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. 2021 Feb 9;19(2):97.
doi: 10.3390/md19020097.

New from Old: Thorectandrin Alkaloids in a Southern Australian Marine Sponge, Thorectandra choanoides (CMB-01889)

Affiliations

New from Old: Thorectandrin Alkaloids in a Southern Australian Marine Sponge, Thorectandra choanoides (CMB-01889)

Shamsunnahar Khushi et al. Mar Drugs. .

Abstract

Thorectandra choanoides (CMB-01889) was prioritized as a source of promising new chemistry from a library of 960 southern Australian marine sponge extracts, using a global natural products social (GNPS) molecular networking approach. The sponge was collected at a depth of 45 m. Chemical fractionation followed by detailed spectroscopic analysis led to the discovery of a new tryptophan-derived alkaloid, thorectandrin A (1), with the GNPS cluster revealing a halo of related alkaloids 1a-1n. In considering biosynthetic origins, we propose that Thorectandrachoanoides (CMB-01889) produces four well-known alkaloids, 6-bromo-1',8-dihydroaplysinopsin (2), 6-bromoaplysinopsin (3), aplysinopsin (4), and 1',8-dihydroaplysinopsin (10), all of which are susceptible to processing by a putative indoleamine 2,3-dioxygenase-like (IDO) enzyme to 1a-1n. Where the 1',8-dihydroalkaloids 2 and 10 are fully transformed to stable ring-opened thorectandrins 1 and 1a-1b, and 1h-1j, respectively, the conjugated precursors 3 and 4 are transformed to highly reactive Michael acceptors that during extraction and handling undergo complete transformation to artifacts 1c-1g, and 1k-1n, respectively. Knowledge of the susceptibility of aplysinopsins as substrates for IDOs, and the relative reactivity of Michael acceptor transformation products, informs our understanding of the pharmaceutical potential of this vintage marine pharmacophore. For example, the cancer tissue specificity of IDOs could be exploited for an immunotherapeutic response, with aplysinopsins transforming in situ to Michael acceptor thorectandrins, which covalently bind and inhibit the enzyme.

Keywords: GNPS molecular network; Thorectandra choanoides; aplysinopsins; indoleamine 2,3-dioxygenase; tryptophan alkaloid.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Thorectandrin A (1).
Figure 2
Figure 2
Diagnostic 2D NMR correlations for thorectandrin A (1).
Scheme 1
Scheme 1
Keto-enol tautomerization of thorectandrin A (1).
Scheme 2
Scheme 2
Biosynthetic conversion of L-tryptophan (5) to N-formyl-L-kynurenine (6) to L-kynurenine (7).
Scheme 3
Scheme 3
Possible biosynthetic link between 6-bromo-1′,8-dihydroaplysinopsin (2), N-formyl thorectandrin A (1a), O-methylthorectandrin A (1b), and thorectandrin A (1).
Scheme 4
Scheme 4
Possible biosynthetic link between (Z)-3′-deimino-3′-oxoaplysinopsin (9) and spiroreticulatine (8).
Figure 3
Figure 3
Structures attributed to nodes in the thorectandrin GNPS cluster.
Scheme 5
Scheme 5
Possible biosynthetic link between 6-bromoaplysinopsin (3) and the solvolysis artifacts 1c1g.
Scheme 6
Scheme 6
Possible biosynthetic link between 1′,8-dihydroaplysinopsin (10) and 1h1j.
Scheme 7
Scheme 7
Possible biosynthetic link between aplysinopsin (4) and 1k1n.

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