Absolute configuration by vibrational circular dichroism of anti-inflammatory macrolide briarane diterpenoids from the Gorgonian Briareum asbestinum

Abstract

The four new briarane diterpenoids 2-butyryloxybriarane B-3 (2), 9-acetylbriarenolide S (3), briarenolide W (4), and 12-isobriarenolide P (5), along with briarane B-3 (1) and the five known diterpenes 6-10 were isolated from the gorgonian coral Briareum asbestinum collected from the Mexican Caribbean Sea. The structures were elucidated by 1D and 2D NMR and MS measurements. Since the structure of briarane B-3 (1) was only suggested and published without any spectroscopic support, it was herein confirmed, and the supporting data are now provided. In addition, 1 provided the opportunity to explore the sensitivity of vibrational circular dichroism (VCD) to determine the configuration of a single stereogenic center in the presence of eight other stereogenic centers in a molecule possessing a highly flexible ten-member ring. A single-crystal X-ray diffraction study, in which the Flack and Hooft parameters of 1 were determined, further confirmed that briarane B-3 is (1S,2S,6S,7R,8R,9S,10S,11R,17R)-1. This paper reports for first time the use of VCD in briarane diterpenes and with the presence of chlorine atoms. Biological evaluation of seven isolated compounds evidenced a moderate anti-inflammatory activity for compounds 6 and 9 but it did not show any cytotoxic, antiviral, antibacterial, and topoisomerase inhibitory activity.

Figure 1

Briarane diterpenes isolated from Briareum asbestinum.

Figure 2

¹H-¹H COSY and key HMBC correlations found in 1. Figure was created with Chemdraw V.20 (see permission in https://informatics.perkinelmer.com/sitesubscription/).

Figure 3

The four most stable conformers of briarane B-3 (1). Figure was created with Gaussview v 6.0.

Figure 4

Comparison of the experimental IR (b) and VCD (d) spectra of briarane B-3 (1) with the DFT B3LYP/DGDZVP calculated IR (a) and VCD (c) spectra for (1S,2S,6S,7R,8R,9S,10S,11R,17R)-1.

Figure 5

(a) Key NOESY correlations observed in compound 1. (b) ORTEP X-Ray representation of compound 1.

Figure 6

Comparison of the ¹³C NMR data between 5 and briarenolide P²⁷ (carbon chemical shift differences: Δδ_C > 3 ppm in red and Δδ_C between 0.5 to 1.8 ppm in blue), key coupling constants (see reference) and NOE correlations in 5. Figures were created with Chemdraw 20.0 and Chem3D v.2020.

Figure 7

(A) NF-κB activation in LPS-challenged THP-1 Lucia cells in the presence of compounds 1, 4, 6–10 for 24 h. Incubation with LPS corresponds to maximum NF-κB response, with molecules capable of inhibiting the activation of the transcription factor (6 and 9) presenting lower activity values. (B) Experimental model used for the assessment of NF-κB in THP-1 luciferase-transfected cells. (C) COX-2, IL-6, TNF-α and IL-1β mRNA expression in THP-1 cells. mRNA expression was determined by qPCR after normalization with GAPDH reference gene. Horizontal dashed red line corresponds to the basal expression of the gene in untreated cells. *p < 0.05; **p < 0.01; ***p < 0.001.