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Biomedical subjects

J B Hynes

Publications and source records attributed to J B Hynes.

At least 55 records · Page 3Linked to original sources
PubMed1978

Serine transhydroxymethylase. Equilibrium binding of folate analogs as active site probes.

Formation of a quinoid-like structure within the glycyl-pyridoxal phosphate moiety of serine transhydroxymethylase (5,10-methylenetetrahydrofolate: glycine hydroxymethyltransferase, EC 2.1.2.1) is dependent upon the dissociation of the 2-S hydrogen of glycine which in turn requires the presence of tetrahydrofolate or analogs thereof. Equilibrium binding studies with the series folate, dihydrofolate, and tetrahydrofolate showed that reduction of the pteridine ring enhances both quinoid formation and binding. A 5,8-deazafolate series showed that modifications in the 4 position, 10 position and the glutamyl position yield interrelated alterations of quinoid formation which could not be correlated with binding.

Binding Sites↗
PubMed1977

Quinazolines as inhibitors of dihydrofolate reductase. 4. Classical analogues of folic and isofolic acids.

A series of classical quinazoline analogues of folic and isofolic acids was evaluated for inhibitory activity against the dihydrofolate reductases from rat liver and from Streptococcus faecium. Included in this group were the known active antitumor agents methasquin and chlorasquin as well as methotrexate. Two new compounds, N10-formyl-5,8-deazaaminopterin and N10-formyl-5,8-deazafolic acid, were synthesized specifically for this study. The latter displayed modest activity against L1210 leukemia in mice.

Animals↗
PubMed1977

Sycnthesis of quinazoline analogues of folic acid modified at postion 10.

The quinazoline couterpart of folic acid (5,8-deazafolic acid) as well as its 10-methyl analogue has been shown to be an effective inhibitor of thymidylate synthetase from several different sources. This paper describes the synthesis of modifications in which the nitrogen atom at position 10 is replaced by sulfur, oxygen, or methylene affording 10-thia-5,8-deazafolic acid, 10-oxa-5,8-deazafolic acid, and 5,8,10-deazafolic acid, respectively. In preliminary testing, each of the target compounds displayed marginal activity against L1210 leukemia in mice.

Animals↗
PubMed1977

In vitro screening of biochemical activity of folic acid antagonists in skin.

Dihydrofolate reductase (DHFR) inhibitors, which differ from the classical folate antagonists in physicochemical and pharmacologic parameters such as lipid solubility and mechanisms of cellular transport, were screened for DHFR inhibitory activity and biologic activity in newborn rat skin. The most effective drugs from this screen were tested for their effects on de novo DNA synthesis in psoriatic epidermis in vitro. Of the 24 compounds studied, methotrexate (MTX) was the most potent inhibitor of rat skin DHFR (I50=8.6 X 10(-9) M). Methotrexate-dimethylester, methasquin-diethylester, DDEP (2,4-diamino-5-(3',4'-dichlorophenyl)-6-ethylprimidine), and Baker's triazine antifolate (NSC 139105), while less effective than MTX as DHFR inhibitors, were more effective than MTX as inhibitors of de novo DNA synthesis in rat skin in vitro. Baker's antifolate was the only compound tested which was considerably more effective than MTX as an inhibitor of de novo DNA synthesis in psoriatic epidermis in vitro.

Animals↗
PubMed1975

Synthesis and evaluation of 6-arylactamido-2,4-diaminoquinazolines and related compounds as folic acid antagonists.

A series of 2,4-diaminoquinazolines bearing an aryl function attached to the 6 position through an acetamido or related linkage was synthesized. Each compound was evaluated as an inhibitor of rat liver dihydrofolate reductase as well as for suppressive antimalarial effects against Plasmodium berghei in mice. Significant in vivo activity was found to reside primarily with 5-chloro-6-arylacetamido derivatives. Most of these compounds were also tested for prophylactic activity against sporozoite-induced Plasmodium gallinaceum in chicks. Thirteen compounds, each of which possesses a 5-Cl or 5-CH3 group, displayed curative activity in this test system. Since several of these showed markedly greater potency against the avian infection, selective inhibitory action upon preerythrocytic forms of the malaria parasite is thus implied.

Animals↗
PubMed1975

Synthesis of quinazoline analogs of isofolic acid.

Four quinazoline analogs of isofolic acid were synthesized including 5-methyl-5,8-deazaisofolic acid (8a), 5,8-deazaisofolic acid (8c), as well as their 4-NH2 counterparts 8b and 8d. None of these showed significant activity against L1210 leukemia in mice at dose levels where amethopterin provided significant prolongation in survival.

Animals↗
PubMed1975

Quinazolines as inhibitors of dihydrofolate reductase. 3. Analogs of pteroic and isopteroic acids.

A series of 19 quinazoline analogs of pteroic and isopteroic acid was prepared with particular emphasis being placed upon carboxylic acid esters. Each compound was evaluated as an inhibitor of the dihydrofolate reductases from rat liver as well as from Streptococcus faecium. Several of the more potent inhibitors were found to be inactive against L1210 leukemia in mice at low dose levels and were lethal to mice at 100 mg/kg. Six compounds were also evaluated for antimalarial activity against Plasmodium berghei in mice. Three of these were found to be curative at higher levels, while the remaining compounds were found to be toxic.

Animals↗