Novel SAR for quinazoline inhibitors of EHMT1 and EHMT2.

Detailed structure activity relationship of two series of quinazoline EHMT1/EHMT2 inhibitors (UNC0224 and UNC0638) have been elaborated. New and active alternatives are presented for the ubiquitous substitution patterns found in literature for the linker to the lysine mimicking region and the lysine mimic itself. These findings could allow for advancing EHMT1/EHMT2 inhibitors of that type beyond tool compounds by fine-tuning physicochemical properties making these inhibitors more drug-like.

Asymmetric synthesis of 3-oxa-15-Deoxy-16-(m-tolyl)-17,18,19,20-tetranorisocarbacyclin and its neuroprotective analogue 15-Deoxy-16-(m-tolyl)-17,18,19,20-tetranorisocarbacyclin based on the conjugate addition-azoalkene-asymmetric olefination strategy.

A fully stereocontrolled synthesis of 3-oxa-15-deoxy-16-(m-tolyl)-17,18,19,20-tetranorisocarbacyclin (3-oxa-15-deoxy-TIC, 7 b) and a formal one of 15-deoxy-16-(m-tolyl)-17,18,19,20-tetranorisocarbacyclin (15-deoxy-TIC, 7 a) are described. 15-Deoxy-TIC is specific for the neuronal prostacyclin receptor (IP2) and exhibits neuroprotective activities, and the new 3-oxa-15-deoxy-TIC is expected to be metabolically more stable than 15-deoxy-TIC. The syntheses of 7 a and 7 b are based on the convergent conjugate addition-azoalkene-asymmetric olefination strategy.