Expanding Complex Morpholines Using Systematic Chemical Diversity.

The morpholine heterocycle is a structural unit found in many bioactive compounds and FDA-approved drugs, but the generation of more complex C-functionalized morpholine derivatives remains considerably underexplored. Using systematic chemical diversity (SCD), a concept that guides the expansion of saturated drug-like scaffolds through regiochemical and stereochemical variation, we describe the synthesis of a collection of methyl-substituted morpholine acetic acid esters starting from enantiomerically pure amino acids and amino alcohols. In total, 24 diverse substituted morpholines were produced that vary systematically in regiochemistry and stereochemistry (relative and absolute). These diverse C-substituted morpholines can be directly applied in fragment screening or incorporated as building blocks in medicinal chemistry and library synthesis.

The roles of Cyp1a2 and Cyp2d in pharmacokinetic profiles of serotonin and norepinephrine reuptake inhibitor duloxetine and its metabolites in mice.

Duloxetine (DLX) is widely used to treat major depressive disorder. Little is known about the mechanistic basis for DLX-related adverse effects (e.g., liver injury). Human CYP1A2 and CYP2D6 mainly contributes to DLX metabolism, which was proposed to be involved in its adverse effects. Here, we investigated the roles of Cyp1a2 and Cyp2d on DLX pharmacokinetic profile and tissue distribution using a Cyp1a2 knockout (Cyp1a2-KO) mouse model together with a Cyp2d inhibitor (propranolol). Cyp1a2-KO has the few effects on the systematic exposure (area under the plasma concentration-time curve, AUC) and tissue disposition of DLX and its primary metabolites. Propranolol dramatically increased the AUCs of DLX by 3 folds and 1.5 folds in WT and Cyp1a2-KO mice, respectively. Meanwhile, Cyp2d inhibitor decreased the AUC of Cyp2d-involved DLX metabolites (e.g., M16). Mouse tissue distribution revealed that DLX and its major metabolites were the most abundant in kidney, followed by liver and lung with/without Cyp2d inhibitor. Cyp2d inhibitor significantly increased DLX levels in tissues (e.g., liver) in WT and KO mice and decreases the levels of M3, M15, M16 and M17, while it increased the levels of M4, M28 and M29 in tissues. Our findings indicated that Cyp2d play a fundamental role on DLX pharmacokinetic profile and tissue distribution in mice. Clinical studies suggested that CYP1A2 has more effects on DLX systemic exposure than CYP2D6. Further studies in liver humanized mice or clinical studies concerning CYP2D6 inhibitors-DLX interaction study could clarify the roles of CYP2D6 on DLX pharmacokinetics and toxicity in human.

Max-imizing the Attenuation of Myc Using Small Molecules.

It has been a widely held notion within the biomedical research community that the reliable modulation of transcription factors with small molecules would represent a holy grail, given their role in directly potentiating oncogenic programs. Among the transcription factors that have been held in highest regard is Myc, since its dysregulation is among the most recurrent events in human cancer. Despite intense efforts, the ability to identify compounds that bind directly to Myc, resulting in its functional inhibition, have been met with only moderate success. However, a new approach reported by Struntz et al. (Cell Chem. Biol., 2019) focuses on a different strategy of discovering molecules that bind to Myc's obligate partner Max. Using a small-molecule microarray screen, they report the identification of KI-MS2-008, a compound that results in the stabilization of Max homodimers and the attenuation of Myc. KI-MS2-008 suppresses cancer cell grown both in vitro and within in vivo models.