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Synthesis of novel tylophorine derivatives and evaluation of their anti-inflammatory activity.

ABSTRACT: We have previously demonstrated that DCB-3503, a tylophorine analogue, has an anti-inflammatory property in murine models for autoimmune diseases. However, its mechanism remains unknown. Here, we have synthesized 34 derivatives of DCB-3503 and investigated their effects on T cells differentiation and TNF-? production. Six derivatives (4, 9, 13, 19, 31, and 32) could significantly promote the expression of Foxp3. Among these, the IC50 of 31 and 32 was about 500 ?M. Eight analogues (1, 2, 4, 9, 12, 18, 19, and 21) showed anti-TNF-? effect in Raw 264.7 cells and murine splenocytes, of which 18 and 19 were most significant. Moreover, 31 and 18 showed a better activity and cell survival ratio when compared with DCB-3503 at various concentrations. In summary, we have demonstrated the anti-inflammatory characteristics of 34 novel tylophorine derivatives and discussed their structure-activity relationship in order to explore their therapeutic potentials for inflammatory diseases.

SUBMITTER: Wen T

PROVIDER: S-EPMC4160763 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Synthesis of novel tylophorine derivatives and evaluation of their anti-inflammatory activity.

Wen Ti T Wang Ziwen Z Meng Xianyi X Wu Meng M Li Yangguang Y Wu Xiaoli X Zhao Liqing L Wang Puyue P Yin Zhinan Z Li-Ling Jesse J Wang Qingmin Q

ACS medicinal chemistry letters 20140723 9

We have previously demonstrated that DCB-3503, a tylophorine analogue, has an anti-inflammatory property in murine models for autoimmune diseases. However, its mechanism remains unknown. Here, we have synthesized 34 derivatives of DCB-3503 and investigated their effects on T cells differentiation and TNF-α production. Six derivatives (4, 9, 13, 19, 31, and 32) could significantly promote the expression of Foxp3. Among these, the IC50 of 31 and 32 was about 500 μM. Eight analogues (1, 2, 4, 9, 12 ...[more]

PMID: 25221661

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Project description:PurposeNonsteroidal anti-inflammatory drugs cause a series of adverse reactions. Thus, the search for new cyclooxygenase-2 selective inhibitors have become the main direction of research on anti-inflammatory drugs. Gentiopicroside is a novel selective inhibitor of cyclooxygenase-2 from Chinese herbal medicine. However, it is highly hydrophilic owing to the presence of the sugar fragment in its structure that reduces its oral bioavailability and limits efficacy. This study aimed to design and synthesize novel cyclooxygenase-2 inhibitors by modifying gentiopicroside structure and reducing its polarity.Materials and methodsWe introduced hydrophobic acyl chloride into the gentiopicroside structure to reduce its hydrophilicity and obtained some new derivatives. Their in vitro anti-inflammatory activities were evaluated against NO, TNF-α, PGE2, and IL-6 production in the mouse macrophage cell line RAW264.7 stimulated by lipopolysaccharide. The in vivo inhibitory activities were further tested against xylene-induced mouse ear swelling. Molecular docking predicted that whether new compounds could effectively bind to target protein cyclooxygenase-2. The inhibitory activity of new compounds to cyclooxygenase-2 enzyme were verified by the in vitro experiment.ResultsA total of 21 novel derivatives were synthesized, and exhibit lower polarities than the gentiopicroside. Most compounds have good in vitro anti-inflammatory activity. The in vivo activity results demonstrated that 8 compounds were more active than gentiopicroside. The inhibition rate of some compounds was higher than celecoxib. Molecular docking predicted that 6 compounds could bind to cyclooxygenase-2 and had high docking scores in accordance with their potency of the anti-inflammatory activity. The confirmatory experiment proved that these 6 compounds had significant inhibitory effect against cyclooxygenase-2 enzyme. Structure-activity relationship analysis presumed that the para-substitution with the electron-withdrawing groups may benefit the anti-inflammatory activity.ConclusionThese gentiopicroside derivatives especially PL-2, PL-7 and PL-8 may represent a novel class of cyclooxygenase-2 inhibitors and could thus be developed as new anti-inflammatory agents.

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Synthesis of novel tylophorine derivatives and evaluation of their anti-inflammatory activity.

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Synthesis of novel tylophorine derivatives and evaluation of their anti-inflammatory activity.

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