STEROID AND PHYTO-OESTROGEN BINDING TO SHEEP UTERINE RECEPTORS IN VITRO

1972 ◽  
Vol 52 (2) ◽  
pp. 299-310 ◽  
Author(s):  
D. A. SHUTT ◽  
R. I. COX
Keyword(s):  
Binding Sites ◽  
Biochanin A ◽  
Hydroxyl Group ◽  
Binding Affinities ◽  
Structure Activity ◽  
Biological Potency ◽  
Competitive Protein Binding ◽  
Relationship Of

SUMMARY The binding affinities and receptor specificity of sheep uterine cytosol for steroid oestrogens and also for weak plant oestrogens of the isoflavone and coumestan groups and some synthetic compounds were studied. The binding affinities of the weak oestrogens fall within a range which has usually been neglected. Relative molar binding (RMB) affinities for the steroid oestrogens confirmed the importance of the phenolic 3-hydroxyl group and the influence of substitutions at C-16 and C-17, as seen with uterine cytosols from other species. Relative molar binding affinities were very much lower when the oestrogens were present as sulphate esters, glucosiduronate and methyl ether derivatives; acetates showed similar RMB affinities to their parent compounds. Phyto-oestrogens were found to compete with oestradiol for binding sites. Coumestrol and miroestrol had the highest RMB affinities of about 5 (oestradiol-17β = 100) when incubated at 25 °C, and values for genistein, equol, daidzein and O-desmethylangolensin lay between 1 and 0·05. The mono-methoxy compounds, biochanin A, formononetin and 4′-methoxy-coumestrol had RMB affinities of less than 0·01. Incubation at 37, 25 and 4 °C showed that RMB affinities were greater at the lower temperatures. Relative molar binding affinities of the phyto-oestrogens in vitro compared with their oestrogenic potencies in vivo showed that the ranking of most of the compounds by these two criteria was similar. Structure-activity correlations were deduced from the results. A similar relationship of RMB affinity to biological potency was also noted for the steroid oestrogens and a homologous series of stilbenediols. The results obtained are relevant to competitive protein-binding analyses and to the mechanism of action of oestrogens and phyto-oestrogens.

Discovery and Structure−Activity Relationship of Antagonists of B-Cell Lymphoma 2 Family Proteins with Chemopotentiation Activity in Vitro and in Vivo

2006 ◽  
Vol 49 (3) ◽  
pp. 1165-1181 ◽  
Author(s):  
Michael D. Wendt ◽  
Wang Shen ◽  
Aaron Kunzer ◽  
William J. McClellan ◽  
Milan Bruncko ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Structure Activity Relationship ◽  
Activity Relationship ◽  
Structure Activity ◽  
Relationship Of

scholarly journals Metabolism of apigenin and related compounds in the rat. Metabolite formation in vivo and by the intestinal microflora in vitro

1972 ◽  
Vol 128 (4) ◽  
pp. 901-911 ◽  
Author(s):  
L. A. Griffiths ◽  
G. E. Smith
Keyword(s):  
Oral Administration ◽  
Intestinal Microflora ◽  
Biochanin A ◽  
Hydroxyl Group ◽  
Hydroxyl Groups ◽  
Flavonoid Compounds ◽  
Ring Fission ◽  
Micro Organisms

1. The metabolism of a group of flavonoid compounds related in structure to apigenin (4′,5,7-trihydroxyflavone) and including apigenin, apiin, naringin, phlorrhizin, acacetin, kaempferol, robinin, chrysin, tectochrysin and 4′,7-dihydroxyflavone, was studied both in vivo after oral administration to the rat, and in vitro in cultures of micro-organisms derived from the intestine of the rat. 2. The rat intestinal microflora is capable of effecting degradation of flavonoid compounds to metabolites observed in the urine after oral administration of the specific flavonoid. 3. All compounds possessing free 5- and 7-hydroxyl groups in the A ring and a free 4′-hydroxyl group in the B ring gave rise to ring-fission products, which included 4′-hydroxyphenylacyl derivatives. 4. On anaerobic incubation in a thioglycollate medium, intestinal micro-organisms can effect flavonoid-ring fission, cleavage of glycosidic bonds and the reduction of double bonds in the side chains of certain metabolites. 5. Two flavonoids (chrysin and tectochrysin) undergo hydroxylation in the 4′-position in vivo but not during incubation with the intestinal microflora in vitro. 6. Observations on the metabolism of other compounds substituted in the 4′-position, e.g. epiafzelechin, pelargonin and the isoflavones, genistein, biochanin A, daidzein and formononetin, by the intestinal microflora of the rat are also reported.

scholarly journals Novel 3′-Substituted-1′,2′,4′-Oxadiazole Derivatives of 18βH-Glycyrrhetinic Acid and Their O-Acylated Amidoximes: Synthesis and Evaluation of Antitumor and Anti-Inflammatory Potential In Vitro and In Vivo

2020 ◽  
Vol 21 (10) ◽  
pp. 3511 ◽  
Author(s):  
Andrey V. Markov ◽  
Aleksandra V. Sen’kova ◽  
Irina I. Popadyuk ◽  
Oksana V. Salomatina ◽  
Evgeniya B. Logashenko ◽  
...  
Keyword(s):  
Active Sites ◽  
Glycyrrhetinic Acid ◽  
Hydroxyl Group ◽  
Selective Toxicity ◽  
In Silico Study ◽  
Anti Inflammatory ◽  
C 30 ◽  
Relationship Of

A series of novel 18βH-glycyrrhetinic acid (GA) derivatives containing 3′-(alkyl/phenyl/pyridin(-2″, -3″, and -4″)-yl)-1′,2′,4′-oxadiazole moieties at the C-30 position were synthesized by condensation of triterpenoid’s carboxyl group with corresponding amidoximes and further cyclization. Screening of the cytotoxicity of novel GA derivatives on a panel of tumor cell lines showed that the 3-acetoxy triterpenoid intermediates—O-acylated amidoxime 3a-h—display better solubility under bioassay conditions and more pronounced cytotoxicity compared to their 1′,2′,4′-oxadiazole analogs 4f-h (median IC50 = 7.0 and 49.7 µM, respectively). Subsequent replacement of the 3-acetoxy group by the hydroxyl group of pyridin(-2″, 3″, and -4″)-yl-1′,2′,4′-oxadiazole-bearing GA derivatives produced compounds 5f-h, showing the most pronounced selective toxicity toward tumor cells (median selectivity index (SI) > 12.1). Further detailed analysis of the antitumor activity of hit derivative 5f revealed its marked proapoptotic activity and inhibitory effects on clonogenicity and motility of HeLa cervical carcinoma cells in vitro, and the metastatic growth of B16 melanoma in vivo. Additionally, the comprehensive in silico study revealed intermediate 3d, bearing the tert-butyl moiety in O-acylated amidoxime, as a potent anti-inflammatory candidate, which was able to effectively inhibit inflammatory response induced by IFNγ in macrophages in vitro and carrageenan in murine models in vivo, probably by primary interactions with active sites of MMP9, neutrophil elastase, and thrombin. Taken together, our findings provide a basis for a better understanding of the structure–activity relationship of 1′,2′,4′-oxadiazole-containing triterpenoids and reveal two hit molecules with pronounced antitumor (5f) and anti-inflammatory (3d) activities.

Synthesis and Fungicidal Activity of Novel N-Nitro-2-Pyrimidinamine Derivatives

2013 ◽  
Vol 634-638 ◽  
pp. 1184-1191
Author(s):  
Wen Yan Qu ◽  
Jian Zhao ◽  
Bei Bei Gao ◽  
Shuo Chen ◽  
Zhi Fu Jiang ◽  
...  
Keyword(s):  
Ethyl Acetoacetate ◽  
Fungicidal Activity ◽  
High Efficiency ◽  
Fungal Species ◽  
Dimethyl Malonate ◽  
Mycelium Growth ◽  
Structure Activity ◽  
Relationship Of

Two series of novel N-nitro-2-pyrimidinamine derivatives were synthesized from ethyl acetoacetate, dimethyl malonate and nitroguanidine with good yields and high efficiency. The fungicidal activities of the synthesized compounds against nine fungal species were studied both in vitro and in vivo. Some of these compounds like 4,6-dihydr oxy -N-nitro-2-pyrimidinamine and 4,6-dihydroxy-5-isopentyl-N-nitro-2-pyrimidinamine showed obvious inhibitory of the mycelium growth at 50 mg/L. The structure-activity relationship of these compounds was also discussed.

Structure−Activity Relationship of 2-[[(2-Pyridyl)methyl]thio]-1H- benzimidazoles as AntiHelicobacter pyloriAgents in Vitro and Evaluation of their in Vivo Efficacy

1998 ◽  
Vol 41 (11) ◽  
pp. 1777-1788 ◽  
Author(s):  
Thomas C. Kühler ◽  
Marianne Swanson ◽  
Vladimir Shcherbuchin ◽  
Håkan Larsson ◽  
Björn Mellgård ◽  
...  
Keyword(s):  
Structure Activity Relationship ◽  
Activity Relationship ◽  
In Vivo Efficacy ◽  
Structure Activity ◽  
Relationship Of

Neurotoxicity of Pesticides: The Roadmap for the Cubic Mode of Action

2020 ◽  
Vol 27 (1) ◽  
pp. 54-77 ◽  
Author(s):  
Bogdan Bumbăcilă ◽  
Mihai V. Putz
Keyword(s):  
Biological Activity ◽  
Wiener Index ◽  
Laboratory Animals ◽  
Covalent Bonds ◽  
Organophosphate Compounds ◽  
Sar Studies ◽  
Structure Activity ◽  
Cubic Structure

Pesticides are used today on a planetary-wide scale. The rising need for substances with this biological activity due to an increasing consumption of agricultural and animal products and to the development of urban areas makes the chemical industry to constantly investigate new molecules or to improve the physicochemical characteristics, increase the biological activities and improve the toxicity profiles of the already known ones. Molecular databases are increasingly accessible for in vitro and in vivo bioavailability studies. In this context, structure-activity studies, by their in silico - in cerebro methods, are used to precede in vitro and in vivo studies in plants and experimental animals because they can indicate trends by statistical methods or biological activity models expressed as mathematical equations or graphical correlations, so a direction of study can be developed or another can be abandoned, saving financial resources, time and laboratory animals. Following this line of research the present paper reviews the Structure-Activity Relationship (SAR) studies and proposes a correlation between a topological connectivity index and the biological activity or toxicity made as a result of a study performed on 11 molecules of organophosphate compounds, randomly chosen, with a basic structure including a Phosphorus atom double bounded to an Oxygen atom or to a Sulfur one and having three other simple covalent bonds with two alkoxy (-methoxy or -ethoxy) groups and to another functional group different from the alkoxy groups. The molecules were packed on a cubic structure consisting of three adjacent cubes, respecting a principle of topological efficiency, that of occupying a minimal space in that cubic structure, a method that was called the Clef Method. The central topological index selected for correlation was the Wiener index, since it was possible this way to discuss different adjacencies between the nodes in the graphs corresponding to the organophosphate compounds molecules packed on the cubic structure; accordingly, "three dimensional" variants of these connectivity indices could be considered and further used for studying the qualitative-quantitative relationships for the specific molecule-enzyme interaction complexes, including correlation between the Wiener weights (nodal specific contributions to the total Wiener index of the molecular graph) and the biochemical reactivity of some of the atoms. Finally, when passing from SAR to Q(uantitative)-SAR studies, especially by the present advanced method of the cubic molecule (Clef Method) and its good assessment of the (neuro)toxicity of the studied molecules and of their inhibitory effect on the target enzyme - acetylcholinesterase, it can be seen that a predictability of the toxicity and activity of different analogue compounds can be ensured, facilitating the in vivo experiments or improving the usage of pesticides.

Synthesis and Antitumor Activity Evaluation of New Phenanthrene-Based Tylophorine Derivatives

2019 ◽  
Vol 16 (6) ◽  
pp. 462-467
Author(s):  
Songtao Li ◽  
Hongling Zhao ◽  
Zhifeng Yin ◽  
Shuhua Deng ◽  
Yang Gao ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Cell Lines ◽  
Antitumor Activities ◽  
Human Carcinoma ◽  
Carcinoma Cell Lines ◽  
Structure Activity ◽  
Human Carcinoma Cell ◽  
Ic50 Values ◽  
Relationship Of

A series of new phenanthrene-based tylophorine derivatives (PBTs) were synthesized in good yield and their structures were characterized by 1H-NMR spectroscopy and ESI MS. In vitro antitumor activity of these compounds against five human carcinoma cell lines, including HCT116 (colorectal), BGC-823 (gastric), HepG-2 (hepatic), Hela (cervical) and H460 (lung) cells, was evaluated by MTT assay. Among these PBTs, compound 6b showed the highest antitumor activities against HCT116 and HepG-2 cell lines with IC50 values of 6.1 and 6.4 μM, respectively, which were comparable to that of adriamycin hydrochloride. The structure-activity relationship of these compounds was also discussed based on the results of their antitumor activity.

Design, Synthesis, and Pharmacokinetic Evaluation of O-Carbamoyl Tizoxanide Prodrugs

2020 ◽  
Vol 16 ◽  
Author(s):  
Xi He ◽  
Wenjun Hu ◽  
Fanhua Meng ◽  
Xingzhou Li
Keyword(s):  
Plasma Concentration ◽  
Broad Spectrum ◽  
Plasma Concentrations ◽  
Antiviral Drug ◽  
Systemic Exposure ◽  
Pharmacokinetic Profile ◽  
Hydroxyl Group ◽  
First Pass

Background: The broad-spectrum antiparasitic drug nitazoxanide (N) has been repositioned as a broad-spectrum antiviral drug. Nitazoxanide’s in vivo antiviral activities are mainly attributed to its metabolitetizoxanide, the deacetylation product of nitazoxanide. In reference to the pharmacokinetic profile of nitazoxanide, we proposed the hypotheses that the low plasma concentrations and the low system exposure of tizoxanide after dosing with nitazoxanide result from significant first pass effects in the liver. It was thought that this may be due to the unstable acyloxy bond of nitazoxanide. Objective: Tizoxanide prodrugs, with the more stable formamyl substituent attached to the hydroxyl group rather than the acetyl group of nitazoxanide, were designed with the thought that they might be more stable in plasma. It was anticipated that these prodrugs might be less affected by the first pass effect, which would improve plasma concentrations and system exposure of tizoxanide. Method: These O-carbamoyl tizoxanide prodrugs were synthesized and evaluated in a mouse model for pharmacokinetic (PK) properties and in an in vitro model for plasma stabilities. Results: The results indicated that the plasma concentration and the systemic exposure of tizoxanide (T) after oral administration of O-carbamoyl tizoxanide prodrugs were much greater than that produced by equimolar dosage of nitazoxanide. It was also found that the plasma concentration and the systemic exposure of tizoxanide glucuronide (TG) were much lower than that produced by nitazoxanide. Conclusion: Further analysis showed that the suitable plasma stability of O-carbamoyl tizoxanide prodrugs is the key factor in maximizing the plasma concentration and the systemic exposure of the active ingredient tizoxanide.

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