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Synthesis, DFT Analyses, Antiproliferative Activity, and Molecular Docking Studies of Curcumin Analogues
Mohamed Jawed Ahsan1, Kavita Choudhary1, Amena Ali2
1Department of Pharmaceutical Chemistry, Maharishi Arvind College of Pharmacy, Jaipur 302 039, Rajasthan, India.
Abstract:
With 19.3 million new cases and almost 10 million deaths in 2020, cancer has become a leading cause of death today. Curcumin and its analogues were found to have promising anticancer activity. Inspired by curcumin’s promising anticancer activity, we prepared three semi-synthetic analogues by chemically modifying the diketone function of curcumin to its pyrazole counterpart. The curcumin analogues (3a−c) were synthesized by two different methods, followed by their DFT analyses to study the HOMO/LUMO configuration to access the stability of compounds (∆E = 3.55 to 3.35 eV). The curcumin analogues (3a−c) were tested for antiproliferative activity against a total of five dozen cancer cell lines in a single (10 µM) and five dose (0.001 to 100 µM) assays. 3,5-Bis(4-hydroxy-3-methoxystyryl)-1H-pyrazole-1-yl-(phenoxy)ethanone (3b) and 3,5-bis(4-hydroxy-3-methoxystyryl)-1H-pyrazole-1-yl-(2,4-dichlorophenoxy)ethanone (3c) demonstrated the most promising antiproliferative activity against the cancer cell lines with growth inhibitions of 92.41% and 87.28%, respectively, in a high single dose of 10 µM and exhibited good antiproliferative activity (%GIs > 68%) against 54 out of 56 cancer cell lines and 54 out of 60 cell lines, respectively. The compound 3b and 3c demonstrated the most potent antiproliferative activity in a 5-dose assay with GI50 values ranging between 0.281 and 5.59 µM and 0.39 and 0.196 and 3.07 µM, respectively. The compound 3b demonstrated moderate selectivity against a leukemia panel with a selectivity ratio of 4.59. The HOMO-LUMO energy-gap (∆E) of the compounds in the order of 3a > 3b > 3c, was found to be in harmony with the anticancer activity in the order of 3c ≥ 3b > 3a. Following that, all of the curcumin analogues were molecular docked against EGFR, one of the most appealing targets for antiproliferative activity. In a molecular docking simulation, the ligand 3b exhibited three different types of interactions: H-bond, π-π-stacking and π-cationic. The ligand 3b displayed three H-bonds with the residues Met793 (with methoxy group), Lys875 (with phenolic group) and Asp855 (with methoxy group). The π-π-stacking interaction was observed between the phenyl (of phenoxy) and the residue Phe997, while π-cationic interaction was displayed between the phenyl (of curcumin) and the residue Arg841. Similarly, the ligand 3c displayed five H-bonds with the residue Met793 (with methoxy and phenolic groups), Lys845 (methoxy group), Cys797 (phenoxy oxygen), and Asp855 (phenolic group), as well as a halogen bond with residue Cys797 (chloro group). Furthermore, all the compound 3a−c demonstrated significant binding affinity (−6.003 to −7.957 kcal/mol) against the active site of EGFR. The curcumin analogues described in the current work might offer beneficial therapeutic intervention for the treatment and prevention of cancer. Future anticancer drug discovery programs can be expedited by further modifying these analogues to create new compounds with powerful anticancer potentials.
Insights
Researchers developed novel curcumin analogues with significant anticancer properties. These compounds show potent antiproliferative activity against various cancer cell lines and favorable interactions with the EGFR target, suggesting potential for cancer therapy.
Area of Science:
- Medicinal Chemistry
- Organic Synthesis
- Computational Chemistry
Background:
- Cancer is a leading cause of death globally, necessitating novel therapeutic strategies.
- Curcumin and its derivatives have demonstrated promising anticancer activities.
- Semi-synthetic analogues of curcumin were explored to enhance anticancer potential.
Purpose of the Study:
- To synthesize and characterize novel curcumin analogues with a pyrazole core.
- To evaluate the antiproliferative activity of these analogues against a broad spectrum of cancer cell lines.
- To investigate the binding interactions of these analogues with the Epidermal Growth Factor Receptor (EGFR) through molecular docking.
Main Methods:
- Chemical synthesis of three curcumin analogues (3a-c) by modifying the diketone function to a pyrazole.
- Density Functional Theory (DFT) analysis for HOMO/LUMO configuration and stability assessment.
- In vitro antiproliferative assays against multiple cancer cell lines at single and multiple doses.
- Molecular docking simulations against the EGFR active site.
Main Results:
- Compounds 3b and 3c exhibited significant antiproliferative activity, with growth inhibitions of 92.41% and 87.28% at 10 µM, respectively.
- Compounds 3b and 3c showed potent activity across 54/56 and 54/60 cancer cell lines, respectively, with GI50 values in the low micromolar range.
- Molecular docking revealed favorable binding interactions of analogues 3b and 3c with EGFR, including hydrogen bonds, π-π stacking, and halogen bonds, with binding affinities ranging from -6.003 to -7.957 kcal/mol.
Conclusions:
- The synthesized curcumin analogues, particularly 3b and 3c, possess potent antiproliferative activity against a wide range of cancer cell lines.
- The observed anticancer activity correlates with the calculated HOMO-LUMO energy gaps and favorable binding interactions with EGFR.
- These novel analogues represent promising candidates for further development as therapeutic agents in cancer treatment and prevention.
