Computationally Assisted Discovery and Assignment of a Highly Strained and PANC-1 Selective Alkaloid from Alaska's Deep Ocean

J Am Chem Soc. 2019 Mar 13;141(10):4338-4344. doi: 10.1021/jacs.8b11403. Epub 2019 Mar 5.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alaska
  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / isolation & purification
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Drug Discovery
  • Humans
  • Indole Alkaloids / chemistry
  • Indole Alkaloids / isolation & purification
  • Indole Alkaloids / pharmacology*
  • Mice
  • Models, Chemical
  • Molecular Structure
  • Porifera / chemistry
  • Stereoisomerism

Substances

  • Antineoplastic Agents
  • Indole Alkaloids