New Isatin-Indole Conjugates: Synthesis, Characterization, and a Plausible Mechanism of Their in vitro
Reem I Al-Wabli1, Aliyah A Almomen1, Maha S Almutairi1
1Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
Background:
Cancer remains the leading cause of human morbidity universally. Hence, we sought to assess the in vitro antiproliferative activity of new isatin-based conjugates (5a-s) against three human cancer cell lines.
Methods:
The antiproliferative activities of compounds 5a-s were evaluated in vitro and their ADME (absorption, distribution, metabolism and excretion) was carried out using standard protocols. Subsequently, Western blot analysis was conducted to elucidate the potential antiproliferative mechanism of compounds 5a-s.
Results:
The in vitro antiproliferative activities of compounds 5a-s against the tested cancer cell lines ranged from 20.3 to 95.9%. Compound 5m had an IC50 value of 1.17 µM; thus, its antiproliferative potency was approximately seven-fold greater than that of sunitinib (IC50 = 8.11 µM). In-depth pharmacological testing was conducted with compound 5m to gain insight into the potential antiproliferative mechanism of this class of compounds. Compound 5m caused an increase in the number of cells in the G1 phase, with a concomitant reduction of those in the G2/M and S phases. Additionally, compound 5m significantly and dose-dependently reduced the amount of phosphorylated retinoblastoma protein detected. Compound 5m enhanced expression of B cell translocation gene 1, cell cycle-associated proteins (cyclin B1, cyclin D1, and phosphorylated cyclin-dependent kinase 1), and a pro-apoptotic protein (Bcl-2-associated X protein gene), and activated caspase-3. ADME predictions exposed the oral liability of compounds 5a-s.
Conclusion:
Herein, we revealed the antiproliferative activity and ADME predictions of the newly-synthesized compounds 5a-s and provided a detailed insight into the pharmacological profile of compound 5m. Thus, compounds 5a-s can potentially be exploited as new antiproliferative lead compounds for cancer chemotherapeutic.
Insights
Newly synthesized isatin-based conjugates show significant in vitro antiproliferative activity against human cancer cell lines. Compound 5m demonstrates potent anticancer effects, suggesting potential as novel chemotherapeutic lead compounds.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Oncology
Background:
- Cancer is a leading global cause of mortality.
- Isatin-based conjugates are being investigated for their therapeutic potential.
Purpose of the Study:
- To synthesize and evaluate the in vitro antiproliferative activity of novel isatin-based conjugates (compounds 5a-s).
- To investigate the ADME properties and antiproliferative mechanisms of these compounds.
Main Methods:
- In vitro antiproliferative assays against three human cancer cell lines.
- ADME (absorption, distribution, metabolism, and excretion) predictions.
- Western blot analysis to elucidate the mechanism of action.
Main Results:
- Compounds 5a-s exhibited antiproliferative activities ranging from 20.3% to 95.9%.
- Compound 5m showed superior potency (IC50 = 1.17 µM), outperforming sunitinib.
- Compound 5m induced G1 cell cycle arrest, reduced phosphorylated retinoblastoma protein, enhanced specific gene/protein expression (BTG1, cyclins, BAX), and activated caspase-3.
Conclusions:
- Newly synthesized isatin-based compounds (5a-s) possess significant antiproliferative potential.
- Compound 5m exhibits a promising pharmacological profile and mechanism of action.
- These compounds represent potential lead candidates for developing new cancer chemotherapeutics.
