Designing strategies, structural activity relationship and biological activity of recently developed nitrogen containing heterocyclic compounds as epidermal growth factor receptor tyrosinase inhibitors

Pal, Rohit; Teli, Ghanshyam; Matada, Gurubasavaraja Swamy Purawarga; Dhiwar, Prasad Sanjay

doi:10.1016/j.molstruc.2023.136021

Cited by 17 publications

(6 citation statements)

References 137 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A variety of quinazolines have been discovered in recent years to inhibit EGFR [15]. It is suggested that the 4-anilinoquinazoline scaffold interacts with ATP at the EGFR binding site [16]. Gefitinib (1) and erlotinib (2), the first-generation EGFR inhibitors, have received FDA approval for the treatment of non-small cell lung cancer (NSCLC) [17].…”

Section: Epidermal Growth Factor Receptor (Egfr) Inhibitorsmentioning

confidence: 99%

Recent Advances in Structural Optimization of Quinazoline-Based Protein Kinase Inhibitors for Cancer Therapy (2021–Present)

Abdel-Mohsen,

Anwar,

Ahmed

et al. 2024

Molecules

View full text Add to dashboard Cite

Cancer is a complicated, multifaceted disease that can impact any organ in the body. Various chemotherapeutic agents have a low selectivity and are very toxic when used alone or in combination with others. Resistance is one of the most important hurdles that develop due to the use of many anticancer therapeutics. As a result, treating cancer requires a target-specific palliative care strategy. Remarkable scientific discoveries have shed light on several of the molecular mechanisms underlying cancer, resulting in the development of various targeted anticancer agents. One of the most important heterocyclic motifs is quinazoline, which has a wide range of biological uses and chemical reactivities. Newer, more sophisticated medications with quinazoline structures have been found in the last few years, and great strides have been made in creating effective protocols for building these pharmacologically active scaffolds. A new class of chemotherapeutic agents known as quinazoline-based derivatives possessing anticancer properties consists of several well-known compounds that block different protein kinases and other molecular targets. This review highlights recent updates (2021–2024) on various quinazoline-based derivatives acting against different protein kinases as anticancer chemotherapeutics. It also provides guidance for the design and synthesis of novel quinazoline analogues that could serve as lead compounds.

show abstract

Section: Epidermal Growth Factor Receptor (Egfr) Inhibitorsmentioning

confidence: 99%

Recent Advances in Structural Optimization of Quinazoline-Based Protein Kinase Inhibitors for Cancer Therapy (2021–Present)

Abdel-Mohsen,

Anwar,

Ahmed

et al. 2024

Molecules

View full text Add to dashboard Cite

show abstract

“… 11 Moreover, in recent years, N-heterocyclic derivatives have been exposed as potential EGFR inhibitors and specifically target the mutated tyrosine kinase domain of EGFR. 12 In this study, leveraging the distinctive characteristics of spiro-class heterocyclic molecules, we have aimed to assess the apoptotic and antiproliferative activities of these spiro-pyrrolopyridazine derivatives (SPPs). By focusing on EGFR, a pivotal protein in cancer progression, our research aims to contribute insights into the development of targeted cancer therapies, addressing the limitations associated with current treatments including drug resistance and adverse effects on normal cells.…”

Section: Introductionmentioning

confidence: 99%

“… Notably, β-enaminones are also valuable building blocks and pharmacophores in drug development . Moreover, in recent years, N-heterocyclic derivatives have been exposed as potential EGFR inhibitors and specifically target the mutated tyrosine kinase domain of EGFR . In this study, leveraging the distinctive characteristics of spiro-class heterocyclic molecules, we have aimed to assess the apoptotic and antiproliferative activities of these spiro-pyrrolopyridazine derivatives (SPPs).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Novel Spiro-pyrrolopyridazine Derivatives as Anticancer Compounds: In Vitro Selective Cytotoxicity, Induction of Apoptosis, EGFR Inhibitory Activity, and Molecular Docking Analysis

Atmaca,

Ilhan,

Çamli Pulat

et al. 2024

ACS Omega

View full text Add to dashboard Cite

Cancer, characterized by uncontrolled cell proliferation, remains a global health challenge. Despite advancements in cancer treatment, drug resistance and adverse effects on normal cells remain challenging. The epidermal growth factor receptor (EGFR), a transmembrane tyrosine kinase protein, is crucial in controlling cell proliferation and is implicated in various cancers. Here, the cytotoxic and apoptotic potential of 21 newly synthesized spiro-pyrrolopyridazine (SPP) derivatives was investigated on breast (MCF-7), lung (H69AR), and prostate (PC-3) cancer cells. XTT assay was used for cytotoxicity assessment. Flow cytometry and western blot (WB) analyses were conducted for apoptosis detection. Additionally, the EGFR inhibitory potential of these derivatives was evaluated via a homogeneous timeresolved fluorescence (HTRF) assay, and WB and molecular docking studies were conducted to analyze the binding affinities of SPP10 with EGFR. SPPs, especially SPP10, exhibit significant cytotoxicity across MCF-7, H69AR, and PC-3 cancer cells with IC 50 values of 2.31 ± 0.3, 3.16 ± 0.8, and 4.2 ± 0.2 μM, respectively. Notably, SPP10 demonstrates selective cytotoxicity against cancer cells with a low impact on nontumorigenic cells (IC 50 value: 26.8 ± 0.4 μM). Flow cytometric analysis demonstrated the potent induction of apoptotic cell death by SPP10 in all of the tested cancer cells. Western blot analysis revealed the involvement of key apoptotic proteins, with SPP10 notably inhibiting antiapoptotic Bcl-2 while inducing pro-apoptotic Bax and cytochrome c. SPP10 exhibited significant EGFR kinase inhibitory activity, surpassing the efficacy of the reference drug erlotinib. Molecular docking studies support these findings, revealing strong binding affinities of SPP10 with both wild-type and mutated EGFR. The study underscores the significance of heterocyclic compounds, particularly spiro-class heterocyclic molecules, in advancing cancer research. Overall, SPP10 emerges as a promising candidate for further investigations in cancer treatment, combining potent cytotoxicity, apoptotic induction, and targeted EGFR inhibition.

show abstract

“…[14] Pyrazole represents one of the essential nitrogen-containing heterocycle, featured predominantly in numerous FDA-approved drugs (Figure 1) such as Avapritinib, Asciminib, Crizotinib, Darolutamide, Encorafenib, Erdafitinib, Pralsetinib, Pirtobrutinib, Pyrazofurin, and Ruxolitinib. [15] Pyrazole derivatives have become key pharmacophores in targeting various signaling molecules and transcriptional factors within the cancer pathway, [16] such as ER-α, [17,18] aromatase, Epidermal Growth Factor Receptor (EGFR), [19,20] and HER-2. [21] Studies by S. R. Stauffer et al have extensively explored pyrazole core substitutions to identify an optimized core, propyl-pyrazole triol (PPT), for high-affinity ER binding.…”

Section: Introductionmentioning

confidence: 99%

“…(Scheme 1) General synthesis of compound 8 a-n. Chemicals and conditions: (i) ethanol, acetic acid, warm, 1-4 h (ii) POCl 3 & DMF at 0 °C, 2-5 h, and neutralized through K 2 CO 3 ; (iii) K 2 CO 3 , Acetone, 0 °C -r.t., 4-5 h; (iv) aq.40 % NaOH & ethanol, r.t.,[12][13][14][15][16][17][18][19][20][21][22][23][24]…”

mentioning

confidence: 99%

Novel Pyrazole‐Chalcone Hybrids: Synthesis and Computational Insights Against Breast Cancer

Dabhade,

Rathod

et al. 2024

Chemistry & Biodiversity

View full text Add to dashboard Cite

More women die of breast cancer than of any other malignancy. The resistance and toxicity of traditional hormone therapy created an urgent need for potential molecules for treating breast cancer effectively. Novel biphenyl‐substituted pyrazole chalcones linked to a pyrrolidine ring were designed by using a hybridization approach. The hybrids were assessed against MCF‐7 and MDA‐MB‐231 cells by NRU assay. Among them, 8k, 8d, 8m, 8h, and 8f showed significantly potent IC50 values: 0.17, 5.48, 8.13, 20.51, and 23.61 µM) respectively, on MCF‐7 cells compared to the positive control Raloxifene and Tamoxifen. Furthermore, most active compound 8k [3‐(3‐(4‐fluorophenyl)‐1‐phenyl‐1H‐pyrazol‐4‐yl)‐1‐(2‐(2‐(pyrrolidin‐1‐yl)‐ethoxy)‐phenyl)‐chalcone] showed cell death induced through apoptosis, cell cycle arrest at the G2/M phase, and demonstrated decrease of ER‐α protein in western blotting study. Docking studies of 8k and 8d established adequate interactions with estrogen receptor‐α as required for SERM binding. The active hybrids exhibited good pharmacokinetic properties for oral bioavailability and drug‐likeness. Whereas, RMSD, RMSF, and Rg values from Molecular dynamics studies stipulated stability of the complex formed between compound 8k and receptor. All of these findings strongly indicate the antiproliferative potential of pyrazole‐chalcone hybrids for the treatment of breast cancer.

show abstract

Designing strategies, structural activity relationship and biological activity of recently developed nitrogen containing heterocyclic compounds as epidermal growth factor receptor tyrosinase inhibitors

Cited by 17 publications

References 137 publications

Recent Advances in Structural Optimization of Quinazoline-Based Protein Kinase Inhibitors for Cancer Therapy (2021–Present)

Recent Advances in Structural Optimization of Quinazoline-Based Protein Kinase Inhibitors for Cancer Therapy (2021–Present)

Evaluation of Novel Spiro-pyrrolopyridazine Derivatives as Anticancer Compounds: In Vitro Selective Cytotoxicity, Induction of Apoptosis, EGFR Inhibitory Activity, and Molecular Docking Analysis

Novel Pyrazole‐Chalcone Hybrids: Synthesis and Computational Insights Against Breast Cancer

Contact Info

Product

Resources

About