1,3-Disubstituted-1,2,4-triazin-6-ones with potent activity against androgen receptor-dependent prostate cancer cells.

Synthesis and biological evaluation of a small, focused library of 1,3-disubstituted-1,2,4-triazin-6-ones for in vitro inhibitory activity against androgen-receptor-dependent (22Rv1) and androgen-receptor independent (PC3) castration-resistant prostate cancer (CRPC) cells led to highly active compounds with in vitro IC50 values against 22Rv1 cells of <200 nM, and with apparent selectivity for this cell type over PC3 cells. From metabolic/PK evaluations of these compounds, a 3-benzyl-1-(2,4-dichlorobenzyl) derivative had superior properties and showed considerably stronger activity, by nearly an order of magnitude, against AR-dependent LNCaP and C4-2B cells compared to AR-independent DU145 cells. This lead compound decreased AR expression in a dose and time dependent manner and displayed promising therapeutic effects in a 22Rv1 CRPC xenograft mouse model. Computational target prediction and subsequent docking studies suggested three potential known prostate cancer targets: p38a MAPK, TGF-ß1, and HGFR/c-Met, with the latter case of c-Met appearing stronger, owing to close structural similarity of the lead compound to known pyridazin-3-one derivatives with potent c-Met inhibitory activity. RNA-seq analysis showed dramatic reduction of AR signalling pathway and/or target genes by the lead compound, subsequently confirmed by quantitative PCR analysis. The lead compound was highly inhibitory against HGF, the c-Met ligand, which fitted well with the computational target prediction and docking studies. These results suggest that this compound could be a promising starting point for the development of an effective therapy for the treatment of CRPC.

1-Benzyloxy-5-phenyltetrazole derivatives highly active against androgen receptor-dependent prostate cancer cells.

A series of 1-benzyloxy-5-phenyltetrazole derivatives and similar compounds were synthesized and evaluated for their in vitro inhibitory activity against androgen-receptor-dependent (22Rv1) and androgen-receptor independent (PC3) prostate cancer cells. The most active compounds had in vitro IC50 values against 22Rv1 cells of <50 nM and showed apparent selectivity for this cell type over PC3 cells; however, these active compounds had short half-lives when incubated with mouse liver microsomes and/or when plasma concentration was monitored during in vivo pharmacokinetic studies in mice or rats. Importantly, lead compound 1 exhibited promising inhibitory effects on cell proliferation, expression of AR and its splicing variant AR-v7 as well as AR regulated target genes in 22Rv1 cells, which are so called castration-resistant prostate cancer (CRPC) cells, and a 22Rv1 CRPC xenograft tumour model in mice. Structural changes which omitted the N-O-benzyl moiety led to dramatic or total loss of activity and S-benzylation of a cysteine derivative, as a surrogate for in vivo S-nucleophiles, by representative highly active compounds, suggested a possible chemical reactivity basis for this "activity cliff" and poor pharmacokinetic profile. However, representative highly active compounds did not inhibit a cysteine protease, indicating that the mode of activity is unlikely to be protein modification by S-benzylation. Despite our efforts to elucidate the mode of action, the mechanism remains unclear.

Managing the efficiencies of three different bacterial isolates for removing atrazine from wastewater.

Three individual bacterial isolates previously isolated from two types of soil with a different history of atrazine applications were chosen, purified, and subjected to subsequent work. Identification of the individual bacterial isolates was conducted using molecular methods 16S rRNA and then tested for their atrazine degradation potentials. Effects of different parameters like mixing, starvation, UV exposure, and sodium citrate for enhancing the atrazine bioremediation process by identified bacteria were also studied. The molecular method identified individual bacterial isolates as Stenotrophomonas sp. strain SD2 (strain SD2), Bacillus cereus strain BC3 (strain BC3), and Paenarthrobacter ureafaciens strain AD3 (strain AD3). The bacterial isolate strain AD3 was able to degrade 47.95% of atrazine after 28 days. Mixing strain AD3 with strain BC3 showed almost doubled of atrazine degradation percentage (61.39%) of using strain BC3 as an individual isolate (36.59%). The atrazine degradation efficacy for Stenotrophomonas sp. strain SD2, Bacillus cereus strain BC3, and Paenarthrobacter ureafaciens strain AD3 was increased between 1.28 and 4.32 folds after the starvation process. The UV exposure enhanced the efficiencies of the tested isolates either individual or mixtures (from 1.08 to 4.63-fold). Adding sodium citrate as a stimulator to the media of growing the tested isolates enhanced their potential for atrazine degradation.