Journal
CHEMICAL BIOLOGY & DRUG DESIGN
Volume 86, Issue 4, Pages 753-763Publisher
WILEY-BLACKWELL
DOI: 10.1111/cbdd.12548
Keywords
acute lung injury; C66; chemical stability; drug design; synthesis
Funding
- National Natural Science Funding of China [21202124, 21472142, 81402783]
- Zhejiang Medical & Health Science and Technology Project [2013KYB168]
- SRF for ROCS, SEM
- Zhejiang Key Group Project in Scientific Innovation [2010R50042]
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We previously reported a symmetric monocarbonyl analog of curcumin (MACs), C66, which demonstrated potential anti-inflammatory activity and low toxicity. In continuation of our ongoing research, we designed and synthesized 34 asymmetric MACs based on C66 as a lead molecule. A majority of the C66 analogs effectively inhibited LPS induction of TNF- and IL-6 expression. Additionally, a preliminary SAR was conducted. Furthermore, active compounds 4a11 and 4a16 were found to effectively reduce theW/D ratio in the lungs and the protein concentration in the bronchoalveolar lavage fluid (BALF). Meanwhile, a histopathological examination indicated that these two analogs significantly attenuate tissue injury in the lungs with LPS-induced ALI rats. 4a11 and 4a16 also inhibited mRNA expression of several inflammatory cytokines, including TNF-, IL-6, IL-1, COX-2, ICAM-1 and VCAM-1, in the Beas-2B cellsafter LPS challenge. Altogether, the data exhibit a series of new C66 analogs as promising anti-inflammatory agents for the treatment of LPS-induced ALI.
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