title: Total Synthesis and Biological Evaluation of Natural and Designed Tubulysins.
abstract: A streamlined total synthesis of N(14)-desacetoxytubulysin H (Tb1) based on a C-H activation strategy and a short total synthesis of pretubulysin D (PTb-D43) are described. Applications of the developed synthetic strategies and technologies to the synthesis of a series of tubulysin analogues (Tb2-Tb41 and PTb-D42) are also reported. Biological evaluation of the synthesized compounds against an array of cancer cells revealed a number of novel analogues (e.g., Tb14), some with exceptional potencies against certain cell lines [e.g., Tb32 with IC50 = 12 pM against MES SA (uterine sarcoma) cell line and 2 pM against HEK 293T (human embryonic kidney) cell line], and a set of valuable structure-activity relationships. The highly potent cytotoxic compounds discovered in this study are highly desirable as payloads for antibody-drug conjugates and other drug delivery systems for personalized targeted cancer chemotherapies.
authors.affiliation: Department of Chemistry, BioScience Research Collaborative, and Department of Chemical and Biomolecular Engineering, Rice University , 6100 Main Street, Houston, Texas 77005, United States.
authors.forename: K C
authors.initials: KC
authors.lastname: Nicolaou
authors.affiliation: Department of Chemistry, BioScience Research Collaborative, and Department of Chemical and Biomolecular Engineering, Rice University , 6100 Main Street, Houston, Texas 77005, United States.
authors.forename: Jun
authors.initials: J
authors.lastname: Yin
authors.affiliation: Department of Chemistry, BioScience Research Collaborative, and Department of Chemical and Biomolecular Engineering, Rice University , 6100 Main Street, Houston, Texas 77005, United States.
authors.forename: Debashis
authors.initials: D
authors.lastname: Mandal
authors.affiliation: Department of Chemistry, BioScience Research Collaborative, and Department of Chemical and Biomolecular Engineering, Rice University , 6100 Main Street, Houston, Texas 77005, United States.
authors.forename: Rohan D
authors.initials: RD
authors.lastname: Erande
authors.affiliation: Department of Chemistry, BioScience Research Collaborative, and Department of Chemical and Biomolecular Engineering, Rice University , 6100 Main Street, Houston, Texas 77005, United States.
authors.forename: Philipp
authors.initials: P
authors.lastname: Klahn
authors.affiliation: Department of Chemistry, BioScience Research Collaborative, and Department of Chemical and Biomolecular Engineering, Rice University , 6100 Main Street, Houston, Texas 77005, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Jin
authors.affiliation: Stemcentrx Inc. , 450 East Jamie Court, South San Francisco, California 94080, United States.
authors.forename: Monette
authors.initials: M
authors.lastname: Aujay
authors.affiliation: Stemcentrx Inc. , 450 East Jamie Court, South San Francisco, California 94080, United States.
authors.forename: Joseph
authors.initials: J
authors.lastname: Sandoval
authors.affiliation: Stemcentrx Inc. , 450 East Jamie Court, South San Francisco, California 94080, United States.
authors.forename: Julia
authors.initials: J
authors.lastname: Gavrilyuk
authors.affiliation: Department of Chemistry, BioScience Research Collaborative, and Department of Chemical and Biomolecular Engineering, Rice University , 6100 Main Street, Houston, Texas 77005, United States.|Laboratory of Chemical Biology of Natural Products & Designed Molecules, National Centre of Scientific Research "Demokritos" , Agia Paraskevi-Athens GR-15310, Greece.
authors.forename: Dionisios
authors.initials: D
authors.lastname: Vourloumis
mesh_terms: D045744:Cell Line, Tumor; D057809:HEK293 Cells; D006801:Humans; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D009842:Oligopeptides; C575012:pretubulysin