A Tryptoline Ring‐Distortion Strategy Leads to Complex and Diverse Biologically Active Molecules from the Indole Alkaloid Yohimbine

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 mole...

Full description

Saved in:
Bibliographic Details
Published in:Chemistry : a European journal 2017-03, Vol.23 (18), p.4327-4335
Main Authors: Paciaroni, Nicholas G., Ratnayake, Ranjala, Matthews, James H., Norwood, Verrill M., Arnold, Austin C., Dang, Long H., Luesch, Hendrik, Huigens, Robert W.
Format: Article
Language:English
Subjects:
Alkaloids
Animals
Biological Products - chemistry
Carbolines - chemistry
Cell Survival - drug effects
Chemistry
drug discovery
Genes
HCT116 Cells
high-throughput screening
Humans
Indole Alkaloids - chemistry
Indoles
Inhibition
Kinases
Mice
Molecular Conformation
natural products
RAW 264.7 Cells
ring distortion
Scaffolds
Screening
Small Molecule Libraries - chemical synthesis
Small Molecule Libraries - chemistry
Small Molecule Libraries - toxicity
Stereoisomerism
Strategy
Synthesis
Yohimbine - chemistry
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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 sp3 character 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. Generating diversity: A tryptoline ring‐distortion strategy is described that enables the rapid synthesis of 70 complex and diverse compounds from yohimbine; an indole alkaloid. The compounds synthesized had architecturally complex and unique scaffolds, unlike that of yohimbine and other scaffolds.
ISSN:0947-6539
1521-3765
DOI:10.1002/chem.201604795