Natural product evodiamine-inspired medicinal chemistry: Anticancer activity, structural optimization and structure-activity relationship

European Journal of Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 247, P. 115031 - 115031

Published: Dec. 17, 2022

Language: Английский

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Evo312: An Evodiamine Analog and Novel PKCβI Inhibitor with Potent Antitumor Activity in Gemcitabine-Resistant Pancreatic Cancer

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(17), P. 14885 - 14911

Published: Aug. 16, 2024

As an obstinate cancer pancreatic (PC) poses a major challenge due to limited treatment options which include resection surgery, radiation therapy, and gemcitabine-based chemotherapy. In cells, protein kinase C βI (PKCβI) participates in diverse cellular processes, including cell proliferation, invasion, apoptotic pathways. the present study, we created scaffold develop PKCβI inhibitors using evodiamine-based synthetic molecules. Among candidate inhibitors, Evo312 exhibited highest antiproliferative efficacy against PC PANC-1, acquired gemcitabine-resistant PANC-GR. Additionally, robustly inhibited activity. Mechanistically, effectively suppressed upregulation of expression, leading induction cycle arrest apoptosis PANC-GR cells. Furthermore, exerted antitumor activity cell-implanted xenograft mouse model. These findings position as promising lead compound for overcoming gemcitabine resistance through novel mechanisms.

Language: Английский

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Development of a new drug candidate for the inhibition of Lassa virus glycoprotein and nucleoprotein by modification of evodiamine as promising therapeutic agents

Frontiers in Microbiology, Journal Year: 2023, Volume and Issue: 14

Published: July 11, 2023

The Lassa virus (LASV), an RNA prevalent in West and Central Africa, causes severe hemorrhagic fever with a high fatality rate. However, no FDA-approved treatments or vaccines exist. Two crucial proteins, LASV glycoprotein nucleoprotein, play vital roles pathogenesis are potential therapeutic targets. As effective for many emerging infections remain elusive, cutting-edge drug development approaches essential, such as identifying molecular targets, screening lead molecules, repurposing existing drugs. Bioinformatics computational biology expedite discovery pipelines, using data science to identify predict structures, model interactions. These techniques also facilitate leads optimal drug-like properties, reducing time, cost, complexities associated traditional development. Researchers have employed advanced design methods docking, pharmacokinetics, drug-likeness, dynamics simulation investigate evodiamine derivatives inhibitors. results revealed remarkable binding affinities, outperforming standard compounds. Additionally, active suggest stability when bound target receptors. promising findings indicate that may offer superior pharmacokinetics drug-likeness serving valuable resource professionals developing synthetic drugs combat the virus.

Language: Английский

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N(14)-substituted evodiamine derivatives as dual topoisomerase 1/tubulin-Inhibiting anti-gastrointestinal tumor agents

European Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 255, P. 115366 - 115366

Published: April 20, 2023

Language: Английский

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Decoding the Role of MDM2 as a Potential Ubiquitin E3 Ligase and Identifying the Therapeutic Efficiency of Alkaloids against MDM2 in Combating Glioblastoma

ACS Omega, Journal Year: 2023, Volume and Issue: 8(5), P. 5072 - 5087

Published: Jan. 26, 2023

Glioblastomas (GBMs) represent the most aggressive form of brain tumor arising from malignant transformation astrocytes. Despite various advancements, treatment options remain limited to chemotherapy and radiotherapy followed by surgery giving an overall survival 14–15 months. These therapies are somewhere restricted in a better cure. There is need for new therapeutics that could potentially target GBM based on molecular pathways pathology. Here, ubiquitin E3 ligases can be used as targets they bind wide array substrates therefore attractive inhibitors. Through this study, we have tried sort their expression, which these associated, mutational frequencies, then screen potent inhibitors against favorable ligase very few studies available concerning inhibition GBM. Our study found MDM2 ideal further compounds under alkaloid class. Molecular Docking MD simulations combined with ADMET properties BBB scores revealed only evodiamine sanguinarine were effective inhibiting MDM2. We also give proposed mechanism how mediate p53 signaling Therefore, scaffolds predicted computational approach help designing promising therapeutic agents targeting glioblastoma.

Language: Английский

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An A-ring substituted evodiamine derivative with potent anticancer activity against human non-small cell lung cancer cells by targeting heat shock protein 70

Biochemical Pharmacology, Journal Year: 2023, Volume and Issue: 211, P. 115507 - 115507

Published: March 21, 2023

Language: Английский

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Evodiamine release from interlinked porous polycaprolactone scaffold for cancer therapy

Process Biochemistry, Journal Year: 2024, Volume and Issue: 140, P. 1 - 9

Published: Feb. 7, 2024

Language: Английский

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Evodiamine: A Extremely Potential Drug Development Candidate of Alkaloids from Evodia rutaecarpa

International Journal of Nanomedicine, Journal Year: 2024, Volume and Issue: Volume 19, P. 9843 - 9870

Published: Sept. 1, 2024

Evodiamine (EVO) is a tryptamine indole alkaloid and the main active ingredient in

Language: Английский

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Pharmacophore‐Based Modeling, Synthesis, and Biological Evaluation of Novel Quinazoline/Quinoline Derivatives: Discovery of EGFR Inhibitors with Low Nanomolar Activity

Advanced Theory and Simulations, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 18, 2024

Abstract The main aim of this study is to obtain novel molecules that are more selective on cancer cells compared healthy cells. For purpose, four hit identified using 11 new pharmacophore hypotheses followed by scanning the in‐house database. Then, based those molecules, synthesis and analysis different series (three quinazolines one quinoline series) carried out, their anticancer activity investigated. Finally, molecular docking dynamics simulation methods, binding mode structure–activity relationship examined. Among quinazolin‐4( 3H )‐one derivatives, containing halogen atom found be potentially effective, while best epidermal growth factor receptor (EGFR) inhibition apoptosis induction displayed compounds 4‐amino‐1,2,4‐triazole moiety. Notably, ( 4h, 8d, 8l, 8m ) show EGFR at 5.298 ± 0.164, 5.46 0.221, 2.670 0.124, 2.191 0.908 × 10 −9 m , inhibitory similar or stronger than gefitinib (IC 50 : 4.169 0.156 ). In addition, inhibitor concentration 4g, 8e, 8o determined as 27588 6.945, 52.41 2.312, 33657 8.512 . These findings indicate generated successfully determine inhibitors. conclusion, compounds, active with fewer side effects, reached, relationships clarified.

Language: Английский

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Synthesis and Biological Activities of 11‐ and 12‐Substituted Benzophenanthridinone Derivatives as DNA Topoisomerase IB and Tyrosyl‐DNA Phosphodiesterase 1 Inhibitors

ChemMedChem, Journal Year: 2023, Volume and Issue: 18(10)

Published: March 17, 2023

Abstract Herein, a series of 11‐ or 12‐substituted benzophenanthridinone derivatives was designed and synthesized for the discovery dual topoisomerase IB (TOP1) tyrosyl‐DNA phosphodiesterase 1 (TDP1) inhibitors. Enzyme‐based assays indicated that two compounds 12 38 showed high TOP1 inhibitory potency (+++), four 35, 37, 39 43 good TDP1 inhibition with IC 50 values ranging from 10 to 18 μM. could induce cellular TOP1cc formation, resulting in highest cytotoxicity against HCT‐116 cells (0.25 μM). The most potent inhibitor (10 μM) TDP1cc formation enhance topotecan‐induced DNA damage strong synergistic topotecan both MCF‐7 MCF‐7/TDP1 cells.

Language: Английский

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