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

Almansour AI 1 , Kumar RS 1 , Beevi F 2 , Shirazi AN 3 , Osman H 4 , Ismail R 5 Show all authors , Choon TS 6 , Sullivan B 3 , McCaffrey K 3 , Nahhas A 3 , Parang K 7 , Ali MA 8

Affiliations 

  • 1 Department of Chemistry, College of Science, King Saud University, P.O.Box 2455, Riyadh 11451, Saudi Arabia
  • 2 New Drug Discovery Research, Department of Medicinal Chemistry, Sunrise University, Alwar, Rajasthan-301030, India
  • 3 Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USA
  • 4 School of Chemical Sciences, Universiti Sains Malaysia, Minden 11800, Penang, Malaysia
  • 5 Centre of Excellence for Research in AIDS, University Malaya, Kuala Lumpur 50603, Malaysia
  • 6 Institute for Research in Molecular Medicine, Universiti Sains Malaysia, Minden 11800, Penang, Malaysia
  • 7 Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USA. parang@chapman.edu
  • 8 New Drug Discovery Research, Department of Medicinal Chemistry, Sunrise University, Alwar, Rajasthan-301030, India. drashraf@usm.my
Molecules, 2014 Jul 10;19(7):10033-55.
PMID: 25014532 DOI: 10.3390/molecules190710033

Abstract

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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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