ChemInform Abstract: HIGHLY STEREOSELECTIVE HYDROGENATION OF 3‐OXO‐4‐ENE AND ‐1,4‐DIENE STEROIDS TO 5β COMPOUNDS WITH PALLADIUM CATALYST

Tsuji, Natsuko; Suzuki, Jun; Shiota, Michio; Takahashi, Izumi; Nishimura, Shigeo

doi:10.1002/chin.198047127

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“…We chose to explore the importance of the half-chair conformation of the A-ring system of compound 2 on the potency. Stereoselective reduction of the enone of 2 with Li/NH 3 provided trans -decalone 4 (Scheme ), whereas hydrogenation catalyzed with Pd/C in presence of pyridine yielded the cis -decalone as the major product (ratio of ∼9:1). Protection of the piperidine nitrogen of cis -decalone as a benzyl carbamate provided stereochemically pure material ( 5 ) after silica gel chromatography, and removal of protecting group provided 6 .…”

Section: Chemistrymentioning

confidence: 99%

Discovery of a Potent and Orally Active Hedgehog Pathway Antagonist (IPI-926)

et al. 2009

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Recent evidence suggests that blocking aberrant hedgehog pathway signaling may be a promising therapeutic strategy for the treatment of several types of cancer. Cyclopamine, a plant Veratrum alkaloid, is a natural product antagonist of the hedgehog pathway. In a previous report, a seven-membered D-ring semisynthetic analogue of cyclopamine, IPI-269609 (2), was shown to have greater acid stability and better aqueous solubility compared to cyclopamine. Further modifications of the A-ring system generated three series of analogues with improved potency and/or solubility. Lead compounds from each series were characterized in vitro and evaluated in vivo for biological activity and pharmacokinetic properties. These studies led to the discovery of IPI-926 (compound 28), a novel semisynthetic cyclopamine analogue with substantially improved pharmaceutical properties and potency and a favorable pharmacokinetic profile relative to cyclopamine and compound 2. As a result, complete tumor regression was observed in a Hh-dependent medulloblastoma allograft model after daily oral administration of 40 mg/kg of compound 28.

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Section: Chemistrymentioning

confidence: 99%