COX Inhibitory and Cytotoxic Naphthoketal-Bearing Polyketides from Sparticola junci

Abstract

Axenic fermentation on solid rice of the saprobic fungus Sparticola junci afforded two new highly oxidized naphthalenoid polyketide derivatives, sparticatechol A (1) and sparticolin H (2) along with sparticolin A (3). The structures of 1 and 2 were elucidated on the basis of their NMR and HR-ESIMS spectroscopic data. Assignment of absolute configurations was performed using electronic circular dichroism (ECD) experiments and Time-Dependent Density Functional Theory (TDDFT) calculations. Compounds 1-3 were evaluated for COX inhibitory, antiproliferative, cytotoxic and antimicrobial activities. Compounds 1 and 2 exhibited strong inhibitory activities against COX-1 and COX-2. Molecular docking analysis of 1 conferred favorable binding against COX-2. Sparticolin H (2) and A (3) showed a moderate antiproliferative effect against myelogenous leukemia K-562 cells and weak cytotoxicity against HeLa and mouse fibroblast cells.

Keywords: COX inhibitory; ECD-TDDFT; Sparticola junci; antiproliferative; cytotoxic; molecular docking; structure elucidation.

Figure 1

Dioxynaphthalenoids 1–3 from Sparticola junci.

Figure 2

COSY and HMBC correlations in 1 and 2.

Figure 3

Experimental ECD spectrum of sparticatechol A (1, black solid curve) compared with B3LYP/6-31G(d)-calculated ECD spectra (red solid curve) for the B3LYP/6-31G(d)-optimized conformers of (8S,22R)-1.

Figure 4

Experimental ECD spectrum of sparticolin H (2, black solid curve) compared with WB97XD/DGDZVP (PCM/MeCN)-calculated ECD spectra (red solid curve) for the WB97XD/DGDZVP-optimized conformers of (4S,5S,7R)-2.

Figure 5

3D and 2D docked poses of sparticatechol A (1) against (A) COX-2 (PDB ID: 3LN1) and (B) COX-1 (PDB ID: 3KK6).

Figure 6

Prediction of GI tract and brain permeation of compounds 1–3 by brain or the intestinal estimated permeation predictive model (BOILED-Egg) method.