Facile, regio- and diastereoselective synthesis of spiro-pyrrolidine and pyrrolizine derivatives and evaluation of their antiproliferative activities

A number of novel spiro-pyrrolidines/pyrrolizines derivatives were synthesized through [3+2]-cycloaddition of azomethine ylides with 3,5-bis[(E)-arylmethylidene]tetrahydro-4(1H)-pyridinones 2a-n. Azomethine ylides were generated in situ from the reaction of 1H-indole-2,3-dione (isatin, 3) with N-met...

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Published in:Molecules (Basel, Switzerland) Switzerland), 2014-07, Vol.19 (7), p.10033-10055
Main Authors: Almansour, Abdulrahman I, Kumar, Raju Suresh, Beevi, Farzana, Shirazi, Amir Nasrolahi, Osman, Hasnah, Ismail, Rusli, Choon, Tan Soo, Sullivan, Brian, McCaffrey, Kellen, Nahhas, Alaa, Parang, Keykavous, Ali, Mohamed Ashraf
Format: Article
Language:English
Subjects:
Alzheimer's disease
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - pharmacology
antiproliferative activity
Cancer
Cell Line, Tumor
Cell Proliferation - drug effects
Chemistry
Chemistry Techniques, Synthetic
diastereoselective synthesis
Humans
Pharmacy
Pyrrolidines - chemical synthesis
Pyrrolidines - pharmacology
pyrrolizine
regio-selective synthesis
Spiro Compounds - chemical synthesis
Spiro Compounds - pharmacology
spiro-pyrolidine
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Summary:A number of novel spiro-pyrrolidines/pyrrolizines derivatives were synthesized through [3+2]-cycloaddition of azomethine ylides with 3,5-bis[(E)-arylmethylidene]tetrahydro-4(1H)-pyridinones 2a-n. Azomethine ylides were generated in situ from the reaction of 1H-indole-2,3-dione (isatin, 3) with N-methylglycine (sarcosine), phenylglycine, or proline. All compounds (50 μM) were evaluated for their antiproliferative activity against human breast carcinoma (MDA-MB-231), leukemia lymphoblastic (CCRF-CEM), and ovarian carcinoma (SK-OV-3) cells. N-α-Phenyl substituted spiro-pyrrolidine derivatives (5a-n) showed higher antiproliferative activity in MDA-MB-231 than other cancer cell lines. Among spiro-pyrrolizines 6a-n, a number of derivatives including 6a-c and 6i-m showed a comparable activity with doxorubicin in all three cell lines. Among all compounds in three classes, 6a, 6b, and 6m, were found to be the most potent derivatives showing 64%, 87%, and 74% antiproliferative activity in MDA-MB-231, SK-OV-3, and CCRF-CEM cells, respectively. Compound 6b showed an IC50 value of 3.6 mM in CCRF-CEM cells. These data suggest the potential antiproliferative activity of spiro-pyrrolidines/pyrrolizines.
ISSN:1420-3049
1420-3049
DOI:10.3390/molecules190710033