title: Improved total synthesis and biological evaluation of potent apratoxin S4 based anticancer agents with differential stability and further enhanced activity.
abstract: Apratoxins are cytotoxic natural products originally isolated from marine cyanobacteria that act by preventing cotranslational translocation early in the secretory pathway to downregulate receptor levels and inhibit growth factor secretion, leading to potent antiproliferative activity. Through rational design and total synthesis of an apratoxin A/E hybrid, apratoxin S4 (1a), we have previously improved the antitumor activity and tolerability in vivo. Compound 1a and newly designed analogues apratoxins S7-S9 (1b-d), with various degrees of methylation at C34 (1b,c) or epimeric configuration at C30 (1d), were efficiently synthesized utilizing improved procedures. Optimizations have been applied to the synthesis of key intermediate aldehyde 7 and further include the application of Leighton's silanes and modifications of Kelly's methods to induce thiazoline ring formation in other crucial steps of the apratoxin synthesis. Apratoxin S9 (1d) exhibited increased activity with subnanomolar potency. Apratoxin S8 (1c) lacks the propensity to be deactivated by dehydration and showed efficacy in a human HCT116 xenograft mouse model.
authors.affiliation: Department of Medicinal Chemistry and ‡Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida , Gainesville, Florida, United States.
authors.forename: Qi-Yin
authors.initials: QY
authors.lastname: Chen
authors.forename: Yanxia
authors.initials: Y
authors.lastname: Liu
authors.forename: Weijing
authors.initials: W
authors.lastname: Cai
authors.forename: Hendrik
authors.initials: H
authors.lastname: Luesch
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects*; D002851:Chromatography, High Pressure Liquid; D047630:Depsipeptides / Q000138:chemical synthesis* / Q000494:pharmacology*; D045325:HCT116 Cells; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D008861:Microsomes / Q000187:drug effects*; D008958:Models, Molecular; D015394:Molecular Structure; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D047630:Depsipeptides; C000589313:apratoxin S4