Vascular endothelial cell proliferation and angiogenesis are all crucially impacted by Endothelial Growth Factor Receptor-2 (VEGFR-2). Its expression is significantly boosted throughout pathologic ...angiogenesis causing the development of tumors. Sothat, inhibition of VEGFR-2 has crucial role in cancer treatment. In this study, novel semisynthetic theobromine derivatives were rationally designed as VEGFR-2 inhibitors and subjected to in vitro testing for their ability to block VEGFR-2 activation. Furthermore, the antiproliferative effects of these derivatives were evaluated. Compound 7 g exhibited the most potent anti-VEGFR-2 activity, with an IC
50
value of 0.072 µM, and demonstrated excellent dose-dependent inhibitory activity against both MCF-7 and HepG2 cancer cells with IC
50
values of 19.35 and 27.89 µM, respectively. Notably, compound 7 g exhibited high selectivity indices of 2.6 and 1.8 against MCF-7 and HepG2 cells, respectively. Compound 7 g induced G2/M phase cell cycle arrest, promoted apoptosis, and boosted immunomodulation by downregulating TNF-α expression and upregulating IL-2 levels in MCF-7 cells. The molecular docking analysis revealed that compound 7 g could bind effectively to the active site of VEGFR-2, and molecular dynamic simulations confirmed the stability of the VEGFR-2/compound 7 g complex. Furthermore, ADME and toxicity profiling indicated the potential suitability of these compounds as drug candidates. In summary, compound 7 g hold promise as a VEGFR-2 inhibitor.
Communicated by Ramaswamy H. Sarma
A new compound, C
23
H
20
BrN
3
OS, containing a quinoline-based iminothiazoline with a thiazoline ring, was synthesized and its crystal and molecular structures were analyzed through single crystal ...X-ray analysis. The compound belongs to the triclinic system
P
− 1 space group, with dimensions of a = 9.2304 (6) Å, b = 11.1780 (8) Å, c = 11.3006 (6) Å, α = 107.146 (5)°, β = 93.701 (5)°, γ = 110.435 (6)°, Z = 2 and V = 1025.61 (12) Å
3
. The crystal structure showed that C–H···N and C–H···O hydrogen bond linkages, forming infinite double chains along the b-axis direction, and enclosing R
2
2
(14) and R
2
2
(16) ring motifs. The Hirshfeld surface analysis revealed that H…H (44.1%) and H…C/C…H (15.3%) interactions made the most significant contribution. The newly synthesized (Z)-4-bromo-N-(4-butyl-3 (quinolin-3-yl)thiazol-2(3H)-ylidene)benzamide, in comparison to oleanolic acid, exhibited more strong potential against elastase with an inhibition value of 1.21 µM. Additionally, the derivative was evaluated using molecular docking and molecular dynamics simulation studies, which showed that the quinoline based iminothiazoline derivative has the potential to be a novel inhibitor of elastase enzyme. Both theoretical and experimental findings suggested that this compound could have a number of biological activities.
The overexpression of the Epidermal Growth Factor Receptor (EGFR) marks it as a pivotal target in cancer treatment, with the aim of reducing its proliferation and inducing apoptosis. This study aimed ...at the CADD of a new apoptotic EGFR inhibitor. The natural alkaloid, theobromine, was used as a starting point to obtain a new semisynthetic (di-ortho-chloro acetamide) derivative (T-1-DOCA). Firstly, T-1-DOCA’s total electron density, energy gap, reactivity indices, and electrostatic surface potential were determined by DFT calculations, Then, molecular docking studies were carried out to predict the potential of T-1-DOCA against wild and mutant EGFR proteins. T-1-DOCA’s correct binding was further confirmed by molecular dynamics (MD) over 100 ns, MM-GPSA, and PLIP experiments. In vitro, T-1-DOCA showed noticeable efficacy compared to erlotinib by suppressing EGFRWT and EGFRT790M with IC50 values of 56.94 and 269.01 nM, respectively. T-1-DOCA inhibited also the proliferation of H1975 and HCT-116 malignant cell lines, exhibiting IC50 values of 14.12 and 23.39 µM, with selectivity indices of 6.8 and 4.1, respectively, indicating its anticancer potential and general safety. The apoptotic effects of T-1-DOCA were indicated by flow cytometric analysis and were further confirmed through its potential to increase the levels of BAX, Casp3, and Casp9, and decrease Bcl-2 levels. In conclusion, T-1-DOCA, a new apoptotic EGFR inhibitor, was designed and evaluated both computationally and experimentally. The results suggest that T-1-DOCA is a promising candidate for further development as an anti-cancer drug.
Aim: The aim of this study was to design and examine a novel epidermal growth factor receptor (EGFR) inhibitor with apoptotic properties by utilizing the essential structural characteristics of ...existing EGFR inhibitors as a foundation. Method: The study began with the natural alkaloid theobromine and developed a new semisynthetic derivative (T-1-PMPA). Computational ADMET assessments were conducted first to evaluate its anticipated safety and general drug-likeness. Deep density functional theory (DFT) computations were initially performed to validate the three-dimensional (3D) structure and reactivity of T-1-PMPA. Molecular docking against the EGFR proteins was conducted to investigate T-1-PMPA’s binding affinity and inhibitory potential. Additional molecular dynamics (MD) simulations over 200 ns along with MM-GPSA, PLIP, and principal component analysis of trajectories (PCAT) experiments were employed to verify the binding and inhibitory properties of T-1-PMPA. Afterward, T-1-PMPA was semisynthesized to validate the proposed design and in silico findings through several in vitro examinations. Results: DFT studies indicated T-1-PMPA’s reactivity using electrostatic potential, global reactive indices, and total density of states. Molecular docking, MD simulations, MM-GPSA, PLIP, and ED suggested the binding and inhibitory properties of T-1-PMPA against the EGFR protein. The in silico ADMET predicted T-1-PMPA’s safety and general drug-likeness. In vitro experiments demonstrated that T-1-PMPA effectively inhibited EGFRWT and EGFR790m, with IC50 values of 86 and 561 nM, respectively, compared to Erlotinib (31 and 456 nM). T-1-PMPA also showed significant suppression of the proliferation of HepG2 and MCF7 malignant cell lines, with IC50 values of 3.51 and 4.13 μM, respectively. The selectivity indices against the two cancer cell lines indicated the overall safety of T-1-PMPA. Flow cytometry confirmed the apoptotic effects of T-1-PMPA by increasing the total percentage of apoptosis to 42% compared to 31, and 3% in Erlotinib-treated and control cells, respectively. The qRT-PCR analysis further supported the apoptotic effects by revealing significant increases in the levels of Casp3 and Casp9. Additionally, T-1-PMPA controlled the levels of TNFα and IL2 by 74 and 50%, comparing Erlotinib’s values (84 and 74%), respectively. Conclusion: In conclusion, our study’s findings suggest the potential of T-1-PMPA as a promising apoptotic anticancer lead compound targeting the EGFR.
EGFR has been considered a vital molecular target in cancer management.
The discovery of new thieno2,3-
pyrimidine derivatives as EGFR tyrosine kinase inhibitors.
Nine derivatives were designed, ...synthesized and subjected to
and
studies.
Compound
significantly inhibited the growth of HepG2 and PC3 cells for both EGFR wild-type and EGFR
. Compound
caused a significant apoptotic effect, arresting HepG2 cells' growth in the S and G2/M phases. Docking and molecular dynamics simulation studies confirmed the correct and stable binding modes of the synthesized compounds against the active sites.
Compound
is a promising dual EGFR inhibitor for cancer treatment.
In this study, new thieno2,3-dpyrimidine derivatives that could have potential anticancer activity by inhibiting the VEGFR-2 receptor have been designed, synthesized, and investigated. The ...thieno2,3-dpyrimidine derivatives showed strong in vitro abilities to inhibit VEGFR-2 and to prevent cancer cell growth in two different types of cancer cells, MCF-7 and HepG2. Particularly, compound 22 showed the most potent anti-VEGFR-2 activity with an IC50 value of 0.58 µM. Additionally, compound 22 exhibited good anti-proliferative activity against both MCF-7 and HepG2 cancer cell lines, with IC50 values of 11.32 ± 0.32 and 16.66 ± 1.22 µM, respectively. Further investigations revealed that compound 22 induced cell cycle arrest at the G2/M phase and promoted both early and late apoptosis in the MCF-7 cancer cells. Compound 22 also increased the level of BAX (2.8-fold), and reduced the level of Bcl-2 (2.2-fold), hence increasing the rate of apoptosis. Compound 22 also revealed 2.9-fold and 2.8-fold higher levels of caspase-8 and caspase-9, respectively, in the treated MCF-7 cancer cells compared to the control cell lines. The MD simulations showed that the VEGFR-2-22 complex was structurally and energytically stable over 100 ns, while the MM-GBSA study indicated its stable thermodynamic behavior. The bi-dimensional projection analysis confirmed the proper binding of the VEGFR-2-22 complex, while the DFT studies provided optimized geometry, charge distribution, FMO, ESP, the total density of state, and QTAIM maps of compound 22. Finally, computational ADMET studies were performed to assess the drug development potential of the thieno2,3-dpyrimidine derivatives. Overall, this study suggests that compound 22 has the potential as an anticancer lead compound by inhibiting VEGFR-2, which may be a guide for future drug design and development.
Display omitted
•A new series of thieno2,3-dpyrimidine derivatives has been designed and synthesized as VEGFR-2 inhibitors.•VEGFR-2 inhibitory activity and cytotoxic effect were assessed.•The effect on cell cycle and apoptosis was determined.•The effect of the most active compound against caspase-8, caspase-9, Bax, BcL2, TNF-α and IL-2 was assessed.•In silico docking, MD simulation, ADMET, and toxicity studies were carried out.
The encapsulation of the famous alkaloid, anabasine, with β-CD was studied to obtain a more stable and bioavailable inclusion complex. Various in silico and experimental studies of the obtained ...β-CD-anabasine complex are presented. Firstly, molecular docking studies were conducted against the α, β, and γ cyclodextrins to explore which subclass is the best for encapsulation. The obtained results that pointed at β-cyclodextrin were further confirmed by five MD simulations and MM-PBSA studies. Experimentally, the spectral properties of the anabasine β-cyclodextrin complex were determined by FT-IR, 1H, and 13C-NMR spectroscopic methods. Additionally, the surface morphology of the anabasine β-cyclodextrin was investigated using a scanning electron microscope. Furthermore, the outputs of the thermographic measurements utilizing a differential scanning calorimeter were displayed. The activation energy of the reaction of thermo-oxidative destruction of the clathrate complex was calculated, and the kinetic parameters of the thermal destruction processes were decided using the Freeman–Carroll, Sharpe–Wentworth, Achar, and Coates–Redfern methods. The kinetic parameters of the thermal decomposition of the anabasine β-cyclodextrin were in agreement and verified the reliability of the obtained results. The obtained computational, spectral, morphological, and thermogravimetric results verified the successful formation of the anabasine β-cyclodextrin complex.
This study was carried out to identify the synthesis of a new group of thiazole-linked thioureas with aromatic and aliphatic side chains (
4a
–
k
) using a one-pot three-component strategy which are ...well known for their material and medicinal properties. Using all the standard protocols, the synthesized compounds were assessed for alkaline phosphatase (AP) assay.
1
H and
13
C NMR were utilized for identification of the chemical structures of all the synthesized compounds. The density functional theory (DFT) studies and molecular docking studies of synthesized derivatives were carried out to understand the reactivity profile and binding behavior of all the compounds. The outcome of this study suggests that the synthesized compounds are potent alkaline phosphatase inhibitors whereas
4c
and
4g
are best compounds with lowest IC
50
value i.e., 0.057 and 0.019 µM, respectively. The docking energies of
4c
and
4g
are highest among all the compounds i.e., −32.18 and −30.09 kJ/mol, respectively. The results suggested that these derivatives can be utilized in future for the synthesis of more potent inhibitors of alkaline phosphatase that can be used in future for treating different types of cancer especially breast cancer.
Graphical abstract
The current study included density function theory calculations, molecular docking studies, SeeSAR analysis, molecular dynamics studies and assessments of the absorption, distribution, metabolism, ...excretion and toxicity properties (ADMET) of N-(4-acetyl-4,5-dihydro-5-(7,8,9-substituted-tetrazolo1,5-a acetamides of -quinolin-4-yl)-1,3,4-thiadiazol-2-yl) that is 4a-j. These derivatives have previously been identified as anticancer agents against a human cervical cancer cell line. The primary goal of this work is to assess the potential of these derivatives as caspase-3 inhibitors using extensive computational analysis. The binding interactions of these compounds with caspase-3 protein (PDB ID: 4JJ8) were found and all compounds demonstrated strong binding interactions within the active pocket of the targeted protein. Interestingly, derivative 4e showed maximum potential and was found to have the strongest interactions with a binding energy of −29.6 kJ/mol. Furthermore, the findings were discovered to be in comparison with the reference drug, adriamycin (−26.5 kJ/mol). In addition to molecular docking, ADMET and simulation studies were carried out to determine their safety profiles, with the results correlating to molecular docking investigations. Finally, SeeSAR analysis and molecular dynamics simulation investigations were carried out. In conclusion, this molecule may be a “lead candidate’ for making a more powerful caspase-3 inhibitor that can be used in tumors where the levels of caspase-3 are aberrantly high.
