scholarly journals Antiproliferative S-Trityl-l-Cysteine -Derived Compounds as SIRT2 Inhibitors: Repurposing and Solubility Enhancement

Molecules ◽  
2019 ◽  
Vol 24 (18) ◽  
pp. 3295 ◽  
Author(s):  
Mohamed O. Radwan ◽  
Halil I. Ciftci ◽  
Taha F. S. Ali ◽  
Doha E. Ellakwa ◽  
Ryoko Koga ◽  
...  
Keyword(s):  
Inhibitory Effect ◽  
Cytotoxic Agents ◽  
Carboxyl Groups ◽  
New Class ◽  
Potent Inhibitory Effect ◽  
Terminal Amino ◽  
Kinesin Eg5 ◽  
Mitotic Kinesin Eg5 ◽  
In Silico Molecular Docking

S-trityl-l-cysteine (STLC) is a well-recognized lead compound known for its anticancer activity owing to its potent inhibitory effect on human mitotic kinesin Eg5. STLC contains two free terminal amino and carboxyl groups that play pivotal roles in binding to the Eg5 pocket. On the other hand, such a zwitterion structure complicates the clinical development of STLC because of the solubility issues. Masking either of these radicals reduces or abolishes STLC activity against Eg5. We recently identified and characterized a new class of nicotinamide adenine dinucleotide-dependent deacetylase isoform 2 of sirtuin protein (SIRT2) inhibitors that can be utilized as cytotoxic agents based on an S-trityl-l-histidine scaffold. Herein, we propose new STLC-derived compounds that possess pronounced SIRT2 inhibition effects. These derivatives contain modified amino and carboxyl groups, which conferred STLC with SIRT2 bioactivity, representing an explicit repurposing approach. Compounds STC4 and STC11 exhibited half maximal inhibitory concentration values of 10.8 ± 1.9 and 9.5 ± 1.2 μM, respectively, against SIRT2. Additionally, introduction of the derivatizations in this study addressed the solubility limitations of free STLC, presumably due to interruption of the zwitterion structure. Therefore, we could obtain drug-like STLC derivatives that work by a new mechanism of action. The new derivatives were designed, synthesized, and their structure was confirmed using different spectroscopic approaches. In vitro and cellular bioassays with various cancer cell lines and in silico molecular docking and solubility calculations of the synthesized compounds demonstrated that they warrant attention for further refinement of their bioactivity.

Mobilization of Fibrinogen Receptor Sites on Human Platelets Stimulated with ADP is Prevented by Prostacyclin

1979 ◽  
Author(s):  
J. Hawiger ◽  
S. Parkinson ◽  
S. Timmons
Keyword(s):  
Inhibitory Effect ◽  
Human Platelets ◽  
Affinity Constant ◽  
Human Fibrinogen ◽  
Fibrinogen Receptor ◽  
Receptor Sites ◽  
Plasma Factor ◽  
Potent Inhibitory Effect

Fibrinogen is a plasma factor required for aggregation of human platelets by ADP. The mechanism of platelet-ADP-fibrinogen interaction was studied by measuring the equilibrium binding of 125I-fibrinogen to human platelets separated from plasma proteins. Binding of 125I-fibrinogen to platelets not stimulated with ADP was low and unaffected by an excess of unlabel led fibrinogen. However, when platelets were stimulated with 4μM of ADP, there was an eightfold increase In the number of available binding sites for human fibrinogen, with affinity constant of 1.9 x 109M-1. This striking increase in fibrinogen receptor sites on human platelets was specific for ADP as contrasted to ATP, AMP, and adenosine. Prostacyclin (Prostaglandin I2, PGI2), a novel prostaglandin produced by the blood vessel wall, completely blocked this ADP-induced increase in fibrinogen receptor sites on human platelets. The effect of PGI2 was prompt and concentration dependent, reaching maximum at 10-9M. 6-keto PGF2 a stable derivative ot PGI2, did not have such an effect. Thus movement of fibrinogen receptor sites on human platelet membrane stimulated with ADP is prevented by PGI2. This represents a new biologic property of this vascular hormone and contributes to better understanding of its potent inhibitory effect in vitro and in vivo on ADP-induced platelet aggregation requiring mobilization of fibrinogen receptor.

Design, synthesis, and biological evaluation of new series of 2-amido-1,3,4-thiadiazole derivatives as cytotoxic agents

2016 ◽  
Vol 71 (3) ◽  
pp. 205-210 ◽  
Author(s):  
Ali Almasirad ◽  
Loghman Firoozpour ◽  
Maliheh Nejati ◽  
Najmeh Edraki ◽  
Omidreza Firuzi ◽  
...  
Keyword(s):  
Human Tumor ◽  
Inhibitory Effect ◽  
Biological Evaluation ◽  
Cytotoxic Agents ◽  
Antitumor Activities ◽  
Design Synthesis ◽  
Ethidium Bromide Staining ◽  
Thiadiazole Derivatives ◽  
Synthesis And Biological Evaluation

AbstractA series of novel 1,3,4-thiadiazole derivatives bearing an amide moiety were designed, synthesized, and evaluated for their in vitro antitumor activities against HL-60, SKOV-3 and MOLT-4 human tumor cell lines by MTT assay. Ethyl 2-((5-(4-methoxybenzamido)-1,3,4-thiadiazol-2-yl)thio)acetate (5f) showed the best inhibitory effect against SKOV-3 cells, with an IC50 value of 19.5 μm. In addition, the acridine orange/ethidium bromide staining assay in SKOV-3 cells suggested that the cytotoxic activity of 5f occurs via apoptosis.

Synthesis and structural analysis of curdlan sulfate with a potent inhibitory effect in vitro of AIDS virus infection

1990 ◽  
Vol 23 (16) ◽  
pp. 3717-3722 ◽  
Author(s):  
Takashi Yoshida ◽  
Kenichi Hatanaka ◽  
Toshiyuki Uryu ◽  
Yutaro Kaneko ◽  
Eiichiro Suzuki ◽  
...  
Keyword(s):  
Structural Analysis ◽  
Virus Infection ◽  
Inhibitory Effect ◽  
Aids Virus ◽  
Potent Inhibitory Effect

Lead Generation for Human Mitotic Kinesin Eg5 using Structure-based Virtual Screening and Validation by in vitro and Cell-based Assays

2020 ◽  
Vol 16 ◽  
Author(s):  
Himesh Makala ◽  
Soundarya Priya Alexandar ◽  
Devipriya Nagarajan ◽  
Santanu Kar Mahapatra ◽  
Venkatasubramanian Ulaganathan
Keyword(s):  
Virtual Screening ◽  
Cell Lines ◽  
Cancer Cell ◽  
Mitotic Cell ◽  
Cancer Cell Lines ◽  
Allosteric Site ◽  
Drug Candidates ◽  
Kinesin Eg5 ◽  
Mitotic Kinesin Eg5

Background: Human mitotic kinesins play a crucial role in mitotic cell division. Targeting the spindle separation phase of mitosis has gained much attention pharmaceutically in cancer chemotherapy. Spindle segregation is carried out mainly by Eg5 kinesin, and currently, it has many inhibitors in different phases of clinical trials. All the current drug candidates bind un-competitively with ATP/ADP at allosteric site 1 (formed by loop L5, helix α2 and helix α3). Recent experiments show that inhibitors that bind to the site 2 (formed by helix α4 and helix α6) are either competitive or uncompetitive to ATP/ADP. Objectives: To identify suitable lead compounds that target the mitotic kinesin Eg5, using in silico screening and their validation using in vitro and cell-based assays. Methodology: We have screened for potential inhibitors for human Eg5 (kinesin-5) through structure-based virtual screening and validated the top-scoring compounds using steady-state ATPase assay, differential scanning fluorimetry and microscale thermophoresis. The anticancer activity of the compounds was evaluated in the epithelial (A549) and chronic myelogenous leukaemia (K562) cancer cell lines. A known strong binding inhibitor S-trityl-L-cystine is used as a reference compound. Results & Conclusion: Of the many compounds tested, MM01 and MM03 showed good cell-based activity against the cancer cell lines A549 and K562 and can be further studied in animal models.

Potent inhibitory effect of naturally occurring flavonoids quercetin and kaempferol on in vitro osteoclastic bone resorption

2003 ◽  
Vol 65 (1) ◽  
pp. 35-42 ◽  
Author(s):  
Alice Wattel ◽  
Said Kamel ◽  
Romuald Mentaverri ◽  
Florence Lorget ◽  
Christophe Prouillet ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Inhibitory Effect ◽  
Osteoclastic Bone Resorption ◽  
Naturally Occurring ◽  
Potent Inhibitory Effect

scholarly journals Sunitinib Reduces Acute Myeloid Leukemia Clonogenic Cells <i>in Vitro</i> and Has Potent Inhibitory Effect on Sorted AML ALDH+ Cells

2016 ◽  
Vol 06 (01) ◽  
pp. 9-16 ◽  
Author(s):  
Asad M. Ilyas ◽  
Youssri Ahmed ◽  
Mamdooh Gari ◽  
Mohammed H. Alqahtani ◽  
Taha A. Kumosani ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Inhibitory Effect ◽  
Potent Inhibitory Effect ◽  
Acute Myeloid ◽  
Clonogenic Cells

scholarly journals Inhibitory Effect of Ascorbic Acid on in vitro Enzymatic Digestion of Raw and Cooked Starches

2021 ◽  
Vol 8 ◽  
Author(s):  
Jiayue Guo ◽  
Alyssa Gutierrez ◽  
Libo Tan ◽  
Lingyan Kong
Keyword(s):  
Ascorbic Acid ◽  
Potato Starch ◽  
Digestive Enzyme ◽  
Enzymatic Digestion ◽  
Inhibitory Effect ◽  
Starch Digestion ◽  
Potent Inhibitory Effect ◽  
High Amylose ◽  
Dose Dependent

Ascorbic acid, also known as vitamin C, was previously reported to inhibit the activity of pancreatic α-amylase, the primary digestive enzyme for starch. A major implication of such inhibition is a slowed rate of starch digestion into glucose, which thereby reduces postprandial hyperglycemia. The aim of this study was to explore the inhibitory effects of ascorbic acid at various concentrations on the in vitro digestion of high amylose maize starch (HAMS) and potato starch (PS) in both raw and cooked conditions. Resistant starch (RS) content, defined as the starch that remained after 4 h of simulated in vitro enzymatic digestion, was measured for the starch samples. Upon the addition of ascorbic acid, the RS contents increased in both raw and cooked starches. Cooking significantly reduced the RS contents as compared to raw starches, and less increase in RS was observed with the addition of ascorbic acid. The inhibitory effect of ascorbic acid on the digestion of raw starches showed a dose-dependent trend until it reached the maximum extent of inhibition. At the concentrations of 12.5 and 18.75 mg/mL, ascorbic acid exhibited the most potent inhibitory effect on the in vitro starch digestion in raw and cooked conditions, respectively. Overall, our results strongly indicate that ascorbic acid may function as a glycemic modulatory agent beyond other important functions, and its effects persist upon cooking with certain concentrations applied.

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