Computationally Assisted Discovery and Assignment of a Highly Strained and PANC-1 Selective Alkaloid from Alaska’s Deep Ocean
| Autor: | Mark T. Hamann, Pankaj Pandey, Clemens Anklin, Yike Zou, Robert J. Doerksen, Bin Wang, Daneel Ferreira, Mitchell A. Avery, James Sims, Frederick A. Valeriote, Michelle Kelly, Colin L Welsh, Robert P. Stone, Xiaojuan Wang |
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| Rok vydání: | 2019 |
| Předmět: |
Stereochemistry
Antineoplastic Agents Stereoisomerism Latrunculia 010402 general chemistry 01 natural sciences Biochemistry Catalysis Indole Alkaloids Mice Colloid and Surface Chemistry Latrunculiidae Cell Line Tumor Drug Discovery Animals Humans Solid tumor Molecular Structure biology Drug discovery Chemistry Alkaloid General Chemistry biology.organism_classification Porifera 0104 chemical sciences Models Chemical Pancreatic cancer cell Poecilosclerida Alaska |
| Zdroj: | Journal of the American Chemical Society. 141:4338-4344 |
| ISSN: | 1520-5126 0002-7863 |
| DOI: | 10.1021/jacs.8b11403 |
| Popis: | We report here the orchestration of molecular ion networking and a set of computationally assisted structural elucidation approaches in the discovery of a new class of pyrroloiminoquinone alkaloids that possess selective bioactivity against pancreatic cancer cell lines. Aleutianamine represents the first in a new class of pyrroloiminoquinone alkaloids possessing a highly strained multibridged ring system, discovered from Latrunculia ( Latrunculia) austini Samaai, Kelly & Gibbons, 2006 (class Demospongiae, order Poecilosclerida, family Latrunculiidae) recovered during a NOAA deep-water exploration of the Aleutian Islands. The molecule was identified with the guidance of mass spectrometry, nuclear magnetic resonance, and molecular ion networking (MoIN) analysis. The structure of aleutianamine was determined using extensive spectroscopic analysis in conjunction with computationally assisted quantifiable structure elucidation tools. Aleutianamine exhibited potent and selective cytotoxicity toward solid tumor cell lines including pancreatic cancer (PANC-1) with an IC50 of 25 nM and colon cancer (HCT-116) with an IC50 of 1 μM, and represents a potent and selective candidate for advanced preclinical studies. |
| Databáze: | OpenAIRE |
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