Facile, Regio- and Diastereoselective Synthesis of Spiro-Pyrrolidine and Pyrrolizine Derivatives and Evaluation of Their Antiproliferative Activities

Molecules

Abdulrahman I. Almansour⁴  Raju Suresh Kumar⁴  Farzana Beevi¹  Amir Nasrolahi Shirazi⁶  Hasnah Osman³  Rusli Ismail²  Tan Soo Choon⁵  Brian Sullivan⁶  Kellen McCaffrey⁶  Alaa Nahhas⁶  Keykavous Parang⁶ 

[1] New Drug Discovery Research, Department of Medicinal Chemistry, Sunrise University, Alwar, Rajasthan-301030, India;Centre of Excellence for Research in AIDS, University Malaya, Kuala Lumpur 50603, Malaysia;School of Chemical Sciences, Universiti Sains Malaysia, Minden 11800, Penang, Malaysia;Department of Chemistry, College of Science, King Saud University, P.O.Box 2455, Riyadh 11451, Saudi Arabia;Institute for Research in Molecular Medicine, Universiti Sains Malaysia, Minden 11800, Penang, Malaysia;Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USA

关键词: antiproliferative activity;    diastereoselective synthesis;    pyrrolizine;    regio-selective synthesis;    spiro-pyrolidine;   

DOI  :  10.3390/molecules190710033

来源: mdpi

【 摘 要 】

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 μM in CCRF-CEM cells. These data suggest the potential antiproliferative activity of spiro-pyrrolidines/pyrrolizines.

【 授权许可】

CC BY   
© 2014 by the authors; licensee MDPI, Basel, Switzerland.