Abstract
Four novel compounds (1–4) as well as fourteen reported compounds (5–18) were isolated and purified from Salvia miltiorrhiza Bunge (Danshen). The structures of novel compounds were determined by 1D and 2D NMR, HRESIMS data, etc. The anti-inflammatory properties of all the compounds on RAW264.7 macrophages and their cytotoxicity on H1299 and Bel-7402 cell lines coupled with a structure-activity relationship (SAR) were investigated. Compound 4 demonstrated the best anti-inflammatory activity and was chosen for further research. Compound 4 greatly suppressed secretion of nitric oxide (NO), tumor necrosis factor (TNF)-α and interleukin-6 (IL-6) in the RAW264.7 macrophages stimulated by LPS. Additionally, the protein expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) was decreased and the nuclear translocation of NF-κB was attenuated after treatment with compound 4 in vitro. Compound 4 was able to dramatically inhibit LPS-induced activation of JNK1/2 and ERK1/2 and remarkably disrupted the TLR4 dimerization in LPS-induced RAW264.7 macrophages. Thus, the new compound 4 suppressed LPS-induced inflammation partially is due to the blocking TLR4 dimerization. In addition, the anti-cancer activity investigation indicated that most of isolated compounds exhibited cytotoxicity and the SAR analysis showed that the intact D ring was indispensable and unsaturated D ring played vital role.
Highlights
Properties, the compounds isolated from Danshen can be categorized as water-soluble and lipid-soluble constituents[13]
The IR adsorptions 1637, 2967 and 3368 cm−1 indicated the presence of methyl, hydroxyl and carbonyl groups, respectively. 1H NMR data revealed the presence of one tertiary methyl, one secondary methyl, and AB pattern for ortho-aromatic protons (Table 1)
The stereochemistry of compound 1 was elucidated by NOESY spectrum (Fig. 2) and literatures published[20,21]
Summary
Properties, the compounds isolated from Danshen can be categorized as water-soluble and lipid-soluble constituents[13]. The anti-inflammatory activity of tanshinone IIA and cryptotanshinone has been well established[24,25], most of the known compounds isolated by our group such as compounds 5, 6, 7, 9, 10, 11, 12, 13 and 14 have not been reported. 18 compounds were primarily screened with a LPS stimulated RAW264.7 macrophage cell model for their anti-inflammatory activities evaluation.
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