Background and purpose: Selective androgen receptor modulators are of great value in the treatment of prostate cancer. The purpose of this study was to provide a preliminary characterization of a new class of non-steroidal androgen receptor modulators discovered in a high-throughput screening campaign. Experimental approach: Competitive receptor binding, luciferase-based reporter methods, cell proliferation and in vivo assays were employed to evaluate an initial set of compounds from chemistry efforts. Key results: Forty-nine analogues from the chemistry efforts showed high affinity binding to androgen receptors, agonist and/ or antagonist activities in both CV-1 and MDA-MB-453 transfection assays. A proliferation assay in LNCaP cells also exhibited this profile. A representative of these non-steroidal compounds (compound 21) was devoid of activity at other nuclear receptors (oestrogen, progesterone, glucocorticoid and mineralocorticoid receptors) in the CV-1 co-transfection assay. At the same time, in an immature castrated rat model, it behaved as an androgen receptor antagonist against the growth of prostate, seminal vesicles and levator ani induced by exogenous androgen. Separation of compound 21 into its enantiomers showed that nearly all the androgen receptor modulating activity and binding resided in the dextrorotatory compound (23) while the laevorotatory isomer (22) possessed weak or little effect depending on the cell type studied. Conclusions and implications: These non-steroidal compounds may represent a new class of androgen receptor modulators for the treatment of not only prostate cancer but other clinical conditions where androgens and androgen receptors are involved in the pathological processes.

Mycobacterium tuberculosis (MTB) remains one of the most significant human pathogens since its discovery in 1882. An estimated 1.5 million people died from tubercle bacillus (TB) in 2006, and globally, there were an estimated 9.27 million incident cases of TB in 2007. Glyoxylate bypass pathway occurs in a wide range of pathogens and plays a key role in the pathogenesis of Mycobacterium tuberculosis. Isocitrate lyase (ICL) can catalyses the first step of this pathway, and reversibly cleaves isocitrate into succinate and glyoxylate. So, ICL may represent a good drug target for the treatment of tuberculosis. ICL was cloned, expressed, and purified, and a high-throughput screen (HTS) developed to screen active molecule from a mannich base compounds library for inhibition of ICL. This assay had signal to noise (S/N) of 650.6990 and Z' factor of 0.8141, indicating that the assay was suitable for HTS. Screening of a collection of 124 mannich base compounds resulted in the identification of one mannich base compound, which has a significant inhibitory activity. So, a new family of compound was first reported to inhibit the activity of Mycobacterium tuberculosis ICL. This family of compound might offer new avenue to explore better anti-tuberculosis and fungi drugs.

Gastrointestinal motility disorders are one of the main pathogenic factors responsible for functional dyspepsia (FD). Platelet-derived growth factor receptor-α-positive (PDGFRα+) cells participate in regulating gastrointestinal motility; however, the underlying mechanisms remain unclear. Herein, we aimed to assess the therapeutic effects of electroacupuncture (EA) and determine whether EA modulates the phospholipase C (PLC)-inositol-1,4,5-trisphosphate (PLC-IP3) pathway in PDGFRα+ cells to improve gastrointestinal motility disorders in FD. Accordingly, FD rats stimulated by tail-clamping were treated with EA (with or without PLC inhibitor U73122). We observed that the PLC-IP3 pathway was modulated in PDGFRα+ cells, which improved gastrointestinal motility in FD model rats. Based on western blotting and immunofluorescence assay results, EA increased the expression of PDGFRα+ cells and promoted the expression of PLC, P-PLC, and IP3 in the gastric sinuses of FD rats. U73122-mediated inhibition of PLC expression treatment considerably reduced the frequency of gastrointestinal motility. However, there was no significant difference between the effects of antagonist and antagonist + EA treatments; EA treatment was superior to antagonist and antagonist + EA treatment alone. Overall, these results suggest that EA could ameliorate gastrointestinal motility disorders in FD rats by activating the PLC-IP3 pathway in PDGFRα+ cells.