thiohydantoins and pyridine

Five new thiohydantoin derivatives (

Topics: Animals; Cell Survival; Corticosterone; Desipramine; Humans; Lepidium; Neuroprotective Agents; PC12 Cells; Plant Extracts; Pyridines; Rats; Thiohydantoins

Prostate cancer (PC) is the most diagnosed type of malignancy in men and the major frequently cause of cancer-related death worldwide. The androgen receptor (AR) has become a promising drug target for the treatment of PC. Here, we reported the design, optimization and evaluation of pyridine tetrahydroisoquinoline thiohydantoin derivatives with improved activity and safety as potent AR antagonists. The most promising compound 42f exhibited potent inhibitory activity on AR and strongly blocked AR nuclear translocation. Moreover, 42f displayed promising in vitro antitumor activity toward AR-dependent prostate cancer cell lines (LNCaP) and also demonstrated therapeutic effects in LNCaP xenograft tumor model in mice (TGI: 79%) with no apparent toxicity observed in vivo. More importantly, 42f showed negligible penetration of the brain-blood barrier (BBB) compared with enzalutamide. These results provide a foundation for the development of a new class of androgen receptor antagonists for potential therapeutics against PC with lower seizurogenic risk for patients.

Topics: Androgen Receptor Antagonists; Animals; Antineoplastic Agents; Blood-Brain Barrier; Cell Proliferation; Dose-Response Relationship, Drug; Drug Discovery; Drug Screening Assays, Antitumor; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Structure; Neoplasms, Experimental; Pyridines; Receptors, Androgen; Structure-Activity Relationship; Tetrahydroisoquinolines; Thiohydantoins; Tumor Cells, Cultured

A new derivatizing reagent, acetyl isothiocyanate (AITC), is applied for C-terminal peptide sequencing. It has been successfully used to sequence six C-terminal residues of a synthetic peptide at low nanomole levels. According to the mechanism study of the derivatization of C-terminal amino acid with various reagents, the derivatizing reagents (R-N=C=S or SCN-) were classified into three types: type I, the ionic compound (e.g., HSCN, NH4SCN, KSCN); type II, R is a good leaving group (e.g., TMS-ITC, TBSn-ITC); type III, R is reactive (e.g., AITC, BITC, DPP-ITC). Type III reagents are superior to other reagents because their double-function of activation and derivatization. Unlike type I and type II reagents, type III reagent chemistry does not require oxazolinone formation which can cause racemization. Compared with benzoyl isothiocyanate, diphenyl phosphoroisothiocyanatidate, trimethylsilyl isothiocyanate, and ammonium thiocyanate, AITC is the most effective derivatizing reagent. As a type III reagent, AITC possesses some features such as no need for oxazolinone formation, no requirement for separate activation step, high reactivity, easy preparation, and low absorption at 260-270 nm. Different reaction conditions were investigated for optimization and the chemical mechanism of AITC chemistry is illustrated. A convenient and efficient approach for synthesis of amino acid thiohydantoins as reference standards has also been developed.

Topics: Amino Acids; Chromatography, High Pressure Liquid; Ethylamines; Isothiocyanates; Mass Spectrometry; Morpholines; Peptides; Pyridines; Sequence Analysis; Spectrophotometry, Ultraviolet; Temperature; Thiohydantoins