Rational design, synthesis, pharmacophore modeling, and docking studies for identification of novel potent DNA-PK inhibitors

Ihmaid, Saleh; Ahmed, Hany E. A.; Ali, Adeeb Al-Sheikh; Sherif, Yousery E.; Tarazi, Hamadeh; Riyadh, Sayed M.; Zayed, Mohamed F.; Abulkhair, Hamada S.; Rateb, Heba S.

doi:10.1016/j.bioorg.2017.04.014

Cited by 28 publications

(16 citation statements)

References 28 publications

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“…Docking involves fitting virtual ligands, typically derived from large virtual libraries, into targeted binding sites employing computer algorithms. A well-studied virtual ligand–protein interaction complex model is an essential prerequisite toward the design and subsequent optimization of novel bioactive compounds, including new anticancer agents 14 .…”

Section: Introductionmentioning

confidence: 99%

The cyclohexene derivative MC-3129 exhibits antileukemic activity via RhoA/ROCK1/PTEN/PI3K/Akt pathway-mediated mitochondrial translocation of cofilin

Zheng

Ouyang

et al. 2018

Cell Death Dis

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The effects of MC-3129, a synthetic cyclohexene derivative, on cell viability and apoptosis have been investigated in human leukemia cells. Exposure of leukemia cells to MC-3129 led to the inhibition of cell viability and induction of apoptosis through the dephosphorylation and mitochondrial translocation of cofilin. A mechanistic study revealed that interruption of the RhoA/ROCK1/PTEN/PI3K/Akt signaling pathway plays a crucial role in the MC-3129-mediated dephosphorylation and mitochondrial translocation of cofilin and induction of apoptosis. Our in vivo study also showed that the MC-3129-mediated inhibition of the tumor growth in a mouse leukemia xenograft model is associated with the interruption of ROCK1/PTEN/PI3K/Akt signaling and apoptosis. Molecular docking suggested that MC-3129 might activate the RhoA/ROCK1 pathway by targeting LPAR2. Collectively, these findings suggest a hierarchical model, in which the induction of apoptosis by MC-3129 primarily results from the activation of RhoA/ROCK1/PTEN and inactivation of PI3K/Akt, leading to the dephosphorylation and mitochondrial translocation of cofilin, and culminating in cytochrome c release, caspase activation, and apoptosis. Our study reveals a novel role for RhoA/ROCK1/PTEN/PI3K/Akt signaling in the regulation of mitochondrial translocation of cofilin and apoptosis and suggests MC-3129 as a potential drug for the treatment of human leukemia.

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Section: Introductionmentioning

confidence: 99%

The cyclohexene derivative MC-3129 exhibits antileukemic activity via RhoA/ROCK1/PTEN/PI3K/Akt pathway-mediated mitochondrial translocation of cofilin

Zheng

Ouyang

et al. 2018

Cell Death Dis

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“…Such screens coupled with next generation sequencing (NGS)-based readout can also inform on mutagenic outcomes of metabolic compounds/inhibitors. These chemical libraries can be designed based on available databases inventorying drugs, metabolites, and toxic compounds [202][203][204], or based on computer-aided molecular design [205,206]. Overview of currently available high-throughput technologies and approaches to discover new crosstalk between metabolism and the DNA damage response (DDR).…”

Section: Outlook: Approaches To Identify Interactions Between Metabolmentioning

confidence: 99%

“…Such screens coupled with next generation sequencing (NGS)-based readout can also inform on mutagenic outcomes of metabolic compounds/inhibitors. These chemical libraries can be designed based on available databases inventorying drugs, metabolites, and toxic compounds [ 202 , 203 , 204 ], or based on computer-aided molecular design [ 205 , 206 ].…”

Section: Outlook: Approaches To Identify Interactions Between Metamentioning

confidence: 99%

Interplay between Cellular Metabolism and the DNA Damage Response in Cancer

Moretton

Loizou

2020

Cancers

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Metabolism is a fundamental cellular process that can become harmful for cells by leading to DNA damage, for instance by an increase in oxidative stress or through the generation of toxic byproducts. To deal with such insults, cells have evolved sophisticated DNA damage response (DDR) pathways that allow for the maintenance of genome integrity. Recent years have seen remarkable progress in our understanding of the diverse DDR mechanisms, and, through such work, it has emerged that cellular metabolic regulation not only generates DNA damage but also impacts on DNA repair. Cancer cells show an alteration of the DDR coupled with modifications in cellular metabolism, further emphasizing links between these two fundamental processes. Taken together, these compelling findings indicate that metabolic enzymes and metabolites represent a key group of factors within the DDR. Here, we will compile the current knowledge on the dynamic interplay between metabolic factors and the DDR, with a specific focus on cancer. We will also discuss how recently developed high-throughput technologies allow for the identification of novel crosstalk between the DDR and metabolism, which is of crucial importance to better design efficient cancer treatments.

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“…Also, 2‐( N ‐substituted‐amino)[1,3,4]thiadiazole derivatives, incorporating sulfonamide group, have been endowed with diverse pharmacological properties such as carbonic anhydrase inhibitors (antiglaucoma drugs), antiparasitic agents, and acetazolamide (antiepileptic drugs). Given these precedents and as a part of our research interest towards developing new routes for the synthesis of a variety of novel heterocyclic systems with promising biological and pharmacological activities . ] We herein report a facile synthesis of a new series of hydrazonothiazoles and hydrazono‐[1,3,4]thiadiazoles ] as privileged scaffolds incorporating sulfonamide group with different substituent of various environments to be screened for their antimicrobial, anticancer, and DHFR activities.…”

Section: Introductionmentioning

confidence: 99%

“…Given these precedents and as a part of our research interest towards developing new routes for the synthesis of a variety of novel heterocyclic systems with promising biological and pharmacological activities. [15] [16] We herein report a facile synthesis of a new series of hydrazonothiazoles [17] and hydrazono- [1,3,4]thiadiazoles [17] [18] as privileged scaffolds incorporating sulfonamide group with different substituent of various environments to be screened for their antimicrobial, anticancer, and DHFR activities.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Biological Evaluation, and Molecular Docking of Novel Thiazoles and [1,3,4]Thiadiazoles Incorporating Sulfonamide Group as DHFR Inhibitors

Riyadh

El-Motairi

Ahmed

et al. 2018

Chemistry & Biodiversity

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2-(1-{4-[(4-Methylphenyl)sulfonamido]phenyl}ethylidene)thiosemicarbazide (3) was exploited as a starting material for the synthesis of two novel series of 5-arylazo-2-hydrazonothiazoles 6a - 6j and 2-hydrazono[1,3,4]thiadiazoles 10a - 10d, incorporating sulfonamide group, through its reactions with appropriate hydrazonoyl halides. The structures of the newly synthesized products were confirmed by spectral and elemental analyses. Also, the antimicrobial, anticancer, and DHFR inhibition potency for two series of thiazoles and [1,3,4]thiadiazoles were evaluated and explained by molecular docking studies and SAR analysis.

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Rational design, synthesis, pharmacophore modeling, and docking studies for identification of novel potent DNA-PK inhibitors

Cited by 28 publications

References 28 publications

The cyclohexene derivative MC-3129 exhibits antileukemic activity via RhoA/ROCK1/PTEN/PI3K/Akt pathway-mediated mitochondrial translocation of cofilin

The cyclohexene derivative MC-3129 exhibits antileukemic activity via RhoA/ROCK1/PTEN/PI3K/Akt pathway-mediated mitochondrial translocation of cofilin

Interplay between Cellular Metabolism and the DNA Damage Response in Cancer

Synthesis, Biological Evaluation, and Molecular Docking of Novel Thiazoles and [1,3,4]Thiadiazoles Incorporating Sulfonamide Group as DHFR Inhibitors

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