Somalactams A-D: Anti-inflammatory Macrolide Lactams with Unique Ring Systems from an Arctic Actinomycete Strain.
Fan YangMoli SangJing-Rong LuHui-Min ZhaoYike ZouWei WuYong YuYa-Wei LiuWencheng MaYun ZhangWei ZhangHou-Wen LinPublished in: Angewandte Chemie (International ed. in English) (2023)
Four new PKS-NRPS-derived macrolide lactams with three unique ring fusion types were discovered from the Arctic sponge associated actinomycete Streptomyces somaliensis 1107 using a genome mining strategy. Their structures were elucidated by a combination of MS, NMR spectroscopic analysis, and single-crystal X-ray diffraction. Biosynthetically, a novel gene cluster sml consisting of three polyketide synthases and one hybrid polyketide synthase-nonribosomal peptide synthetase together with cytochrome P450s and flavin-containing monooxygenases and oxidoreductases was demonstrated to assemble the unique skeleton. Pharmacological studies revealed that compound 1 displayed a potent anti-inflammatory effect without cytotoxicity. It inhibited IL-6 and TNF-α release in the serum of LPS-stimulated RAW264.7 macrophage cells with IC 50 values of 5.76 and 0.18 μM, respectively, and modulated the MAPK pathway. Moreover, compound 1 alleviated LPS-induced systemic inflammation in our transgenic fluorescent zebrafish model.
Keyphrases
- anti inflammatory
- lps induced
- high resolution
- inflammatory response
- climate change
- induced apoptosis
- genome wide
- signaling pathway
- mass spectrometry
- rheumatoid arthritis
- multiple sclerosis
- cell cycle arrest
- magnetic resonance
- molecular docking
- oxidative stress
- quantum dots
- adipose tissue
- copy number
- solid state
- pi k akt
- cell proliferation
- magnetic resonance imaging
- cell death
- fluorescent probe