Molecular docking, DFT and antiproliferative properties of 4‐(3,4‐dimethoxyphenyl)−3‐(4‐methoxyphenyl)−1‐phenyl‐1H‐pyrazolo[3,4‐b]pyridine as potent anticancer agent with CDK2 and PIM1 inhibition potency DOI

Faizah A. Binjubair,

Basma S. Almansour,

Noha I. Ziedan

et al.

Drug Development Research, Journal Year: 2024, Volume and Issue: 85(7)

Published: Oct. 28, 2024

Abstract Due to the limited effeteness and safety concerns associated with current cancer treatments, there is a pressing need develop novel therapeutic agents. 4‐(3,4‐Dimethoxyphenyl)−3‐(4‐methoxyphenyl)−1‐phenyl‐1 H ‐pyrazolo[3,4‐ b ]pyridine ( 3 ) was synthesized Initially screened on 59 cell lines showed promising anticancer activity, so, it chosen for 5‐dose experiment by NCI/USA. The GI 50 values ranged from 1.04 8.02 μM entire nine panels (57 lines), of 2.70 (MG‐MID) panel, indicating an encouraging action. To further explore molecular attributes compound , we optimized its structure using DFT B3LYP/6‐31 + G(d,p) basis set. We have considered vibrational analysis, bond lengths angles, FMOs, MEP structure. Additionally, pharmacokinetic assessments were conducted various in‐silico platforms evaluate safety. A modeling study created kinase profile 44 different kinases. This allowed us our compound's binding affinity these kinases compare co‐crystallized one. Our findings revealed exhibited better half tested kinases, suggesting potential as multi‐kinase inhibitor. validate computational results, inhibitory effects CDK2 PIM1. Compound IC 0.30 µM inhibition, making five times less active than Roscovitine, which has 0.06 µM. However, demonstrated slightly inhibition PIM1 compared Staurosporine. These suggest that agent development into highly compound.

Language: Английский

Development of 1,2,3-triazole hybrids as multi-faced anticancer agents co-targeting EGFR/mTOR pathway and tubulin depolymerization DOI
Mennatallah A. Shaheen, Khaled M. Darwish, Safaa M. Kishk

et al.

Bioorganic Chemistry, Journal Year: 2025, Volume and Issue: 156, P. 108153 - 108153

Published: Jan. 11, 2025

Language: Английский

Citations

2
Discovery of 1-phenyl-1,2,3-triazole ureas as dual VEGFR-2/JNK-1 type II kinase inhibitors targeting pancreatic cancer DOI
Wagdy M. Eldehna, Eslam Roshdy,

Maha-Hamadien Abdulla

et al.

International Journal of Biological Macromolecules, Journal Year: 2025, Volume and Issue: unknown, P. 142372 - 142372

Published: March 1, 2025

Language: Английский

Citations

0
Development of indole hybrids for potential lung cancer treatment-part I: nitrogen-containing six-membered aromatic heterocycles DOI

Shijia Zhao,

Zhi Xu

Future Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 17

Published: March 29, 2025

Lung cancer is the most prevalent invasive malignancy and leading cause of cancer-related death. Chemotherapy vital for lung therapy, but multidrug resistance responsible majority fatalities, creating an imperative demand to develop novel chemotherapeutics. Indole a valuable anti-lung pharmacophore since its derivatives could act on cells through various mechanisms. Notably, indole hybrids inhibit multiple targets simultaneously have potential overcome shortcomings traditional Moreover, many such as indole-pyrimidine hybrid osimertinib indole-hydroxamic acid panobinostat, are either under clinical evaluations or already been approved therapy. This indicates that rational design represents highly prospective approach development new chemotherapeutic agents. review focuses exploring therapeutic delves into their action mechanisms well structure-activity correlations, covering articles published between 2021 present. The ultimate goal offer foundation in future.

Language: Английский

Citations

0
Design, synthesis, and molecular dynamics-driven evaluation of quinoline-sulfonamide derivatives as potent and selective EGFR inhibitors with promising anti-cancer efficacy and safety profiles DOI
Mahmoud S. Elkotamy, Mohamed K. Elgohary,

Islam A. Elkelesh

et al.

Bioorganic Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 108247 - 108247

Published: Feb. 1, 2025

Language: Английский

Citations

0
Design, synthesis and biological evaluation of pyrazolo[3,4- b ]pyridine derivatives as dual CDK2/PIM1 inhibitors with potent anti-cancer activity and selectivity DOI
Mahmoud S. Elkotamy, Mohamed K. Elgohary, Mahmoud Abdelrahman Alkabbani

et al.

Journal of Biomolecular Structure and Dynamics, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 25

Published: March 13, 2025

The discovery of novel, selective inhibitors targeting CDK2 and PIM1 kinases, which regulate cell survival, proliferation, treatment resistance, is crucial for advancing cancer therapy. This study reports the design, synthesis, biological evaluation three novel pyrazolo[3,4-b]pyridine derivatives (6a-c), confirmed via spectral analyses. These compounds were assessed anti-cancer activity against breast, colon, liver, cervical cancers using MTT assay. Among tested compounds, 6b exhibited superior efficacy, with higher selectivity indices HCT-116 (15.05) HepG2 (9.88) compared to reference drug staurosporine. Mechanistic studies revealed that induced apoptosis (63.04-fold increase) arrested cycle at G0-G1 phase, highlighting its anti-proliferative effects. In an in-vivo solid Ehrlich carcinoma (SEC) mouse model, compound significantly reduced tumor weight volume, exceeding efficacy doxorubicin. Additionally, potently inhibited kinases (IC50: 0.27 0.67 µM, respectively) tumor-promoting TNF-alpha expression, as by histopathological immunohistochemical studies. Computational analyses, including molecular docking, dynamics simulations, DFT calculations, provided insights into binding stability interaction mechanisms PIM1, while in-silico pharmacokinetic toxicity evaluations favorable drug-like profile safety. highlights a promising dual CDK2/PIM1 inhibitor potent selectivity, paving way further optimization development lead molecule in

Language: Английский

Citations

0
Molecular docking, DFT and antiproliferative properties of 4‐(3,4‐dimethoxyphenyl)−3‐(4‐methoxyphenyl)−1‐phenyl‐1H‐pyrazolo[3,4‐b]pyridine as potent anticancer agent with CDK2 and PIM1 inhibition potency DOI

Faizah A. Binjubair,

Basma S. Almansour,

Noha I. Ziedan

et al.

Drug Development Research, Journal Year: 2024, Volume and Issue: 85(7)

Published: Oct. 28, 2024

Abstract Due to the limited effeteness and safety concerns associated with current cancer treatments, there is a pressing need develop novel therapeutic agents. 4‐(3,4‐Dimethoxyphenyl)−3‐(4‐methoxyphenyl)−1‐phenyl‐1 H ‐pyrazolo[3,4‐ b ]pyridine ( 3 ) was synthesized Initially screened on 59 cell lines showed promising anticancer activity, so, it chosen for 5‐dose experiment by NCI/USA. The GI 50 values ranged from 1.04 8.02 μM entire nine panels (57 lines), of 2.70 (MG‐MID) panel, indicating an encouraging action. To further explore molecular attributes compound , we optimized its structure using DFT B3LYP/6‐31 + G(d,p) basis set. We have considered vibrational analysis, bond lengths angles, FMOs, MEP structure. Additionally, pharmacokinetic assessments were conducted various in‐silico platforms evaluate safety. A modeling study created kinase profile 44 different kinases. This allowed us our compound's binding affinity these kinases compare co‐crystallized one. Our findings revealed exhibited better half tested kinases, suggesting potential as multi‐kinase inhibitor. validate computational results, inhibitory effects CDK2 PIM1. Compound IC 0.30 µM inhibition, making five times less active than Roscovitine, which has 0.06 µM. However, demonstrated slightly inhibition PIM1 compared Staurosporine. These suggest that agent development into highly compound.

Language: Английский

Citations

3