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Antineoplastic multi-targeted spiro[indoline-3,2'-pyrrolidines] incorporating urea function: Rational design,
Nehmedo G Fawzy1, Siva S Panda2, Mohamed S Bekheit1
1Department of Pesticide Chemistry, National Research Centre, Dokki, Giza 12622, Egypt.
Bioorganic Chemistry
|May 27, 2026
Summary
Novel urea-containing spiro[indoline-3,2'-pyrrolidines] were synthesized as multi-functional antineoplastic agents. Compound 15l showed potent anti-colon cancer activity, while 15h demonstrated significant efficacy against skin cancer and VEGFR-2 inhibition.
Area of Science:
- Medicinal Chemistry
- Organic Synthesis
- Cancer Research
Background:
- Development of novel multi-functional antineoplastic agents is crucial for overcoming cancer drug resistance.
- Spiro[indoline-3,2'-pyrrolidines] scaffold offers a promising platform for designing targeted cancer therapies.
- Urea functionality can be incorporated to modulate biological activity and target interactions.
Purpose of the Study:
- To synthesize novel spiro[indoline-3,2'-pyrrolidine] derivatives incorporating a urea moiety.
- To investigate the multi-targeted mechanism of action of these compounds as antineoplastic agents.
- To identify potent drug candidates for various cancer types.
Main Methods:
- 1,3-Dipolar cycloaddition reaction utilized for the synthesis of spiro-analogs (15a-m).
- In situ generation of azomethine ylide from isatins and sarcosine.
- Biological evaluation including in vitro cancer cell line assays, mechanistic studies (VEGFR-2 inhibition, MDM2-p53 interaction), apoptosis assays, cell cycle analysis, and anti-angiogenesis assays.
- Molecular docking and dynamic simulations for binding validation.
Main Results:
- Compounds 15a-m were synthesized in high yields.
- Compound 15l exhibited significant potency against HCT116 colon cancer cells, outperforming sunitinib and 5-fluorouracil.
- Compound 15h showed high efficacy against A431 skin squamous carcinoma and VEGFR-2 inhibition.
- Compound 15g acted as a dual MDM2 inhibitor and p53 activator.
- Compounds induced apoptosis, cell cycle arrest, and demonstrated anti-angiogenic potential.
- Molecular docking confirmed stable binding within the MDM2 pocket.
Conclusions:
- The synthesized urea-containing spiro[indoline-3,2'-pyrrolidines] are effective multi-functional antineoplastic agents.
- Compound 15h shows promise as a skin cancer therapeutic with VEGFR-2 inhibitory activity.
- Compound 15g's dual MDM2 inhibition and p53 activation highlight a novel therapeutic strategy.
- Disruption of the MDM2-p53 interaction and VEGFR-2 inhibition are key drivers of antiproliferative effects.
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