scholarly journals The Tumor-Selective Cytotoxic Agent β-Lapachone is a Potent Inhibitor of IDO1

2013 ◽  
Vol 6 ◽  
pp. IJTR.S12094 ◽  
Author(s):  
Hollie E. Flick ◽  
Judith M. LaLonde ◽  
William P. Malachowski ◽  
Alexander J. Muller
Keyword(s):  
Active Site ◽  
Inhibitory Activity ◽  
Tumor Response ◽  
Enzyme Inhibitors ◽  
Potent Inhibitor ◽  
Naturally Occurring ◽  
Anti Cancer ◽  
Cancer Agent ◽  
Tumor Selective ◽  
Clinical Candidate

β-lapachone is a naturally occurring 1,2-naphthoquinone-based compound that has been advanced into clinical trials based on its tumor-selective cytotoxic properties. Previously, we focused on the related 1,4-naphthoquinone pharmacophore as a basic core structure for developing a series of potent indoleamine 2,3-dioxygenase 1 (IDO1) enzyme inhibitors. In this study, we identified IDO1 inhibitory activity as a previously unrecognized attribute of the clinical candidate β-lapachone. Enzyme kinetics-based analysis of β-lapachone indicated an uncompetitive mode of inhibition, while computational modeling predicted binding within the IDO1 active site consistent with other naphthoquinone derivatives. Inhibition of IDO1 has previously been shown to breach the pathogenic tolerization that constrains the immune system from being able to mount an effective anti-tumor response. Thus, the finding that β-lapachone has IDO1 inhibitory activity adds a new dimension to its potential utility as an anti-cancer agent distinct from its cytotoxic properties, and suggests that a synergistic benefit can be achieved from its combined cytotoxic and immunologic effects.

23. Transformation of the Naturally Occurring Frog Skin Peptide, Alyteserin-2a into a Potent Anti-cancer Agent

Toxicon ◽  
2012 ◽  
Vol 60 (2) ◽  
pp. 107
Author(s):  
J. Michael Conlon ◽  
Milena Mechkarska ◽  
Kholoud Arafat ◽  
Samir Attoub
Keyword(s):  
Frog Skin ◽  
Naturally Occurring ◽  
Anti Cancer ◽  
Cancer Agent

scholarly journals Synthesis of Spin-Labelled Bergamottin: A Potent CYP3A4 Inhibitor with Antiproliferative Activity

2020 ◽  
Vol 21 (2) ◽  
pp. 508 ◽  
Author(s):  
Balázs Zoltán Zsidó ◽  
Mária Balog ◽  
Nikolett Erős ◽  
Miklós Poór ◽  
Violetta Mohos ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Active Site ◽  
Normal Cell ◽  
Grapefruit Juice ◽  
Enzyme Inhibitors ◽  
Potent Inhibitor ◽  
Parent Compound ◽  
Docking Studies ◽  
Antitumor Effects ◽  
Cyp3a4 Enzyme

Bergamottin (BM, 1), a component of grapefruit juice, acts as an inhibitor of some isoforms of the cytochrome P450 (CYP) enzyme, particularly CYP3A4. Herein, a new bergamottin containing a nitroxide moiety (SL-bergamottin, SL-BM, 10) was synthesized; chemically characterized, evaluated as a potential inhibitor of the CYP2C19, CYP3A4, and CYP2C9 enzymes; and compared to BM and known inhibitors such as ketoconazole (KET) (3A4), warfarin (WAR) (2C9), and ticlopidine (TIC) (2C19). The antitumor activity of the new SL-bergamottin was also investigated. Among the compounds studied, BM showed the strongest inhibition of the CYP2C9 and 2C19 enzymes. SL-BM is a more potent inhibitor of CYP3A4 than the parent compound; this finding was also supported by docking studies, suggesting that the binding positions of BM and SL-BM to the active site of CYP3A4 are very similar, but that SL-BM had a better ∆Gbind value than that of BM. The nitroxide moiety markedly increased the antitumor activity of BM toward HeLa cells and marginally increased its toxicity toward a normal cell line. In conclusion, modification of the geranyl sidechain of BM can result in new CYP3A4 enzyme inhibitors with strong antitumor effects.

scholarly journals Exploration of Active Site-Directed Plasmin Inhibitors: Beyond Tranexamic Acid

Processes ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 329
Author(s):  
Yuko Tsuda ◽  
Koushi Hidaka ◽  
Keiko Hojo ◽  
Yoshio Okada
Keyword(s):  
Tranexamic Acid ◽  
Active Site ◽  
Docking Studies ◽  
Potential Candidate ◽  
Activity Structure ◽  
Anti Cancer ◽  
Structure Relationship ◽  
Plasmin Inhibitors ◽  
Cancer Agent ◽  
Relationship Of

Plasmin (Plm), a trypsin-like serine protease, is responsible for fibrinolysis pathway and pathologic events, such as angiogenesis, tumor invasion, and metastasis, and alters the expression of cytokines. A growing body of data indicates that a Plm inhibitor is a potential candidate as an anti-inflammatory and anti-cancer agent. A class of active site-directed plasmin inhibitors containing tranexamic acid residue has been designed. As evidenced by docking studies, the inhibitor binds to the active site not to the lysine binding site (LBS) in plasmin, thus preventing plasmin from digesting the substrate. Further optimization of the series, concerning both activity and selectivity, led to the second generation of inhibitors. This review focuses on the Plm inhibitory activity-structure relationship of Plm inhibitors with the goal of realizing their design and clinical application.

Use of inhibitors to study reactions catalyzed by enzymes requiring pyridoxal phosphate as coenzyme

2000 ◽  
Vol 72 (3) ◽  
pp. 373-384 ◽  
Author(s):  
Benjamin Adams ◽  
B. Svante Axelsson ◽  
Kenneth J. M. Beresford ◽  
Nicola J. Church ◽  
Philip A. Spencer ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Active Site ◽  
Aspartate Aminotransferase ◽  
Pyridoxal Phosphate ◽  
Family Formation ◽  
Enzyme Inhibitors ◽  
Acid Oxidase ◽  
Amino Acid Oxidase ◽  
Naturally Occurring

The stereochemistry of a variety of pyridoxal phosphate-mediated enzymic reactions has been studied using enzyme inhibitors that are stereospecifically labeled in the β-position with deuterium. A versatile synthesis has been developed to prepare a wide variety of stereospecifically labeled d- and l-amino acids and inhibitors. Investigation of the "turnover" of β-chloro-d-alanine and d- and l-serine-O-sulfate by d-amino acid aminotransferase and l-aspartate aminotransferase respectively has shown that reaction within the active site of the former enzyme occurs with retention of stereochemistry. Although l-aspartate aminotransferase is an enzyme of the α-family, when it was incubated with β-chloro-l-alanine in the presence of 2-mercaptoethanol, β-substitution occurred. This was shown to involve retention of stereochemistry, an outcome typical of reactions catalyzed by enzymes of the β-family that have little or no homology with enzymes of the α-family. Formation of the "Schnackerz intermediate" has been studied as has the d-amino acid oxidase catalyzed reaction of the naturally occurring inhibitor d-propargylglycine.

Amygdalin from Apricot Kernels Induces Apoptosis and Causes Cell Cycle Arrest in Cancer Cells: An Updated Review

2019 ◽  
Vol 18 (12) ◽  
pp. 1650-1655 ◽  
Author(s):  
Mohammad Saleem ◽  
Jawaria Asif ◽  
Muhammad Asif ◽  
Uzma Saleem
Keyword(s):  
Cell Cycle ◽  
Cancer Cells ◽  
Time Frame ◽  
Central Process ◽  
Naturally Occurring ◽  
Current Review ◽  
Anti Cancer ◽  
Apoptotic Proteins ◽  
Cancer Agent

Background: Amygdalin is a cyanogenic glycoside which is described as a naturally occurring anticancer agent. Current review highlights apoptosis-inducing attributes of amygdalin towards different cancers and its potential application as an anti-cancer agent in cancer therapy. Method: Data about amygdalin was retrieved from all major scientific databases i.e., PubMed, ScienceDirect, Google Scholar, Scopus and Medline by using combination of keywords like amygdalin, apoptosis, laetrile, vitamin B- 17, pro-apoptotic proteins, anti-apoptotic proteins, hydrogen cyanide, mechanism of action of amygdalin and amygdalin therapy on humans. However, no specific time frame was followed for collection of data. Results: Data collected from already published articles revealed that apoptosis is a central process activated by amygdalin in cancer cells. It is suggested to stimulate apoptotic process by upregulating expression of Bax (proapoptotic protein) and caspase-3 and downregulating expression of Bcl-2 (anti-apoptotic protein). It also promotes arrest of cell cycle in G0/G1 phase and decrease number of cells entering S and G2/M phases. Thus, it is proposed to enhance deceleration of cell cycle by blocking cell proliferation and growth. Conclusion: The current review epitomizes published information and provides complete interpretations about all known anti-cancer mechanisms of amygdalin, possible role of naturally occurring amygdalin in fight against cancer and mistaken belief about cyanide toxicity causing potential of amygdalin. However, well-planned clinical trials are still needed to be conducted to prove effectiveness of this substance in vivo and to get approval for human use.

Transformation of the naturally occurring frog skin peptide, alyteserin-2a into a potent, non-toxic anti-cancer agent

Amino Acids ◽  
2012 ◽  
Vol 44 (2) ◽  
pp. 715-723 ◽  
Author(s):  
J. Michael Conlon ◽  
Milena Mechkarska ◽  
Manju Prajeep ◽  
Kholoud Arafat ◽  
Milan Zaric ◽  
...  
Keyword(s):  
Frog Skin ◽  
Naturally Occurring ◽  
Anti Cancer ◽  
Cancer Agent

scholarly journals Development of Specific Inhibitors for Oncogenic Phosphatase PPM1D by Using Ion-Responsive DNA Aptamer Library

Catalysts ◽  
2020 ◽  
Vol 10 (10) ◽  
pp. 1153
Author(s):  
Atsushi Kaneko ◽  
Miyuu Watari ◽  
Masataka Mizunuma ◽  
Hikaru Saito ◽  
Kazuhiro Furukawa ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
Specific Inhibitor ◽  
Dna Aptamer ◽  
Monovalent Cations ◽  
Stimuli Responsive ◽  
Mcf7 Cells ◽  
Normal Cells ◽  
Anti Cancer ◽  
G Quadruplex ◽  
Cancer Agent

(1) Background: Ser/Thr protein phosphatase PPM1D is an oncogenic protein. In normal cells, however, PPM1D plays essential roles in spermatogenesis and immune response. Hence, it is necessary to develop novel PPM1D inhibitors without side effects on normal cells. Stimuli-responsive molecules are suitable for the spatiotemporal regulation of inhibitory activity. (2) Methods: In this study, we designed an ion-responsive DNA aptamer library based on G-quadruplex DNA that can change its conformation and function in response to monovalent cations. (3) Results: Using this library, we identified the PPM1D specific inhibitor M1D-Q5F aptamer. The M1D-Q5F aptamer showed anti-cancer activity against breast cancer MCF7 cells. Interestingly, the induction of the structural change resulting in the formation of G-quadruplex upon stimulation by monovalent cations led to the enhancement of the inhibitory activity and binding affinity of M1D-Q5F. (4) Conclusions: These data suggest that the M1D-Q5F aptamer may act as a novel stimuli-responsive anti-cancer agent.

Characterization of an Abnormal Antithrombin (Milano 2) with Defective Thrombin Binding

1986 ◽  
Vol 56 (03) ◽  
pp. 349-352 ◽  
Author(s):  
A Tripodi ◽  
A Krachmalnicoff ◽  
P M Mannucci
Keyword(s):  
Venous Thromboembolism ◽  
Active Site ◽  
Inhibitory Activity ◽  
Antithrombin Iii ◽  
Factor Xa ◽  
Molecular Defect ◽  
Affinity Adsorption ◽  
Italian Family ◽  
Crossed Immunoelectrophoresis

SummaryFour members of an Italian family (two with histories of venous thromboembolism) had a qualitative defect of antithrombin III reflected by normal antigen concentrations and halfnormal antithrombin activity with or without heparin. Anti-factor Xa activities were consistently borderline low (about 70% of normal). For the propositus’ plasma and serum the patterns of antithrombin III in crossed-immunoelectrophoresis with or without heparin were indistinguishable from those of normal plasma or serum. A normal affinity of antithrombin III for heparin was documented by heparin-sepharose chromatography. Affinity adsorption of the propositus’ plasma to human α-thrombin immobilized on sepharose beads revealed defective binding of the anti thrombin III to thrombin-sepharose. Hence the molecular defect of this variant appears to be at the active site responsible for binding and neutralizing thrombin, thus accounting for the low thrombin inhibitory activity.

Benzoxazinoids in human diet: an anti-cancer agent?

2019 ◽  
Author(s):  
B Bhattarai ◽  
SK Steffensen ◽  
PL Gregersen ◽  
JH Jensen ◽  
KD Sørensen ◽  
...  
Keyword(s):  
Human Diet ◽  
Anti Cancer ◽  
Cancer Agent
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