title: A Tryptoline Ring-Distortion Strategy Leads to Complex and Diverse Biologically Active Molecules from the Indole Alkaloid Yohimbine.
abstract: High-throughput screening (HTS) is the primary driver to current drug-discovery efforts. New therapeutic agents that enter the market are a direct reflection of the structurally simple compounds that make up screening libraries. Unlike medically relevant natural products (e.g., morphine), small molecules currently being screened have a low fraction of sp3character and few, if any, stereogenic centers. Although simple compounds have been useful in drugging certain biological targets (e.g., protein kinases), more sophisticated targets (e.g., transcription factors) have largely evaded the discovery of new clinical agents from screening collections. Herein, a tryptoline ring-distortion strategy is described that enables the rapid synthesis of 70 complex and diverse compounds from yohimbine (1); an indole alkaloid. The compounds that were synthesized had architecturally complex and unique scaffolds, unlike 1 and other scaffolds. These compounds were subjected to phenotypic screens and reporter gene assays, leading to the identification of new compounds that possessed various biological activities, including antiproliferative activities against cancer cells with functional hypoxia-inducible factors, nitric oxide inhibition, and inhibition and activation of the antioxidant response element. This tryptoline ring-distortion strategy can begin to address diversity problems in screening libraries, while occupying biologically relevant chemical space in areas critical to human health.
authors.affiliation: Department of Medicinal Chemistry, University of Florida, Gainesville, FL, 32610, USA.|Center for Natural Product Drug Discovery and Development (CNPD3), University of Florida, Gainesville, FL, 32610, USA.
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Paciaroni
authors.affiliation: Department of Medicinal Chemistry, University of Florida, Gainesville, FL, 32610, USA.|Center for Natural Product Drug Discovery and Development (CNPD3), University of Florida, Gainesville, FL, 32610, USA.
authors.forename: Ranjala
authors.initials: R
authors.lastname: Ratnayake
authors.affiliation: Department of Medicinal Chemistry, University of Florida, Gainesville, FL, 32610, USA.|Center for Natural Product Drug Discovery and Development (CNPD3), University of Florida, Gainesville, FL, 32610, USA.
authors.forename: James H
authors.initials: JH
authors.lastname: Matthews
authors.affiliation: Department of Medicinal Chemistry, University of Florida, Gainesville, FL, 32610, USA.|Center for Natural Product Drug Discovery and Development (CNPD3), University of Florida, Gainesville, FL, 32610, USA.
authors.forename: Verrill M
authors.initials: VM
authors.lastname: Norwood
authors.affiliation: Department of Medicinal Chemistry, University of Florida, Gainesville, FL, 32610, USA.
authors.forename: Austin C
authors.initials: AC
authors.lastname: Arnold
authors.affiliation: Department of Medicinal Chemistry, University of Florida, Gainesville, FL, 32610, USA.|Center for Natural Product Drug Discovery and Development (CNPD3), University of Florida, Gainesville, FL, 32610, USA.|Department of Medicine, University of Florida, Gainesville, FL, 32610, USA.
authors.forename: Long H
authors.initials: LH
authors.lastname: Dang
authors.affiliation: Department of Medicinal Chemistry, University of Florida, Gainesville, FL, 32610, USA.|Center for Natural Product Drug Discovery and Development (CNPD3), University of Florida, Gainesville, FL, 32610, USA.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Luesch
authors.affiliation: Department of Medicinal Chemistry, University of Florida, Gainesville, FL, 32610, USA.|Center for Natural Product Drug Discovery and Development (CNPD3), University of Florida, Gainesville, FL, 32610, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Huigens
mesh_terms: D000818:Animals; D001688:Biological Products / Q000737:chemistry; D002243:Carbolines / Q000737:chemistry*; D002470:Cell Survival / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D026121:Indole Alkaloids / Q000737:chemistry*; D051379:Mice; D008968:Molecular Conformation; D000067996:RAW 264.7 Cells; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D013237:Stereoisomerism; D015016:Yohimbine / Q000737:chemistry*
chemical_list: D001688:Biological Products; D002243:Carbolines; D026121:Indole Alkaloids; D054852:Small Molecule Libraries; D015016:Yohimbine; C009804:tryptoline
keywords: alkaloids; drug discovery; high-throughput screening; natural products; ring distortion