Synthesis of the Antiproliferative Agent Hippuristanol and Its Analogues from Hydrocortisone via Hg(II)-Catalyzed Spiroketalization: Structure−Activity Relationship Ragam Somaiah, † Kontham Ravindar, † Regina Cencic, ‡ Jerry Pelletier, ‡ and Pierre Deslongchamps* ,† † De ́ partement de Chimie, Faculte ́ des Sciences et de Ge ́ nie, Pavillon Alexandre-Vachon, Universite ́ Laval, 1045, Avenue de la Me ́ decine, Ville de Que ́ bec, Que ́ bec, G1V 0A6, Canada ‡ Department of Biochemistry and Oncology, McIntyre Medical Sciences Building, McGill University, Montreal, Quebec, H3G 1Y6, Canada * S Supporting Information ABSTRACT: An efficient synthesis of hippuristanol (1), a marine-derived highly potent antiproliferative steroidal natural product, and nine closely related analogues has been accomplished from the commercially available hydrocortisone utilizing Hg(II)-catalyzed spiroketalization of 3-alkyne-1,7-diol motif as a key strategy. This practical synthetic sequence furnished 1 in 11% overall yield from hydrocortisone in 15 linear steps. Modi fications to the parent molecule 1 encompassed changing the functional groups on rings A and E. Each analogue was screened for their effects on inhibition of cap-dependent translation, and the assay results were used to establish structure−activity relationships. These results suggest that the stereochemistry and all substituents of spiroketal portion (rings E and F) and C3-α and C11-β hydroxyl functional groups on rings A and C, respectively, are critical for the inhibitory activity of natural product 1. ■ INTRODUCTION Hippuristanol (1), a polyoxygenated marine-derived steroidal natural product, was isolated from the Gorgonian Isis hippuris. 1 We have previously identified hippuristanol as a highly potent candidate for the selective inhibition of eukaryotic initiation factor (elF)4A-RNA binding activity that can be used to distinguish between elF4A-dependent and independent modes of translation initiation in vitro and in vivo. 2 Eukaryotic protein synthesis is regulated at the level of initiation; here, a 40s ribosomal subunit and associated factors (43s preinitiation complex) are recruited to an mRNA by four initiation factors, namely, the eIF4F complex, which comprises the cap-binding protein, eIF4E, a large scaffolding protein, eIF4G, and an RNA helicase, elF4A. Eukaryotic initiation factor (elF)4A is the prototypical member of the DEAD-box family of RNA helicases, and it is required to unwind local secondary structure proximal to the 5′ m7GpppN cap structure. Compound 1 binds to eIFA and inhibits its RNA binding activity, thus inhibiting translation initiation. 2 Because of the selective translation inhibition activity of 1 and its effects on cellular proliferation, it is considered a promising lead for the development of anticancer chemotherapeutic agents. Inspired by fascinating structural features and promise as an anticancer and antiviral lead structure and in combination with lowest natural abundance, we have recently disclosed synthetic routes for 1 (in 5.54% overall yield in 12 steps) and its structurally close analogues of spiroketals appendage (E and F rings, Scheme 1) including structure−activity relationship (SAR) studies, starting from hecogenin acetate via 11- ketotigogenin, employing our own protocol of Hg(II)-catalyzed Received: November 21, 2013 Published: March 3, 2014 Scheme 1. Retrosynthetic Analysis of Hippuristanol (1) and Analogues 2−10 Article pubs.acs.org/jmc © 2014 American Chemical Society 2511 dx.doi.org/10.1021/jm401799j | J. Med. Chem. 2014, 57, 2511−2523