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At least 199 records · Page 11Linked to original sources
PubMed1979

[Histochemical demonstration of tetrahydrofolate dehydrogenase in human bone marrow: apparent enzymatic induction after administration of folic acid antagonists].

Folate antagonists interfere to a varying extent with the histochemical demonstration of tetrahydrofolate dehydrogenase. Some aspects of this interaction are investigated in normal hemopoietic cells of patients following antitumor treatment with methotrexate. In this situation the histochemically detectable activity of tetrahydrofolate dehydrogenase exceeds the control levels (apparent enzymatic induction). A protection of the enzyme-metabolite complex from degradation and diffusion might be effective for the changes in reaction intensity.

Bone Marrow↗
PubMed1975

Changes in the pool of deoxyuridine monophosphate in the normal embryogenesis of rats and under the influence of the folic acid antagonist chloridin.

Using the methods of ion exchange and paper chromatography, the content of d-UMP, AMP, GMP, and UMP was measured in 13-15 day rat embryos, and the changes in the pools of these nucleotides under the action of chloridin, one of the inhibitors of dihydrofolate reductase, were also determined. Only the concentration of d-UMP changed appreciably: it increased in the case of normal development from the 13th to the 14th day, apralleling a decrease in the specific activity of TMS, and especially sharply under the action of chloridin, which, inhibiting dihydrofolate reductase, evidently created a deficiency of FA-H4 and thereby blocked the TMS reaction.

Adenosine Monophosphate↗
PubMed1995

[Synthesis and antineoplastic action of iso-piritrexim, a lipophilic folic acid antagonist].

Two strategies towards the synthesis of Iso-Piritrexim (12) are described. A) The Mannich-reaction of ketone 2 yields the bases 4-HCl and 5-HCl. By means of LC base 4 is separated and treated with in situ generated 3,3-diaminoacrylonitrile (9) to yield the 2-aminonicotinonitrile 11. The cyclocondensation of 11 with guanidine provides Iso-PTX (12). B) Reduction and oxidation of the beta-ketoester 15 leads to the beta-ketoaldehyde 17, which is cyclocondensed with 2,4,6-triaminopyrimidine (18) to yield Iso-PTX (12). In the NCl-tumor-test Iso-PTX (12) shows a moderate activity against some leukemia and lung cancer cell lines.

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↗
PubMed1982

Comparative effects of methotrexate, two nonclassic folic acid antagonists, and cytarabine on hematopoietic precursor cells.

The effects of three antifolates, methotrexate (MTX), triazinate (TZT), and a trimethoxyquinazoline derivative (TMQ), and of cytarabine (ara-C) on leukocyte-committed colony-forming cells from three species were compared using an assay allowing in vivo metabolism in an agar diffusion chamber. Dose-survival curves approximated plateaus, and the level of the plateau was variable among species. Canine marrow colony-forming cells were less sensitive to MTX (about 90% survival) than those from mice or man (25%-40% survival). Human marrow colony-forming cells were less sensitive (70% survival) to TZT than those from mice or dogs (25% survival). No interspecies differences were found for TMQ or ara-C. Mouse marrow in situ was less sensitive to iv MTX than mouse marrow in the chamber. No such difference was found for iv TMQ or ara-C. This comparison could not be made for ip TZT.

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↗
PubMed1993

PS-15: a potent, orally active antimalarial from a new class of folic acid antagonists.

A new, orally-active inhibitor of dihydrofolic acid reductase (DHFR), PS-15 (N-(3-(2,4,5-trichlorophenoxy)propyloxy)-N'-(1-methylethyl)- imidocarbonimidic diamide hydrochloride), has significant activity against drug-resistant Plasmodium falciparum. It is not cross-resistant with other inhibitors of DHFR (e.g., pyrimethamine and cycloguanil). Although it bears similarities to proguanil, PS-15 represents a new antifolate class of drugs that we have named oxyguanils or hydroxylamine-derived biguanides. This compound displays intrinsic antimalarial activity and also is metabolized in vivo to WR99210, an extremely active triazine inhibitor of DHFR. When tested in vitro against drug-resistant clones of P. falciparum, PS-15 was more active than proguanil, and the putative metabolite, WR99210, was more active than the proguanil metabolite cycloguanil. The drug is also more active as well as less toxic than proguanil when administered orally to mice infected with P. berghei. When administered orally to Aotus monkeys infected with multidrug-resistant P. falciparum, PS-15 was more active than either proguanil or WR99210. In 1973, WR99210 underwent clinical trials for safety and tolerance in volunteers. The trials showed gastrointestinal intolerance and limited bioavailability; further development of the drug was abandoned. Because PS-15 has intrinsic antimalarial activity, is not cross-resistant with other DHFR inhibitors, and can be metabolized to WR99210 in vivo, oral administration of this new drug should circumvent the shortcomings and retain the advantages found with both proguanil and WR99210.

Administration, Oral↗