Large scale preparation of silicon-functionalized SynPhase Polystyrene lanterns for solid-phase synthesis.

The two-step functionalization of 30,000 SynPhase Polystyrene (PS) Lanterns in a 30-L glass process reactor is described. The first step involves bromination of the polystyrene backbone to afford an aryl bromide handle. Subsequent Suzuki cross coupling with the trialkylborane generated in situ from the reaction of allyldiisopropyl(4-methoxyphenyl)silane and 9-BBN provided an alkylsilyl linker ready for loading of various alcohols for solid-phase synthesis applications.

Pathway development and pilot library realization in diversity-oriented synthesis: exploring Ferrier and Pauson-Khand reactions on a glycal template.

Through a correlation of the ability of small molecules to bind biological macromolecules and their ability to modulate cellular and organismal processes, chemistry can inform biology and vice versa. Diversity-oriented organic synthesis (DOS), which aims to provide structurally complex and diverse small molecules efficiently, can play a key role in such chemical genetic studies. Here we illustrate the trial-and-error experimentation that can refine an initial pathway-planning exercise and result eventually in an effective diversity pathway. By exploring Ferrier and Pauson-Khand reactions on a glycal template, we have developed efficient and stereoselective syntheses of tricyclic compounds. In this pathway, diversity results from the substituents and their spatial relationships about the tricyclic rings. A pilot split-pool library synthesis of 2500 tricyclic compounds highlights the use of planning considerations in DOS and a "one-bead, one-stock solution" technology platform. Additionally, it illustrates a promising synthetic pathway for future chemical genetic studies.

Discovery and development of Hsp90 inhibitors: a promising pathway for cancer therapy.

The Hsp90 chaperone is a master regulator of the stability and activity of multiple oncoproteins such as Her2, Akt, Bcr-Abl, c-Kit, EGFR and mutant BRAF. The promise of inhibition of such a master regulator for cancer therapy is the potential to cause combinatorial inhibition of multiple oncogenic signaling pathways simultaneously. With the recent discovery of feedback loops that effectively negate the efficacy of selectively targeted anti-cancer agents, there is renewed interest in such a multi-pronged approach. There are now 14 drug candidates that target Hsp90 undergoing clinical trials in multiple indications as single agents or combination therapy. These compounds represent a diverse array of chemical matter stemming from natural product scaffolds to synthetic structure-based design. Although the compounds fall into distinct classes with unique properties, each inhibitor binds in the N-terminal ATP pocket and accumulates in tumor tissue while being rapidly cleared from circulation and normal tissue. The most advanced candidates are now in Phase 2 clinical trials and defining the therapeutic window, dosing schedule, and indication are the primary challenges for these potential first-in-class inhibitors.