David J. Madar

Structure-guided design of a series of MCL-1 inhibitors with high affinity and selectivity.

Myeloid cell leukemia 1 (MCL-1) is a BCL-2 family protein that has been implicated in the progression and survival of multiple tumor types. Herein we report a series of MCL-1 inhibitors that emanated from a high throughput screening (HTS) hit and progressed via iterative cycles of structure-guided design. Advanced compounds from this series exhibited subnanomolar affinity for MCL-1 and excellent selectivity over other BCL-2 family proteins as well as multiple kinases and GPCRs. In a MCL-1 dependent human tumor cell line, administration of compound 30b rapidly induced caspase activation with associated loss in cell viability. The small molecules described herein thus comprise effective tools for studying MCL-1 biology.

Synthesis of N-arylated oxazolidinones via a palladium catalyzed cross coupling reaction. Application to the synthesis of the antibacterial agent Dup-721

Abstract A method for the intermolecular coupling of aryl bromides and oxazolidinones is described. Application to intermediates useful for the preparation of a known class of antibacterial agent and the synthesis of the known antibacterial oxazolidinone Dup-721 are described.

Towards the synthesis of streptovaricin D: Synthesis of fully elaborated aromatic precursors and coupling with ansa chain fragments

Abstract The highly functionalized streptovaricin-damavaricin D aromatic precursors 12 and 15 have been prepared and coupled with propionaldehyde or unsaturated aldehydes 16 and 18 via aryllithium intermediates to give 2, 3 and 19.