Carbene–Metal–Amide Bond Deformation, Rather Than Ligand Rotation, Drives Delayed Fluorescence

We report three characteristics of ideal thermally activated delayed fluorescence molecular systems apparent in carbene–metal–amides: (a) an exceptionally small singlet–triplet gap that effectively eliminates the thermal activation barrier to reverse intersystem crossing; (b) significant singlet oscillator strength promoting fluorescence in the region of this small barrier; and (c) enlarged spin–orbit coupling driving reverse intersystem crossing in this region. We carry out highly correlated quantum-chemical calculations to detail the relative energies of and spin–orbit couplings between the singlet and triplet states, finding that they fall closer together in energy and couple more strongly in going from the singlet ground-state to the triplet optimized geometry. This structural reorganization is defined not by rotation of the ligands but by a nontrivial bending of the carbene–metal–amide bond angle. This bending reduces carbene–metal–amide symmetry and enhances singlet–triplet interaction strength. We clarify that the reverse intersystem crossing triggering delayed fluorescence occurs around the coplanar triplet geometric optimum

Carbene–Metal–Amide Bond Deformation, Rather Than Ligand Rotation, Drives Delayed Fluorescence

We report three characteristics of ideal thermally activated delayed fluorescence molecular systems apparent in carbene–metal–amides: (a) an exceptionally small singlet–triplet gap that effectively eliminates the thermal activation barrier to reverse intersystem crossing; (b) significant singlet oscillator strength promoting fluorescence in the region of this small barrier; and (c) enlarged spin–orbit coupling driving reverse intersystem crossing in this region. We carry out highly correlated quantum-chemical calculations to detail the relative energies of and spin–orbit couplings between the singlet and triplet states, finding that they fall closer together in energy and couple more strongly in going from the singlet ground-state to the triplet optimized geometry. This structural reorganization is defined not by rotation of the ligands but by a nontrivial bending of the carbene–metal–amide bond angle. This bending reduces carbene–metal–amide symmetry and enhances singlet–triplet interaction strength. We clarify that the reverse intersystem crossing triggering delayed fluorescence occurs around the coplanar triplet geometric optimum

Highly Potent, Selective, and Orally Bioavailable 4‑Thiazol‑<i>N</i>‑(pyridin-2-yl)pyrimidin-2-amine Cyclin-Dependent Kinases 4 and 6 Inhibitors as Anticancer Drug Candidates: Design, Synthesis, and Evaluation

Cyclin D dependent kinases (CDK4 and CDK6) regulate entry into S phase of the cell cycle and are validated targets for anticancer drug discovery. Herein we detail the discovery of a novel series of 4-thiazol-<i>N</i>-(pyridin-2-yl)­pyrimidin-2-amine derivatives as highly potent and selective inhibitors of CDK4 and CDK6. Medicinal chemistry optimization resulted in <b>83</b>, an orally bioavailable inhibitor molecule with remarkable selectivity. Repeated oral administration of <b>83</b> caused marked inhibition of tumor growth in MV4-11 acute myeloid leukemia mouse xenografts without having a negative effect on body weight and showing any sign of clinical toxicity. The data merit <b>83</b> as a clinical development candidate

Substituted 4‑(Thiazol-5-yl)-2-(phenylamino)pyrimidines Are Highly Active CDK9 Inhibitors: Synthesis, X‑ray Crystal Structures, Structure–Activity Relationship, and Anticancer Activities

Cancer cells often have a high demand for antiapoptotic proteins in order to resist programmed cell death. CDK9 inhibition selectively targets survival proteins and reinstates apoptosis in cancer cells. We designed a series of 4-thiazol-2-anilinopyrimidine derivatives with functional groups attached to the C5-position of the pyrimidine or to the C4-thiazol moiety and investigated their effects on CDK9 potency and selectivity. One of the most selective compounds, <b>12u</b> inhibits CDK9 with IC₅₀ = 7 nM and shows over 80-fold selectivity for CDK9 versus CDK2. X-ray crystal structures of <b>12u</b> bound to CDK9 and CDK2 provide insights into the binding modes. This work, together with crystal structures of selected inhibitors in complex with both enzymes described in a companion paper, provides a rationale for the observed SAR. <b>12u</b> demonstrates potent anticancer activity against primary chronic lymphocytic leukemia cells with a therapeutic window 31- and 107-fold over those of normal B- and T-cells