newly synthesized DNA strands were separated successfully from non-adsorbable parental strands. This system may provide a new tool for the study of DNA replication.
Direct synthesis of the 1- and 9-(5-azido-2,3,5-trideoxy-beta-D-glycero-pent-2-enofuranosyl) derivatives (3a and 3b) of cytosine and adenine, respectively, has been accomplished via treatment of the corresponding 2',3'-unsaturated nucleosides (1a and 1b) with triphenylphosphine and carbon tetrabromide in the presence of lithium azide. Members of a new type of (aminoacyl)amino nucleoside, the 1- and 9-[5-(aminoacyl)amino-2,3,5-trideoxy-beta-D-glycero-pent-2-enofuranosyl] derivatives of cytosine and adenine, respectively, have been obtained by condensation of the corresponding, unsaturated amino nucleosides with the active esters of several amino acid derivatives, followed by deprotection. These nucleosides were examined for in vivo antitumor activity against leukemia L-1210 and Sarcoma 180 (solid tumor) in mice; none of them exhibited antitumor activity against L-1210 in mice, but compounds 1a, 3a, and 1-[2,3,5-trideoxy-5-(L-methionyl)amino-beta-D-glycero-pent-2-enofuranosyl]cytosine exhibited weak activity against Sarcoma 180 (solid tumor).
Antileukemic activity of 5 kinds of sulfur-containing purine ribonucleosides were examined in the presence and absence of amphotericin B against L1210 in mice. Among these compounds, 6-methylthioninosine was potentiated by amphotericin B. 6-Methylthioinosine in combination with amphotericin B produced a 75% increase in the lifespans, which was greater than the increase in lifespans by 6-methylthioinosine (38%) or amphotericin B alone (2%). Antitumor effects of other sulfur-containing ribonucleosides, such as 6-thiocyanatoguanine, 6-thiocyanatopurine, 6-thiocyanatoinosine, and 6-methylthiopurine, were not augmented by amphotericin B.
A continuous spectrophotometric assay for thymidine phosphorylase has been developed and used to analyze the substrate properties of a number of 5-substituted 2'-deoxyuridines. A QSAR was found which relates the catalytic efficiency for various substrates to a single variable, the inductive field constant F.
1-beta-D-Arabinofuranosylthymine (ara-T) was examined for its therapeutic efficacy against encephalitis in mice inoculated intracerebrally with herpes simplex virus. Intraperitoneal treatment with 100 mg of ara-T per kg twice daily for 4.5 days was as effective as treatment with 50 mg of arabinosyladenine 5'-monophosphate per kg. Under the same conditions, doses of 5-iododeoxyuridine or arabinosylcytosine (50 mg/kg each) were not effective. Even when the virus inoculum was as high as 320 or 3,200 50% lethal doses, ara-T increased the life span significantly. Oral treatment with 27 mg of ara-T per kg produced a modest increase in the mean survival time, equal to that of 50 mg of ara-T per kg administered intraperitoneally or subcutaneously. A single dose of ara-T, 800 mg/kg intraperitoneally or 400 mg/kg orally, was effective. The 50% lethal dose of ara-T administered intraperitoneally and that administered orally were more than 10 and 15 g/kg, respectively. The therapeutic indexes (maximal tolerated dose divided by minimal effective dose) in multiple intraperitoneal treatments and in multiple oral treatments were estimated to be more than 25 and 100, respectively.
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