CK-666 (1) is a recently discovered small molecule inhibitor of the Arp2/3 complex, a key actin cytoskeleton regulator with roles in bacterial pathogenesis and motility of cancer cells. While 1 is commercially available, the crystal structure of Arp2/3 (Actin-related protein 2/3) complex with 1 bound has not been reported, making its mechanism of action uncertain. Furthermore, its relatively low potency increases its potential for off target effects in vivo, complicating interpretation of its influence in cell biological studies and precluding its use in clinical applications. Here we report the crystal structure of 1 bound to Arp2/3 complex, which reveals that 1 binds between the Arp2 and Arp3 subunits to stabilize the inactive conformation of the complex. Based on the crystal structure, we used computational docking and free energy perturbation calculations of monosubstituted derivatives of 1 to guide optimization efforts. Biochemical assays of ten newly synthesized compounds led to the identification of compound 2, which exhibits a 3 fold increase in inhibitory activity in vitro. In addition, our computational analyses unveiled a surface groove at the interface of the Arp2 and Arp3 subunits that can be exploited for additional structure-based optimization.

A new methodology for the preparation of substituted naphthalenes starting from readily available indenones, organometal reagents, and trimethylsilyldiazomethane via a catalytic rearrangement process is described. Hindered biaryl naphthalenes, including triortho-substituted biaryls, can be accessed through our method. Our results are consistent with a mechanism involving a benzobenzvalene intermediate.

The synthesis of tetra-ortho-substituted biaryl naphthalenes, including examples bearing multiple ortho-isopropyl groups, has been developed via a catalytic rearrangement process.

Benzofulvenes and their derivatives are useful molecular entities having applications as biologically active molecules, polymer precursors, and optoelectronic devices. We have developed a simple and mild synthetic method for the formulation of a variety of these interesting compounds. Using carbonyl coupling techniques combined with microwave heating, a wide variety of functionalized benzofulvenes can be accessed rapidly in good yield. Furthermore, we have obtained five crystal structures further expanding a limited number of benzofulvene structures available.

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