title: Second-generation derivatives of the eukaryotic translation initiation inhibitor pateamine A targeting eIF4A as potential anticancer agents.
abstract: A series of pateamine A (1) derivatives were synthesized for structure/activity relationship (SAR) studies and a selection of previous generation analogs were re-evaluated based on current information regarding the mechanism of action of these translation inhibitors. Structural modifications in the new generation of derivatives focused on alterations to the C19-C22 Z,E-diene and the trienyl side chain of the previously described simplified, des-methyl, des-amino pateamine A (DMDAPatA, 2). Derivatives were tested for anti-proliferative activity in cell culture and for inhibition of mammalian cap-dependent translation in vitro. Activity was highly dependent on the rigidity and conformation of the macrolide and the functionality of the side chain. The only well tolerated substitutions were replacement of the N,N-dimethyl amino group found on the side chain of 2 with other tertiary amine groups. SAR reported here suggests that this site may be modified in future studies to improve serum stability, cell-type specificity, and/or specificity towards rapidly proliferating cells.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, 8000 Utopia Parkway, Queens, NY 11439, USA. Electronic address: loww@stjohns.edu.
authors.forename: Woon-Kai
authors.initials: WK
authors.lastname: Low
authors.affiliation: Natural Product LINCHPIN Laboratory, Department of Chemistry, Texas A&M University, P.O. Box 300012, College Station, TX 77842-3012, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Natural Product LINCHPIN Laboratory, Department of Chemistry, Texas A&M University, P.O. Box 300012, College Station, TX 77842-3012, USA.
authors.forename: Mingzhao
authors.initials: M
authors.lastname: Zhu
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, 8000 Utopia Parkway, Queens, NY 11439, USA.
authors.forename: Sai Shilpa
authors.initials: SS
authors.lastname: Kommaraju
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, 8000 Utopia Parkway, Queens, NY 11439, USA.
authors.forename: Janki
authors.initials: J
authors.lastname: Shah-Mittal
authors.affiliation: Natural Product LINCHPIN Laboratory, Department of Chemistry, Texas A&M University, P.O. Box 300012, College Station, TX 77842-3012, USA.
authors.forename: Ken
authors.initials: K
authors.lastname: Hull
authors.affiliation: Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, 725 North Wolfe St., Baltimore, MD 21205, USA.
authors.forename: Jun O
authors.initials: JO
authors.lastname: Liu
authors.affiliation: Natural Product LINCHPIN Laboratory, Department of Chemistry, Texas A&M University, P.O. Box 300012, College Station, TX 77842-3012, USA; Department of Chemistry, Texas A&M University, P.O. Box 300012, College Station, TX 77842-3012, USA. Electronic address: romo@chem.tamu.edu.
authors.forename: Daniel
authors.initials: D
authors.lastname: Romo
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001688:Biological Products; D049109:Cell Proliferation; D004852:Epoxy Compounds / Q000276:immunology / Q000378:metabolism*; D039642:Eukaryotic Initiation Factors / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D018942:Macrolides / Q000276:immunology / Q000378:metabolism*; D010442:Peptide Chain Initiation, Translational; D013844:Thiazoles / Q000276:immunology / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D001688:Biological Products; D004852:Epoxy Compounds; D039642:Eukaryotic Initiation Factors; D018942:Macrolides; D013844:Thiazoles; C031799:eIF-4B; C421324:pateamine A
keywords: DMDAPatA; Pateamine A; Stille coupling; Translation initiation; eIF4A