Design, synthesis, biological evaluation and molecular docking of novel moleculesto PARP-1 enzyme

Tok, Fatih; Kaymakçıoğlu, Bedia Koçyiğit; İlhan, Recep; Yılmaz, Sinem; Ballar, Petek; Tok, Tuğba Taşkın

doi:10.3906/kim-1905-15

Cited by 7 publications

(3 citation statements)

References 31 publications

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“…Next, we investigated the effect of SIN1 treatment on the cellular PARylation levels of RA‐differentiated SH‐SY5Y cells. Cellular PARylation levels were measured by a previously established quantitative fluorometric PARylation assay [ 25 ] utilizing monoclonal anti‐PAR primary and FITC‐conjugated secondary antibodies. The obtained PAR signals were normalized with the DAPI signal.…”

Section: Resultsmentioning

confidence: 99%

A new underlying mechanism for the neuroprotective effect of bosutinib: Reverting toxicity‐induced PARylation in SIN1‐mediated neurotoxicity

Yılmaz

Alkan

Ballar

2021

J Biochem & Molecular Tox

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Increased levels of reactive oxygen and nitrogen species play an important role in the development and progression of neurodegenerative diseases, such as Alzheimer's and Parkinson's disease. The overproduction of these highly reactive chemical species leads to DNA damage and subsequent activation of the poly(ADP‐ribose)polymerase (PARP) enzyme. Several studies have demonstrated the potential use of PARP inhibitors for neuroprotection. We previously reported that the dual Src/Abl kinase inhibitor bosutinib (BOS) decreases PARP activity and acts as a chemosensitizer in cancer cells. In this study, we evaluated the neuroprotective potential of BOS with respect to its inhibitory effect on cellular poly(ADP‐ribos)ylation (PARylation) using a 3‐morpholinosydnonimine (SIN1)‐mediated cellular toxicity model. Our data suggest that pretreatment with BOS, especially at lower doses, significantly decreased the level of SIN1‐induced cellular PARylation. This regulation pattern of PARylation was found to be associated with the protective effect of BOS against SIN1 on the viability of retinoic acid‐differentiated SH‐SY5Y cells. Furthermore, while PARP‐1 expression was decreased, phosphorylation of SAPK/JNK was not reverted at the observed neuroprotective doses of BOS. In conclusion, we suggest a novel mechanism for the neuroprotective effect of BOS involving the inhibition of cellular PARylation.

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Section: Resultsmentioning

confidence: 99%

A new underlying mechanism for the neuroprotective effect of bosutinib: Reverting toxicity‐induced PARylation in SIN1‐mediated neurotoxicity

Yılmaz

Alkan

Ballar

2021

J Biochem & Molecular Tox

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“…For the drug development, pharmacokinetics, and safety properties such as absorption, distribution, metabolism, excretion, and toxicity (ADMET) play a significant role. We have used pkCSM predictive model (28,34) to rapidly evaluate pharmacokinetic and toxicity properties. As shown in Table 3 Drug-likeness (35) and medicinal chemistry friendliness of these compounds were predicted by SwissADME predictor (35) and Molsoft's chemical fingerprints (30).…”

Section: Admet and Drug-likeness Propertiesmentioning

confidence: 99%

Section: Admet and Drug-likeness Propertiesmentioning

confidence: 99%

Regioselective Synthesis of Some Rhamnopyranoside Esters for PASS Predication, and ADMET Studies

Matin

Islam

Siddika

et al. 2021

Journal of the Turkish Chemical Society Section A: Chemistry

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Notable biological activities including brains protective activities have made carbohydrate esters as a topic of great interest over the past several decades. In this context, unimolecular treatment of methyl α-L-rhamnopyranoside with dibutyltin oxide gave the corresponding 2,3-O-(dibutylstannylene) derivative which was then allowed to react with 3-chlorobenzoyl chloride. The reaction regioselectively furnished the 3-O-substitution product in excellent yield. To get newer rhamnopyranoside esters chlorobenzoate was further converted into four 2,4-di-O-substituted products with other acylating agents using direct acylation technique. Moreover, thermodynamic properties indicated that these sugar esters (SEs) possess better stability, suitable polar nature and higher binding affinity than the non-ester rhamnopyranoside. Prediction of Activity Spectra for Substances (PASS) predication showed that these SEs should be more potent against fungal pathogens than the bacterial organisms. With these encouraging results absorption, distribution, metabolism, excretion, and toxicity (ADMET) and drug-likeness properties of the SEs are also discussed.

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Synthesis, Biological Evaluation and in Silico Studies of Novel Urea/Thiourea Derivatives of Lenalidomide

Tok,

Abas,

Başoğlu

et al. 2024

J Biochem & Molecular Tox

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Designing new compounds from existing chemotherapeutic drugs to enhance inhibitory effects on tumor cells while overcoming multidrug resistance is one of the important strategies for new drug discovery in medicinal chemistry. A new series of urea and thiourea derivatives based on Lenalidomide as potential anticancer agents have been designed and synthesized. In vitro anticancer activity assay against Caki cancer cells and HUVEC endothelial cells revealed that 1‐(4‐methylphenyl)‐3‐[2‐(2,6‐dioxopiperidin‐3‐yl)‐1‐oxoisoindolin‐4‐yl]urea (11) exhibited the highest anticancer activity and selectivity in the series with IC50 values of 9.88 and 179.03 µM, respectively. Among the compounds, 11 showed significant HDAC1 inhibiton of 68.02 ± 2.44% at 10 µM concentration. TGF‐β, Bax, Bcl‐2 protein levels and scratch assay were analyzed in Caki cells. As a result, compound 11 induced apoptosis in Caki cells. In this study, it has been demonstrated that compound 11 can be a lead compound for further detailed investigation in renal cancer treatment. Through molecular docking studies, it was determined that the most active compound, 11, forms stable interactions with key residues in the enzyme's active site, particularly engaging in hydrogen bonds with GLY149 and coordinating with the zinc ion in the HDAC1 active site. These interactions are crucial for the observed inhibitory activity. Molecular dynamics simulation revealed the binding event of the most active compound with class I histone deacetylase and the stability of the complex in a biological environment.

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Design, synthesis, biological evaluation and molecular docking of novel moleculesto PARP-1 enzyme

Cited by 7 publications

References 31 publications

A new underlying mechanism for the neuroprotective effect of bosutinib: Reverting toxicity‐induced PARylation in SIN1‐mediated neurotoxicity

A new underlying mechanism for the neuroprotective effect of bosutinib: Reverting toxicity‐induced PARylation in SIN1‐mediated neurotoxicity

Regioselective Synthesis of Some Rhamnopyranoside Esters for PASS Predication, and ADMET Studies

Synthesis, Biological Evaluation and in Silico Studies of Novel Urea/Thiourea Derivatives of Lenalidomide

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