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Functionalized Spirocyclic Heterocycle Synthesis and Cytotoxicity Assay
Published on: February 9, 2021
Antiproliferative activity and possible mechanism of action of certain 5-methoxyindole tethered C-5 functionalized
Maha S Almutairi1, Eman S Hassan2, Adam B Keeton3
1Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
Background:
Cancer is one of the most dreaded human diseases, that has become an ever-increasing health problem and is a prime cause of death globally. The potential antiproliferative activity of certain indole-isatin molecular hybrids 5a-w was evaluated in vitro against three human cancer cell lines.
Methods:
Standard protocols were adopted to examine the antiproliferative potential and mechanisms of compounds 5a-w. Western blot analysis was carried out on compound 5o.
Results:
Compounds 5a-w demonstrated in vitro antiproliferative activity in the range of 22.6-97.8%, with compounds 5o and 5w being the most active antiproliferative compounds with IC50 values of 1.69 and 1.91 µM, which is fivefold and fourfold more potent than sunitinib (IC50=8.11 µM), respectively. Compound 5o was selected for in-depth pharmacological testing to understand its possible mechanism of antiproliferative activity. It caused a lengthening of the G1 phase and a reduction in the S and G2/M phases of the cell cycle and had an IC50 value of 10.4 μM with the resistant NCI-H69AR cancer cell line. Moreover, compound 5o significantly decreased the amount of phosphorylated Rb protein in a dose-dependent fashion, which was confirmed via Western blot analysis.
Conclusion:
The current investigation highlighted the potential antiproliferative activity of compounds 5a-w as well as the antiproliferative profile of compound 5o. These compounds can be harnessed as new lead antiproliferatives in the preclinical studies of cancer chemotherapy.
Insights
New indole-isatin hybrids show potent anticancer activity. Compounds 5o and 5w are highly effective against cancer cell lines, offering potential for new chemotherapy treatments.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Cancer Research
Background:
- Cancer remains a leading global cause of death, necessitating novel therapeutic strategies.
- Indole-isatin molecular hybrids are being investigated for their potential anticancer properties.
Purpose of the Study:
- To evaluate the in vitro antiproliferative activity of indole-isatin hybrids 5a-w against human cancer cell lines.
- To investigate the mechanism of action of the most potent compounds.
Main Methods:
- In vitro antiproliferative assays were performed on compounds 5a-w.
- Western blot analysis was used to study the effects of compound 5o on cell cycle proteins.
Main Results:
- Compounds 5a-w exhibited dose-dependent antiproliferative effects.
- Compounds 5o and 5w showed significant potency, with IC50 values lower than sunitinib.
- Compound 5o induced G1 cell cycle arrest and reduced phosphorylated Rb levels.
Conclusions:
- Indole-isatin hybrids 5a-w possess significant antiproliferative potential.
- Compound 5o demonstrates a promising anticancer profile, warranting further investigation.
- These compounds represent potential leads for preclinical cancer chemotherapy development.
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