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

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 IC 50 of 25 nM and colon cancer (HCT-116) with an IC 50 of 1 μM, and represents a potent and selective candidate for advanced preclinical studies.

New Discorhabdin B Dimers with Anticancer Activity from the Antarctic Deep-Sea Sponge Latrunculia biformis

“…The ECD spectroscopy was first employed in the structural elucidation of discorhabdins by Grkovic et al in 2008 [9]. Since then, this technique has become particularly attractive and useful for confirming the absolute configuration of discorhabdins because of their conformationally rigid structures, strong UV absorption and circular dichroism properties [10,11,13,21]. So far, ECD spectroscopy is also one of the most effective techniques to secure the absolute configurations of discorhabdins-type alkaloids with a large number of stereogenic centers.…”

Exploration of the Electrophilic Reactivity of the Cytotoxic Marine Alkaloid Discorhabdin C and Subsequent Discovery of a New Dimeric C-1/N-13-Linked Discorhabdin Natural Product

“…Usually derived from extracts of marine sponges of the genus Latrunculia , these alkaloids have attracted much attention from both chemists and biologists due to their complex structures and associated biological activities [ 1 , 2 ]. While some of the first examples of the discorhabdins e.g., discorhabdin B ( 1 ) and C ( 2 ) ( Figure 1 ) were structurally relatively simple [ 3 , 4 ], recent studies have unveiled unusual dimers [ 5 ], oligomers [ 6 ] and more complex polycyclic variants [ 7 , 8 ].…”

“…In many cases, discorhabdin alkaloids have been reported to exhibit cytotoxicity towards tumour cell lines [ 1 , 2 , 3 , 4 , 6 , 8 , 9 ], with additional biological activities also including inhibition of protein–protein interaction associated with hypoxia-inducible factor 1α and its transcriptional coactivator p300 [ 10 , 11 ], antibacterial [ 12 , 13 , 14 ] and antimalarial [ 13 ] properties. The biological activities of simple dienone-containing examples of the discorhabdins has been attributed to the electrophilic properties of this moiety [ 2 , 15 ].…”

Computationally-assisted discovery and structure elucidation of natural products

“…Computational methods can be used in practically all of the steps of the discovery and structure determination of natural products, and they have been shown to be a very useful tool in such studies. Many studies have used such methods; for example, Hamann and co-workers used MN and DFT-calculated NMR chemical shifts and ECD spectra in the discovery and assignment of aleutianamine, a new class of pyrroloiminoquinone alkaloids isolated from Latrunculia austini [82]. There have been recent effort and initiatives to make raw MS/MS and NMR data publicly available [2, 83].…”