174 research outputs found
Antineoplastic and Cytotoxic Activities of Nickel(II) Complexes of Thiosemicarbazones
Nickel(II) complexes of thiosemicarbazons were observed to be potent cytotoxic agents in human and rodent tissue cultured tumor cells. Each compound demonstrated a slightly different profile in the various histological types of tumors. The nickel complex of Appip demonstrated the most potent in vivo activity in the Ehrlich ascites carcinoma. This agent selectively inhibited L1210 DNA and purine syntheses, and DNA polymerase α, PRPP-amido transferase, IMP-dehydrogenase, dihydrofolate reductase, TMP-kinase and thymidylate synthetase activities. L1210 DNA strand scission was evident and DNA viscosity was reduced after 24 hr incubation. The nickel complexes were not L1210 DNA topoisomerase II inhibitors
Anti-Inflammatory Activity of (Polyphenolic)-Sulfonates and Their Sodium Salts in Rodents
A series of polyphenolic-sulfonated compounds were observed to have potent anti-inflammatory activity
and were protective against induced endotoxic shock in mice at 8 and 16 mg/kg, I.P. These agents proved
to be potent elastase inhibitors in human leukocytes and J774-AI and IC-21 mouse macrophages as well as
prostaglandin cyclo-oxygenase inhibitors in J774-AI macrophages. The compounds from 5 to 50 μM
inhibited TNFα release from IC-21 macrophages and IL-1 release from mouse P388D1 macrophages
induced by LPS. The binding of these cytokines to high affinity receptors on target cells, e.g. L929
fibroblasts and IL-2 in HuT78 T lymphoma cells, were also suppressed by the agents. These compounds
blocked the adhesion of leukocytes and macrophages to the plasma membranes of L929 fibroblasts
Cytotoxicity of Poly(Phenolic)Sulfonates and Their Sodium Salts in L1210 Lymphoid Leukemia Cells
Poly(phenolic)-sulfonates demonstrated very good cytotoxicity against the growth of tumor cell lines
(L1210, Tmolt-3, HeLa-S3) and are comparable in potency with typical clinically used anticancer drugs.
Four of the most active compounds, i.e. GL-2021, GL-2029, GL-2041 and GL-2063, were selected for a
mode of action study in L1210 lymphoid leukemia cells at concentration of 25μM to 100μM for 60 min.
The agents did not alkylate bases of ct-DNA, cause intercalation between base pairs, produce cross linking
of ct-DNA strands or generate free radicals although L1210 DNA fragmentation was observed after 24 hr
incubation. L1210 DNA synthesis was preferentially inhibited which was achieved by (1) suppressing DNA
polymerase α activity which reduced the synthesis of new strands of DNA, (2) reducing of de novo purine
synthesis at the regulatory enzyme PRPP amido transferase which reduced d(GMP) levels, and (3)
inhibiting of nucleoside kinase activities which further reduced DNA synthesis. DNA template activity was
altered by the poly(phenolic)sulfonates since they reduced DNA polymerase α and m-RNA and t-RNA
polymerase activities. The kinetic studies at 50 μM over 2 hr demonstrated that the agents’ effect on
PRPP-amido transferase activity is probably a major target of the compounds
The Hypolipidemic and Anti-Inflammatory Activity of Boronated Aromatic Amino Acids in CF1 Male Mice
The boronated aromatic amino acids were shown to be potent hypolipidemic agents in mice lowering both
serum cholesterol and triglycerides after 16 days. Selective compounds were as effective as the clinical
standards. Furthermore, the compounds were effective anti-inflammatory agents reducing local and central pain
as well as suppressing LPS induced endotoxic shock in mice. These agents inhibited lysosomal and
proteolytic enzymes of the liver and macrophages as a part of their mechanism of action
The Hypolipidemic Activity of Heterocyclic Thiosemicarbazones, Thioureas and Their Metal Complexes in Sprague Dawley Male Rats
Heterocyclic thiosemicarbazones, thioureas and their copper, nickel, and cobalt complexes were shown to
be potent hypolipidemic agents in male Sprague Dawley rats at 8 mg/kg/day, orally. These agents lowered
the activity of rat hepatic rate limiting enzymes for the synthesis of cholesterol and triglycerides. The effects
of these agnets on cytoplasmic ATP-dependent citrate lyase, acetyl CoA synthetase and HMG-CoA
reductase activities were reduced by a magnitude to explain the reduction of serum cholesterol levels
afforded by the compounds. The reduction of acetyl CoA carboxylase, sn-glycerol-3-phosphate synthetase and phosphotidylate phosphohydrolase activities caused by the derivatives is of sufficient magnitude to
explain the observed reduction in serum triglycerides after administration of the agents
Cytotoxic Action of Carboxyborane Heterocyclic Amine Adducts
The heterocyclic carboxyborane amines were found to be potent cytotoxic agents in the murine L1210 lymphoid leukemia and human HeLa suspended carcinoma cells. These agents were observed to inhibit HeLa DNA topoisomerase II activity ~ 200 μM and L1210 topoisomerase II activity ≥ 100 μM. These agents did not cause DNA protein linked breaks themselves, but upon incubation for 14-24 hr did enhance the ability of VP-16 to cause cleavable complexes. The heterocyclic amineboranes inhibited DNA synthesis and caused DNA strand scission. They were additive with VP-16 in affording these results as well as inhibiting colony growth of L1210 cells after co-incubation for 1 hr. The agents inhibited in vitro PKC phosphorylation of both L1210 lymphoid leukemia and human topoisomerase II enzyme
Transepithelial Transport and Metabolism of Boronated Dipeptides Across Caco-2 and HCT-8 Cell Monolayers
Oral delivery of proteins and peptides as therapeutic agents is problematic due to their low bioavailability.
This study examined the effect of boronation on the transepithelial transport and metabolism of three
glycine-phenylalanine dipeptides in Caco-2 and HCT-8 cell monolayers. The three dipeptides exhibited
passive transport characteristics in the monolayer systems. However, metabolism of the boronated
dipeptides did occur, but to a lesser extent than the non-boronated glycine-phenylalanine dipeptide. The
same metabolic scheme was seen in both cell monolayer system, but greater metabolism was seen in the
HCT-8 cell monolayers
The Effects of Amine-Carboxyborane Related Derivatives on UMR-106 Bone Metabolism
The amine-carboxyboranes and related derivatives have been shown to be
potent anti-inflammatory and anti-osteoporosis agents. Their action in
part appears to be mediated by the modulation of cytokines, e.g. TNFα
or IL-1. Previous studies have demonstrated that LPS induced
macrophages release of TNFα maximally at 60 to 90 min. and IL-1 from 5
to 8 hr. The amine-carboxyboranes reduced significantly the release of
these cytokines but also blocked TNFα high affinity binding to UMR-106
receptor at 90 min. at 10 μM, and IL-1 high affinity binding at 5 hr. at
12.5 μM. In addition, the agents suppressed IL-8 binding to CHO K1 high
affinity receptor at 24 hr. at 50 μM and IL-2 binding to HuT-8 receptors
at 25 μM at 90 min. and 5 hr. Correlation of metabolic events
associated with osteoporosis showed that at 90 min., when TNFα receptor
binding was reduced by the agents, calcium uptake into UMR-106 cells was
reduced at 10 μM as well as the acid and alkaline phosphatases, and the
prostaglandin cyclo-oxygenase activities and adhesion of leukocytes and
macrophages to UMR-106 cell monolayers. At 5hr. when the agents reduced
IL-1 binding to UMR-106 receptors, calcitonin and 1,25-dihydrovitamin D3
binding was reduced by the agents as was acid and alkaline phosphatase,
and 5′-lipoxygenase activities and white blood cell adhesion. At this
time calcium uptake and proline incorporation was increased
significantly by the agents. At later times e.g. 18-48 hr. calcium
uptake was still increased, and NAG activity was inhibited in the
presence of the agents. These effects may be related more to the
inhibition of other cytokine receptor binding, e.g. IL-8. Thus, many of
the observed metabolic effects of amine-carboxyboranes as antiosteoporosis
agents can be correlated with their inhibition of cytokine
high affinity binding to target cell receptors
The Anti-Inflammatory Activity of Boron Derivatives in Rodents
Acyclic amine-carboxyboranes were effective anti-inflammatory agents in mice at 8 mg/kg x 2.
These amine-carboxyboranes were more effective than the standard indomethacin at 8 mg/kg x
2, pentoxifylline at 50 mg/kg x 2, and phenylbutazone at 50 mg/kg x 2. The heterocyclic amine
derivatives as well as amine-carbamoylboranes, carboalkoxyboranes, and cyanoboranes were
generally less active. However, selected aminomethyl-phosphonate-N-cyanoboranes
demonstrated greater than 60% reduction of induced inflammation. The boron compounds were
also active in the rat induced edema, chronic arthritis, and pleurisy screens, demonstrating
activity similar to the standard indomethacin. The compounds were effecive in reducing local
pain and decreased the tail flick reflex to pain. The derivatives which demonstrated good anti-inflammatory
activity were effective inhibitors of hydrolytic lysosomal, and proteolytic enzyme
activities with IC50 50
values equal to -6M
in mouse macrophages, human leukocytes, and Be
Sal osteofibrolytic cells. In these same cell lines, the agents blocked prostaglandin
cyclooxygenase activity with IC50 values of -6M. In mouse macrophage and human
leukocytes, 5′ lipoxygenase activity was also inhibited by the boron derivatives with IC50 values
of 10-6M. These IC50 values for inhibition of these enzyme activities are consistent with
published values of known anti-inflammatory agents which target these enzymes
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