Design, synthesis and pharmacological evaluation of novel pyrrolizine derivatives as potential anticancer agents. 2014

Ahmed M Gouda, and Ahmed H Abdelazeem, and El-Shaimaa A Arafa, and Khaled R A Abdellatif
Department of Medicinal Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt; Department of Pharmaceutical Chemistry, College of Pharmacy, Umm Al-Qura University, Mekkah 21955, Saudi Arabia.

A new series of novel pyrrolizine derivatives has been synthesized and biologically evaluated as potential anticancer agents. The starting compounds, 6-amino-7-cyano-N-(3,5-disubstitutedphenyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamides 11a-b, were reacted with different acid chlorides, aldehydes and isocyanates to give the target compounds 12-14. Structural characterizations of the new compounds were performed using spectral and elemental analysis. All compounds were tested for their anticancer activity against human breast cancer and prostate cancer cell lines, MCF-7 and PC-3 respectively. With exception of compounds 11a and 13a, results revealed that all the tested compounds showed half maximal inhibitory concentration (IC50) values less than 40μM. Compound 12b and the three urea derivatives 14b-d showed the most potent anticancer activity with IC50 values less than 2.73μM. The anticancer activity of these compounds was mediated, at least in part, via the induction of apoptosis as indicated by its ability to activate caspase-3/7. In light of the high potency of our novel compounds in targeting both breast and prostate cancers, these compounds warrant continued preclinical development as potential anticancer agents.

UI MeSH Term Description Entries
D011758 Pyrroles Azoles of one NITROGEN and two double bonds that have aromatic chemical properties. Pyrrole
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000970 Antineoplastic Agents Substances that inhibit or prevent the proliferation of NEOPLASMS. Anticancer Agent,Antineoplastic,Antineoplastic Agent,Antineoplastic Drug,Antitumor Agent,Antitumor Drug,Cancer Chemotherapy Agent,Cancer Chemotherapy Drug,Anticancer Agents,Antineoplastic Drugs,Antineoplastics,Antitumor Agents,Antitumor Drugs,Cancer Chemotherapy Agents,Cancer Chemotherapy Drugs,Chemotherapeutic Anticancer Agents,Chemotherapeutic Anticancer Drug,Agent, Anticancer,Agent, Antineoplastic,Agent, Antitumor,Agent, Cancer Chemotherapy,Agents, Anticancer,Agents, Antineoplastic,Agents, Antitumor,Agents, Cancer Chemotherapy,Agents, Chemotherapeutic Anticancer,Chemotherapy Agent, Cancer,Chemotherapy Agents, Cancer,Chemotherapy Drug, Cancer,Chemotherapy Drugs, Cancer,Drug, Antineoplastic,Drug, Antitumor,Drug, Cancer Chemotherapy,Drug, Chemotherapeutic Anticancer,Drugs, Antineoplastic,Drugs, Antitumor,Drugs, Cancer Chemotherapy
D015195 Drug Design The molecular designing of drugs for specific purposes (such as DNA-binding, enzyme inhibition, anti-cancer efficacy, etc.) based on knowledge of molecular properties such as activity of functional groups, molecular geometry, and electronic structure, and also on information cataloged on analogous molecules. Drug design is generally computer-assisted molecular modeling and does not include PHARMACOKINETICS, dosage analysis, or drug administration analysis. Computer-Aided Drug Design,Computerized Drug Design,Drug Modeling,Pharmaceutical Design,Computer Aided Drug Design,Computer-Aided Drug Designs,Computerized Drug Designs,Design, Pharmaceutical,Drug Design, Computer-Aided,Drug Design, Computerized,Drug Designs,Drug Modelings,Pharmaceutical Designs
D017209 Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, i.e., DNA FRAGMENTATION. It is genetically programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Apoptosis, Extrinsic Pathway,Apoptosis, Intrinsic Pathway,Caspase-Dependent Apoptosis,Classic Apoptosis,Classical Apoptosis,Programmed Cell Death,Programmed Cell Death, Type I,Apoptoses, Extrinsic Pathway,Apoptoses, Intrinsic Pathway,Apoptosis, Caspase-Dependent,Apoptosis, Classic,Apoptosis, Classical,Caspase Dependent Apoptosis,Cell Death, Programmed,Classic Apoptoses,Extrinsic Pathway Apoptoses,Extrinsic Pathway Apoptosis,Intrinsic Pathway Apoptoses,Intrinsic Pathway Apoptosis
D045744 Cell Line, Tumor A cell line derived from cultured tumor cells. Tumor Cell Line,Cell Lines, Tumor,Line, Tumor Cell,Lines, Tumor Cell,Tumor Cell Lines
D053148 Caspase 3 A short pro-domain caspase that plays an effector role in APOPTOSIS. It is activated by INITIATOR CASPASES such as CASPASE 9. Isoforms of this protein exist due to multiple alternative splicing of its MESSENGER RNA. CASP3,Apopain,Caspase-3,Pro-Caspase-3,Procaspase-3,Pro Caspase 3,Procaspase 3
D053179 Caspase 7 A short pro-domain caspase that plays an effector role in APOPTOSIS. It is activated by INITIATOR CASPASES such as CASPASE 3 and CASPASE 10. Several isoforms of this protein exist due to multiple alternative splicing of its MESSENGER RNA. Apoptotic Protease Mch-3,Caspase-7,ICE-Like Apoptotic Protease 3,Mch-3 Protease,Pro-caspase 7,Pro-caspase-7,Procaspase 7,Procaspase-7,Apoptotic Protease Mch 3,ICE Like Apoptotic Protease 3,Mch 3 Protease,Mch-3, Apoptotic Protease,Pro caspase 7,Protease Mch-3, Apoptotic,Protease, Mch-3
D061986 MCF-7 Cells An estrogen responsive cell line derived from a patient with metastatic human breast ADENOCARCINOMA (at the Michigan Cancer Foundation.) MCF7 Cells,Michigan Cancer Foundation 7 Cells,Cell, MCF-7,Cell, MCF7,Cells, MCF-7,Cells, MCF7,MCF 7 Cells,MCF-7 Cell,MCF7 Cell

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