Development of sertraline analogues as potential anti-ischemic stroke agents.

Ischemic stroke (IS) is harmful to human health and social development, and there is no medicine available at present. To find the hit compound for treating ischemic stroke, we screened 28 FDA approved nervous system drugs by using an in vitro OGD-induced stroke model. Notably, our in vitro and in vivo studies demonstrated that low-dose sertraline had good neuroprotective activities, while high-dose sertraline showed significant toxicity. Interestingly, the same high-dose sertraline in the control group did not exhibit any obvious toxic effect. Therefore, it is important to modify the structure of sertraline to improve the activity and reduce the toxicity. Stereoisomers of sertraline were first investigated to analyze the influence of stereochemistry on the neuroprotective activities, which showed no obvious difference. Then we evaluated the activity of our previously reported sertraline analogues and found that introducing amide or alkane groups to the amino moiety might be beneficial to enhance the activity and reduce the toxicity. Thus, 10 new analogues were designed, synthesized, and evaluated. Among them, compound OY-201 showed the best safety and neuroprotective activity in both in vitro and in vivo models. Moreover, it exhibited good blood-brain barrier (BBB) permeability, indicating its potential for the development of anti-ischemic stroke drugs.

Total Synthesis and Anti-Inflammatory Bioactivity of (-)-Majusculoic Acid and Its Derivatives.

The first total synthesis of marine natural product, (-)-majusculoic acid (1) and its seven analogs (9-15), was accomplished in three to ten steps with a yield of 3% to 28%. The strategy featured the application of the conformational controlled establishment of the trans-cyclopropane and stereochemical controlled bromo-olefination or olefination by Horner-Wadsworth-Emmons (HWE) reaction. The potential anti-inflammatory activity of the eight compounds (1 and 9-15) was evaluated by determining the nitric oxide (NO) production in the lipopolysaccharide (LPS)-induced mouse macrophages RAW264.7. (-)-Majusculoic acid (1), methyl majusculoate (9), and (1R,2R)-2-((3E,5Z)-6-bromonona-3,5-dien-1-yl)cyclopropane-1-carboxylic acid (12) showed significant effect with inhibition rates of 33.68%, 35.75%, and 43.01%, respectively. Moreover, they did not show cytotoxicity against RAW264.7 cells, indicating that they might be potential anti-inflammatory agents.

Identification of nicotinic acetylcholine receptor subunits in different lung cancer cell lines and the inhibitory effect of alpha-conotoxin TxID on lung cancer cell growth.

Lung cancer is an aggressive tumor with high incidence and mortality rate. There was growing evidence supporting that nicotinic acetylcholine receptors (nAChRs) play vital role inlung cancer development. In this study, the expression of α3, α4, α5, α6, α7, α9, α10, ß2, ß3, ß4 nAChR subunits on protein and mRNA level were studied in A549, NCI-H1299, NCI-H1688, DMS114 and normal human embryonic lung fibroblast (HEL) cell lines by real-time quantitative PCR (qPCR) and Western blot assay respectively. The results indicated that most of these nAChR subunits were expressed in these five cell lines. Compared with normal cells, the expression of α3 and ß4 nAChR subunits were upregulated in A549 and NCI-H1299. Thus, we treated A549 and NCI-H1299 with an antagonist α-conotoxin TxID which potently and selectively blocks α3ß4 nAChRs. TxID treatment could inhibit A549 and NCI-H1299 cell growth and enhance the inhibitory effect of adriamycin when treated simultaneously. To sum up, our study identified the expression of nAChR subunits in different lung cells and the anti-tumor effect of α-conotoxin TxID, which may provide novel strategies for lung cancer therapy.