Clerodane Diterpenes from the Marine Sponge Raspailia bouryesnaultae Collected in South Brazil

Abstract

The marine sponge Raspailia bouryesnaultae, collected in South Brazil, was selected for detailed investigation considering the results of a screening that pointed to an in vitro antiproliferative effect against non-small cells of human lung cancer (A549) and anti-herpes activity against Herpes Simplex virus type 1 (KOS and 29R strains) of ethanolic extracts. The fractionation and chemical investigation of the sponge’s hexanic fraction led to the isolation and structural elucidation of six clerodane diterpenes. The main component was identified as the already-reported raspailol (1), isolated from a sponge of the same genus collected in New Zealand. The structure of a new diterpene (2) with a rearranged skeleton was established by high-resolution mass spectrometry (HRMS) and 1D and 2D Nuclear magnetic resonance spectroscopy (NMR) experiments, and named here as raspadiene. Furthermore, four diterpenes were elucidated as isomers of clerodane diterpenes previously obtained from plants, namely kerlinic acid (3), kerlinic acid methyl ester (4), annonene (5), and 6-hydroxyannonene (6). They differ in their stereochemistry, since these diterpenes are characterized by a trans ring fusion at the decalin moiety and the relative configuration of the two methyl groups at C-8 and C-9 in a cis relationship (type trans/cis). The Raspailia diterpenes have a cis ring fusion at the decalin moiety, and the two methyl groups at C-8 and C-9 are in a trans relationship (type cis/trans). The isolated compounds were evaluated for their potential antiproliferative effects on human cancer cell line A549, and it was observed that the diterpenes bearing a hydroxyl group at C-6 exhibited moderate cytotoxic activity, with 50% inhibitory concentration (IC50) values lower than 25 μM. The evaluation of the potential anti-herpes activity against Herpes Simplex Virus type 1 (HSV-1, KOS and 29R strains) showed that the more promising results were observed for the new compound 2, since it inhibited HSV-1 (KOS and 29R strains) replication by 83% and 74%, respectively.

Natural Products Derived from Marine Sponges with Antitumor Potential against Lung Cancer: A Systematic Review

“…Lhullier et al (2019) isolated six clerodane diterpenes ( 59 – 64 ) from the marine sponge Raspailia bouryesnaultae . The compounds displaying the most potent cytotoxic activity were those containing a hydroxyl group at C-6, with IC 50 values lower than 25 μM [ 54 ].…”

“…Induction of G1 arrest (↑p27 and ↓cyclin D1), apoptosis (↑PARP cleavage and ↑ROS generation), and autophagy (↑LC3B II/I, ↑Atg5, and ↓p62). [ 51 ] Raspailia bouryesnaultae raspailol ( 59 ), raspadiene ( 60 ), kerlinic acid ( 61 ), kerlinic acid methyl ester ( 62 ), annonene ( 63 ), and 6-hydroxyannonene ( 64 ) Clerodane diterpenes Isolation A549 (NSCLC) 59 : 24.12 μM 60 : 100.3 μM 61 : 66.22 μM 62 : 20.63 μM 63 : 143.7 μM 64 : 24.52 μM (48 h) ✗ NR [ 54 ] Acanthodendrilla sp. (S)- acanthodendrilline ( 65 ) and (R)- acanthodendrilline ( 66 ) Bromotyrosine alkaloid Chemical synthesis H292 (NSCLC) 65 : 58.5 ± 6.7 μM 66 : 173.5 ± 24.7 μM (72 h) ✗ NR [ 55 ] Chondrosia corticata halichondramide ( 67 ), jaspisamide A ( 68 ), neohalichondramide ( 69 ), halishigamide D ( 70 ), and (19Z)-halichondramide ( 71 ) Oxazole-containing macrolide Isolation A549 (NSCLC) 67 : 0.045 μM 68 : 32.63 μM 69 : 3.73 μM 70 : 1.65 μM 71 : 0.024 μM (72 h) ✗ G2/M cell cycle arrest (↑p53, ↑GADD45α, ↓cyclin B1, ↓cyclin A, ↓CDC2, and ↓CDC25C) and suppression of the Akt/mTOR signaling pathw...…”

Antimicrobial Diterpenes: Recent Development From Natural Sources

“…A total of six clerodane diterpenoids were isolated from marine sponge Raspailia bouryesnaultae , and their anti-herpes activity was tested against herpes simplex virus type 1 (HSV-1). All of the diterpenoids displayed potential antiviral activity with an IC 50 lower than 25 μM, especially the new compound 120 , which inhibited HSV-1 (KOS and 29R strains) replication by 83% and 74% (IC 50 = 81.39 ± 9.82 and 74.93 ± 7.30 μg/ml) respectively ( Lhullier et al, 2019 ).…”

“…All of the diterpenoids displayed potential antiviral activity with an IC 50 lower than 25 μM, especially the new compound 120, which inhibited HSV-1 (KOS and 29R strains) replication by 83% and 74% (IC 50 = 81.39 ± 9.82 and 74.93 ± 7.30 μg/ml) respectively (Lhullier et al, 2019).…”

The genomes of medicinal skullcaps reveal the polyphyletic origins of clerodane diterpene biosynthesis in the family Lamiaceae

“…Like gibberellins that have been isolated from both plants (He et al, 2020) and fungi (Tudzynski, 2005), clerodanes have been reported from several hundred different plant species (Li et al ., 2016; Merritt and Ley, 1992), as well as fungi (Andersen et al, 1983), bacteria (Nakano et al, 2015) and marine animals (Lhullier et al, 2019). Although clerodanes have been isolated from plants of the Asteraceae, Euphorbiaceae, Flacourtiaceae, and Menispermeaceae families, more than 50% of reported clerodanes have been isolated from members of the family Lamiaceae (Li et al ., 2016; Merritt and Ley, 1992) and these have attracted considerable attention for their biological activities (Li et al ., 2016).…”