title: Facile, regio- and diastereoselective synthesis of spiro-pyrrolidine and pyrrolizine derivatives and evaluation of their antiproliferative activities.
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.
authors.affiliation: Department of Chemistry, College of Science, King Saud University, P.O.Box 2455, Riyadh 11451, Saudi Arabia.
authors.forename: Abdulrahman I
authors.initials: AI
authors.lastname: Almansour
authors.affiliation: Department of Chemistry, College of Science, King Saud University, P.O.Box 2455, Riyadh 11451, Saudi Arabia.
authors.forename: Raju Suresh
authors.initials: RS
authors.lastname: Kumar
authors.affiliation: New Drug Discovery Research, Department of Medicinal Chemistry, Sunrise University, Alwar, Rajasthan-301030, India.
authors.forename: Farzana
authors.initials: F
authors.lastname: Beevi
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USA.
authors.forename: Amir Nasrolahi
authors.initials: AN
authors.lastname: Shirazi
authors.affiliation: School of Chemical Sciences, Universiti Sains Malaysia, Minden 11800, Penang, Malaysia.
authors.forename: Hasnah
authors.initials: H
authors.lastname: Osman
authors.affiliation: Centre of Excellence for Research in AIDS, University Malaya, Kuala Lumpur 50603, Malaysia.
authors.forename: Rusli
authors.initials: R
authors.lastname: Ismail
authors.affiliation: Institute for Research in Molecular Medicine, Universiti Sains Malaysia, Minden 11800, Penang, Malaysia.
authors.forename: Tan Soo
authors.initials: TS
authors.lastname: Choon
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Sullivan
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USA.
authors.forename: Kellen
authors.initials: K
authors.lastname: McCaffrey
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USA.
authors.forename: Alaa
authors.initials: A
authors.lastname: Nahhas
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USA. parang@chapman.edu.
authors.forename: Keykavous
authors.initials: K
authors.lastname: Parang
authors.affiliation: New Drug Discovery Research, Department of Medicinal Chemistry, Sunrise University, Alwar, Rajasthan-301030, India. drashraf@usm.my.
authors.forename: Mohamed Ashraf
authors.initials: MA
authors.lastname: Ali
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D006801:Humans; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D011759:Pyrrolidines; D013141:Spiro Compounds; C032519:pyrrolidine