MChem

The tert-butyl group is a common motif in medicinal chemistry. Its incorporation into bioactive compounds is often accompanied by unwanted property modulation, such as increased lipophilicity and decreased metabolic stability. Several alternative substituents are available for the drug discovery process. Herein, physicochemical data of two series of drug analogues of bosentan and vercirnon are documented as part of a comparative study of tert-butyl, pentafluorosulfanyl, trifluoromethyl, bicyclo[1.1.1]pentanyl, and cyclopropyl-trifluoromethyl substituents.

The alternative scene: Given how common the tert-butyl group is in medicinal chemistry, we set out to explore some isosteric alternatives in hopes of identifying motifs that circumvent the common drawbacks imparted by tert-butyl groups, such as increased lipophilicity and lower metabolic stability.

Androstene derivatives incorporating amino acid methyl esters were prepared, and their anti-inflammatory effects were evaluated in lipopolysaccharide (LPS)-activated BV-2 microglial cells. Several compounds exhibited dose-dependent inhibition. The most active compound, methyl ((3S,10R,13S)-3-hydroxy-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-carbonyl)-L-phenylalaninate (10) significantly suppressed LPS-induced expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). Mechanistic studies revealed that compound 10 markedly inhibits phosphorylation of p38 mitogen-activated protein kinases (MAPKs) and subsequent transcription factor (NF-κB) and activator protein-1 (AP-1) activation. Furthermore, compound 10 decreased LPS-activated microglial neurotoxicity in a condition medium/HT-22 neuroblastoma co-culture model. Taken together, these results suggest 10 is a potential lead compound for the development of a novel therapeutic agent for neurodegenerative diseases.

Protecting the grey matter! Androstenes incorporating amino acid methyl esters were developed against neuroinflammation. Compound 10 markedly suppressed NO production and iNOS, COX-2, TNF-α and IL-6 expression in lipopolysaccharide-induced microglia. Compound 10 also inhibited phosphorylation of mitogen-activated protein kinases and subsequent activator protein-1 activation. These results suggest 10 as a candidate for development as an anti-neurodegenerative agent.

The three-component coupling (3CC) of α-diazoamide, aldehyde and 3-arylideneoxindole using 5 mol-% of Rh₂(OAc)₄ is described to afford a novel class of dispirooxindole derivatives with complete regio- and stereoselectivity. It is a first report on the synthesis of natural product inspired libraries of dispirooxindoles through a carbonyl ylide cycloaddition.

A highly stereoselective synthesis of furo-dispirooxindoles has been achieved by using 5 mol-% of Rh₂(OAc)₄ under mild conditions through 1,3-dipolar cycloaddition of 3-arylideneoxindoles, with carbonyl ylides that are generated from 3-diazooxindole and aldehyde.

In the 10 years since the discovery of lysine-specific demethylase 1 (LSD1), this epigenetic eraser has emerged as an important target of interest in oncology. More specifically, research has demonstrated that it plays an essential role in the self-renewal of leukemic stem cells in acute myeloid leukemia (AML). This review will cover clinical aspects of AML, the role of epigenetics in the disease, and discuss the research that led to the first irreversible inhibitors of LSD1 entering clinical trials for the treatment of AML in 2014. We also review recent achievements and progress in the development of potent and selective reversible inhibitors of LSD1. These compounds differ in their mode of action from tranylcypromine derivatives and could facilitate novel biochemical studies to probe the pathways mediated by LSD1. In this review, we will critically evaluate the strengths and weaknesses of published series of reversible LSD1 inhibitors. Overall, while the development of reversible inhibitors to date has been less fruitful than that of irreversible inhibitors, there is still the possibility for their use to facilitate further research into the roles and functions of LSD1 and to expand the therapeutic applications of LSD1 inhibitors in the clinic.