Oxy-Polybrominated Diphenyl Ethers from the Indonesian Marine Sponge, Lamellodysidea herbacea: X-ray, SAR, and Computational Studies

Abstract

Polybrominated diphenyl ether (PBDE) compounds, derived from marine organisms, originate from symbiosis between marine sponges and cyanobacteria or bacteria. PBDEs have broad biological spectra; therefore, we analyzed structure and activity relationships of PBDEs to determine their potential as anticancer or antibacterial lead structures, through reactions and computational studies. Six known PBDEs (1–6) were isolated from the sponge, Lamellodysdiea herbacea; 13C NMR data for compound 6 are reported for the first time and their assignments are confirmed by their theoretical 13C NMR chemical shifts (RMSE <4.0 ppm). Methylation and acetylation of 1 (2, 3, 4, 5-tetrabromo-6-(3′, 5′-dibromo-2′-hydroxyphenoxy) phenol) at the phenol functional group gave seven molecules (7–13), of which 10, 12, and 13 were new. New crystal structures for 8 and 9 are also reported. Debromination carried out on 1 produced nine compounds (1, 2, 14, 16–18, 20, 23, and 26) of which 18 was new. Debromination product 16 showed a significant IC50 8.65 ± 1.11; 8.11 ± 1.43 µM against human embryonic kidney (HEK293T) cells. Compounds 1 and 16 exhibited antibacterial activity against Gram-positive Staphylococcus aureus and Gram-negative Klebsiella pneumoniae with MID 0.078 µg/disk. The number of four bromine atoms and two phenol functional groups are important for antibacterial activity (S. aureus and K. pneumoniae) and cytotoxicity (HEK293T). The result was supported by analysis of frontier molecular orbitals (FMOs). We also propose possible products of acetylation and debromination using analysis of FMOs and electrostatic charges and we confirm the experimental result.

Effects of sponge-derived polybrominated diphenyl ethers on human cancer cell α-N-acetylgalactosaminidase and bacterial α-d-galactosidase and their antioxidant activity

“…For the present study, polybrominated diphenyl ethers 2-(2′,4′-dibromophenoxy)-3,5-dibromophenol ( 1 , yield 0.03% on the dry weight of the sponge) and 2-(2′,4′-dibromophenoxy)-3,4,5-tribromophenol ( 2 , yield 0.15%) were reisolated from repository sample of a Dysidea sponge and identified by comparison of their spectroscopic data ( 1 H-, 13 C-NMR, HREI MS) with published values. 18–21,58 Reisolation of compounds 3–7 was described previously. 54…”

“…Pure 2 (9.0 mg, 0.15% on dry weight of the sponge) was obtained by several recrystallizations from acetone and identified as 2-(3′,5′-dibromo-2′-hydroxyphenoxy)-3,4,6-tribromophenol. 18–21…”

“…65,66 The reaction mixture (2 mL total volume) consisted of EtOH comparison of their spectroscopic data ( 1 H-, 13 C-NMR, HREI MS) with published values. [18][19][20][21]58 Reisolation of compounds 3-7 was described early. 54 α-PsGal inhibitory potency of compounds 1 and 2.…”

“…17 Naturally produced PBDEs with various degrees of hydroxylation, methoxylation, and bromination have been mainly isolated with high yields from tropical marine sponges of Dysideidae family. [18][19][20][21][22] Spongean PBDEs possess antimicrobial, 19,23 antifungal, 24 antiviral 25 activities, inhibit human aldose reductase 26 and a range of enzymes that are implicated in tumor development, such as inosine monophosphate dehydrogenase, guanosine monophosphate synthetase, 27 15lipoxygenase, 28 Tie2 kinase. 29 They inhibit the assembly of microtubuline proteins, 30 regulate interleukin-8 production, 31 exhibit anti-proliferative activity against cancer cells adapted to glucose starvation.…”