Targeting LRH-1: Virtual screening and molecular modeling were used to identify novel antagonists of liver receptor homolog-1 (LRH-1), an emerging therapeutic target for breast cancer. Hit compounds were synthesized and biologically assayed, and the preliminary results suggest that raloxifene-based analogues, substituted at the position C-7 of the benzothiophene ring, might generate an inactive protein conformation through binding and thus antagonize this nuclear receptor.

An efficient synthesis of the C13–C29 fragment of amphidinolide N is described. The synthesis relies on a new strategy involving palladium-catalyzed asymmetric allylic alkylation to generate diastereoselectively either the cis-or trans-THF unit simply by varying the enantiomer of the ligand. The C19 hydroxyl-bearing stereocenter was introduced using a chelation-controlled allylation which led exclusively to a single diastereoisomer.

The synthesis of des-epoxy-amphidinolide N was achieved in 22 longest linear and 33 total steps. Three generations of synthetic endeavors are reported herein. During the first generation, our key stitching strategy that highlighted an intramolecular Ru-catalyzed alkene-alkyne (Ru AA) coupling and a late-stage epoxidation proved successful, but the installation of the α,α′-dihydroxyl ketone motif employing a dihydroxylation method was problematic. Our second generation of synthetic efforts addressed the scalability problem of the southern fragment synthesis and significantly improved the efficiency of the atom-economical Ru AA coupling, but suffered from several protecting group-based issues that proved insurmountable. Finally, relying on a judicious protecting group strategy together with concise fragment preparation, des-epoxy-amphidinolide N was achieved in a convergent fashion. Calculations disclose a hydrogen-bonding bridge within amphidinolide N. Comparisons of 13 C NMR chemical shift differences using our synthetic des-epoxy-amphidinolide N suggest that amphidinolide N and carbenolide I are probably identical.

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The back cover picture shows superimposed models for two successive events in liver receptor homolog-1 (LRH-1) blockade. In the apo-receptor, the binding site is capped with helix 12 (cream), but antagonist (green) binding fills the entrance and displaces H-12 (orange). Two side chains on the apo-protein H-12 are responsible for the steric clash. For more details, see the Communication by Simak Ali, James P. Snyder, Anthony G. M. Barrett et al. on p. 1909 ff.

The novel steroids (XI) are prepared as single isomers.

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