Evaluating anthranilate synthase as a herbicide target

Weed Science ◽  
1997 ◽  
Vol 45 (5) ◽  
pp. 628-633
Author(s):  
Daniel L. Siehl ◽  
Mani V. Subramanian ◽  
Eric W. Walters ◽  
Jonathan H. Blanding ◽  
Thierry Niderman ◽  
...  
Keyword(s):  
Mode Of Action ◽  
Enzyme Inhibitors ◽  
Herbicidal Activity ◽  
Anthranilate Synthase ◽  
Inhibitor Design ◽  
Methyl Anthranilate ◽  
Active Ingredients ◽  
Target Sites ◽  
Aromatic Pathway

Attempts to discover new active ingredients and target sites within the aromatic pathway have resulted in the synthesis of potent enzyme inhibitors, but no herbicides. As an aid in identifying a new target for inhibitor design and screening, we have determined the mode of action of a compound (6-methyl anthranilate) that exhibits noncommercial levels of herbicidal activity. Our evidence suggests that 6-methyl anthranilate is converted in vivo, by traversing the tryptophan biosynthetic sequence, to 4-methyl tryptophan, which inhibits anthranilate synthase. Inhibitors synthesized by design and those found by target-based screening converged on analogs of tryptophan and anthranilate. None, however, was more herbicidal than 6-methyl anthranilate.

Insulinomimetic properties of trace elements and characterization of their in vivo mode of action

Diabetes ◽  
1990 ◽  
Vol 39 (10) ◽  
pp. 1243-1250 ◽  
Author(s):  
L. Rossetti ◽  
A. Giaccari ◽  
E. Klein-Robbenhaar ◽  
L. R. Vogel
Keyword(s):  
Trace Elements ◽  
Mode Of Action

scholarly journals Chimeric Mouse With Humanized Liver Is an Appropriate Animal Model to Investigate Mode of Action for Porphyria-Mediated Hepatocytotoxicity

2021 ◽  
pp. 019262332110274
Author(s):  
Ayumi Eguchi ◽  
Satoki Fukunaga ◽  
Keiko Ogata ◽  
Masahiko Kushida ◽  
Hiroyuki Asano ◽  
...  
Keyword(s):  
Experimental Model ◽  
Mode Of Action ◽  
Aminolevulinic Acid ◽  
Protoporphyrin Ix ◽  
Human Hepatocytes ◽  
Chimeric Mouse ◽  
Hepatocellular Injury ◽  
Hepatocyte Necrosis ◽  
Key Events

Porphyrinogenic compounds are known to induce porphyria-mediated hepatocellular injury and subsequent regenerative proliferation in rodents, ultimately leading to hepatocellular tumor induction. However, an appropriate in vivo experimental model to evaluate an effect of porphyrinogenic compounds on human liver has not been fully established. Recently, the chimeric mouse with humanized liver (PXB mice) became widely used as a humanized model in which human hepatocytes are transplanted. In the present study, we examined the utility of PXB mice as an in vivo experimental model to evaluate the key events of the porphyria-mediated cytotoxicity mode of action (MOA) in humans. The treatment of PXB mice with 5-aminolevulinic acid, a representative porphyrinogenic compound, for 28 days caused protoporphyrin IX accumulation, followed by hepatocyte necrosis, increased mitosis, and an increase in replicative DNA synthesis in human hepatocytes, indicative of cellular injury and regenerative proliferation, similar to findings in patients with porphyria or experimental porphyria models and corresponding to the key events of the MOA for porphyria-mediated hepatocellular carcinogenesis. We conclude that the PXB mouse is a useful model to evaluate the key events of the porphyria-mediated cytotoxicity MOA in humans and suggest the utility of PXB mice for clarifying the human relevancy of findings in mice.

scholarly journals Identification of a small molecule as inducer of ferroptosis and apoptosis through ubiquitination of GPX4 in triple negative breast cancer cells

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Yahui Ding ◽  
Xiaoping Chen ◽  
Can Liu ◽  
Weizhi Ge ◽  
Qin Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Small Molecule ◽  
Mode Of Action ◽  
Rna Silencing ◽  
Breast Cancer Cells ◽  
Triple Negative ◽  
Parent Compound ◽  
Aggressive Breast Cancer

Abstract Background TNBC is the most aggressive breast cancer with higher recurrence and mortality rate than other types of breast cancer. There is an urgent need for identification of therapeutic agents with unique mode of action for overcoming current challenges in TNBC treatment. Methods Different inhibitors were used to study the cell death manner of DMOCPTL. RNA silencing was used to evaluate the functions of GPX4 in ferroptosis and apoptosis of TNBC cells and functions of EGR1 in apoptosis. Immunohistochemical assay of tissue microarray were used for investigating correlation of GPX4 and EGR1 with TNBC. Computer-aided docking and small molecule probe were used for study the binding of DMOCPTL with GPX4. Results DMOCPTL, a derivative of natural product parthenolide, exhibited about 15-fold improvement comparing to that of the parent compound PTL for TNBC cells. The cell death manner assay showed that the anti-TNBC effect of DMOCPTL mainly by inducing ferroptosis and apoptosis through ubiquitination of GPX4. The probe of DMOCPTL assay indicated that DMOCPTL induced GPX4 ubiquitination by directly binding to GPX4 protein. To the best of our knowledge, this is the first report of inducing ferroptosis through ubiquitination of GPX4. Moreover, the mechanism of GPX4 regulation of apoptosis is still obscure. Here, we firstly reveal that GPX4 regulated mitochondria-mediated apoptosis through regulation of EGR1 in TNBC cells. Compound 13, the prodrug of DMOCPTL, effectively inhibited the growth of breast tumor and prolonged the lifespan of mice in vivo, and no obvious toxicity was observed. Conclusions These findings firstly revealed novel manner to induce ferroptosis through ubiquitination of GPX4 and provided mechanism for GPX4 inducing mitochondria-mediated apoptosis through up-regulation of EGR1 in TNBC cells. Moreover, compound 13 deserves further studies as a lead compound with novel mode of action for ultimate discovery of effective anti-TNBC drug.

Triazol: a privileged scaffold for proteolysis targeting chimeras

2019 ◽  
Vol 11 (22) ◽  
pp. 2919-2973 ◽  
Author(s):  
Li-Wen Xia ◽  
Meng-Yu Ba ◽  
Wei Liu ◽  
Weyland Cheng ◽  
Chao-Ping Hu ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Anticancer Activity ◽  
Mode Of Action ◽  
Critical Analysis ◽  
Enzyme Inhibitors ◽  
Structure Activity Relationship ◽  
Target Protein ◽  
Activity Relationship ◽  
Structure Activity ◽  
Privileged Scaffold

Current traditional drugs such as enzyme inhibitors and receptor agonists/antagonists present inherent limitations due to occupancy-driven pharmacology as the mode of action. Proteolysis targeting chimeras (PROTACs) are composed of an E3 ligand, a connecting linker and a target protein ligand, and are an attractive approach to specifically knockdown-targeted proteins utilizing an event-driven mode of action. The length, hydrophilicity and rigidity of connecting linkers play important role in creating a successful PROTAC. Some PROTACs with a triazole linker have displayed promising anticancer activity. This review provides an overview of PROTACs with a triazole scaffold and discusses its structure–activity relationship. Important milestones in the development of PROTACs are addressed and a critical analysis of this drug discovery strategy is also presented.

Therapeutic properties of organotin complexes with reference to their structural and environmental features

2017 ◽  
Vol 37 (2) ◽  
pp. 51-70 ◽  
Author(s):  
Muhammad Iqbal ◽  
Saqib Ali ◽  
Ali Haider ◽  
Nasir Khalid
Keyword(s):  
Mode Of Action ◽  
Therapeutic Potential ◽  
Biological Systems ◽  
Structural Features ◽  
Present Review ◽  
Environmental Features ◽  
Recent Advances ◽  
Target Sites ◽  
Therapeutic Properties ◽  
Modes Of Interaction

AbstractOrganotin complexes are being extensively studied and screened for their therapeutic potential. Although many recent advances and achievements in this field have been made, the exact mode of action of these complexes is yet to be unveiled. In the present review, an attempt has been made to correlate the therapeutic properties of organotin complexes with their structural features and the environment in which these interact with biological systems. The mechanism, various modes of interaction with biological systems, and physiological target sites of organotin complexes have been highlighted as well.

scholarly journals lncRNAs in development and disease: from functions to mechanisms

Open Biology ◽  
2017 ◽  
Vol 7 (7) ◽  
pp. 170121 ◽  
Author(s):  
M. Joaquina Delás ◽  
Gregory J. Hannon
Keyword(s):  
Differential Expression ◽  
Cell Fate ◽  
Mode Of Action ◽  
Non Coding Rnas

Differential expression of long non-coding RNAs (lncRNAs) during differentiation and their misregulation in cancer highlight their potential as cell fate regulators. While some example lncRNAs have been characterized in great detail, the functional in vivo relevance of others has been called into question. Finding functional lncRNAs will most probably require a combination of complementary approaches that will greatly vary depending on their mode of action. In this review, we discuss the different tools available to dissect genetically lncRNA requirements and how each is best suited to studies in particular contexts. Moreover, we review different strategies used to select candidate lncRNAs and give an overview of lncRNAs described to regulate development and cancer through different mechanisms.

Vasopressin as a neuroendocrine regulator of anterior pituitary hormone secretion

1993 ◽  
Vol 129 (6) ◽  
pp. 489-496 ◽  
Author(s):  
Andreas Kjær
Keyword(s):  
Arginine Vasopressin ◽  
Mode Of Action ◽  
Anterior Pituitary ◽  
Hormone Secretion ◽  
Pituitary Hormones ◽  
Pituitary Hormone ◽  
Anterior Pituitary Hormones ◽  
Anterior Pituitary Hormone

Secretion of the anterior pituitary hormones adrenocorticotropin (ACTH), β-endorphin and prolactin (PRL) is complex and involves a variety of factors. This review focuses on the involvement of arginine-vasopressin (AVP) in neuroendocrine regulation of these anterior pituitary hormones with special reference to receptor involvement, mode of action and origin of AVP. Arginine-vasopressin may act via at least two types of receptors: V1− and V2−receptors, where the pituitary V1−receptor is designated V1b. The mode of action of AVP may be mediating, i.e. anterior pituitary hormone secretion is transmitted via release of AVP, or the mode of action may be permissive, i.e. the presence of AVP at a low and constant level is required for anterior pituitary hormones to be stimulated. Under in vivo conditions, the AVP-induced release of ACTH and β-endorphin is mainly mediated via activation of hypothalamic V1− receptors, which subsequently leads to the release of corticotropin-releasing hormone. Under in vitro conditions, the AVP-stimulated release of ACTH and β-endorphin is mediated via pituitary V1b− receptors. The mode of action of AVP in the ACTH and β-endorphin response to stress and to histamine, which is involved in stress-induced secretion of anterior pituitary hormones, is mediating (utilizing V1− receptors) as well as permissive (utilizing mainly V1− but also V2−receptors). The AVP-induced release of PRL under in vivo conditions is conveyed mainly via activation of V1−receptors but V2−receptors and probably additional receptor(s) may also play a role. In stress- and histamine induced PRL secretion the role of AVP is both mediating (utilizing V1 −receptors) and permissive (utilizing both V1− and V2− receptors). Arginine-vasopressin may be a candidate for the PRL-releasing factor recently identified in the posterior pituitary gland. Arginine-vasopressin of both magno- and parvocellular origin may be involved in the regulation of anterior pituitary hormone secretion and may reach the corticotrophs and the lactotrophs via three main routes: the peripheral circulation, the long pituitary portal vessels or the short pituitary portal vessels.

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