Highly Stereoselective Asymmetric Total Synthesis of (-)-Jimenezin via Sequential Intramolecular Amide Enolate Alkylation.

A highly stereoselective asymmetric total synthesis of (-)-jimenezin (1), a potent anticancer acetogenin, was efficiently completed with the key feature being a sequential intramolecular amide enolate alkylation (IAEA). Our investigation to probe the origin of the complete stereoselectivity in the second IAEA step to form the conformationally flexible tetrahydrofuran with perfect stereocontrol identified the presence of the oxygen atom in the adjacent tetrahydropyran ring to be crucial.

KRCA-0008 suppresses ALK-positive anaplastic large-cell lymphoma growth.

Anaplastic lymphoma kinase (ALK), which belongs to the insulin receptor tyrosine kinase superfamily, plays an important role in nervous system development. Due to chromosomal translocations, point mutations, and gene amplification, constitutively activated ALK has been implicated in a variety of human cancers, including anaplastic large-cell lymphoma (ALCL), non-small cell lung cancer, and neuroblastoma. We evaluated the anti-cancer activity of the ALK inhibitor KRCA-0008 using ALCL cell lines that express NPM (nucleophosmin)-ALK. KRCA-0008 strongly suppressed the proliferation and survival of NPM-ALK-positive ALCL cells. Additionally, it induced G0/G1 cell cycle arrest and apoptosis by blocking downstream signals including STAT3, Akt, and ERK1/2. Tumor growth was strongly suppressed in mice inoculated with Karpas-299 tumor xenografts and orally treated with KRCA-0008 (50 mg/kg, BID) for 2 weeks. Our results suggest that KRCA-0008 will be useful in further investigations of ALK signaling, and may provide therapeutic opportunities for NPM-ALK-positive ALCL patients.

Stereoselective Protection-Free Asymmetric Total Synthesis of (+)-Chamuvarinin, a Potent Anticancer and Antitrypanosomal Agent: Substrate-Controlled Construction of the Adjacently Linked Oxatricyclic Core by Internal Alkylation.

A stereoselective protection-free asymmetric total synthesis of (+)-chamuvarinin (1), a potent anticancer and antitrypanosomal agent, has been accomplished. The adjacently linked [bis(tetrahydrofuran)]tetrahydropyran (THF-THF-THP) core of this natural product with seven stereogenic centers was constructed in a completely substrate-controlled fashion. The inter-ring stereochemistry ( threo,threo,threo) of the oxatricyclic core was established in a stereoselective fashion by a chelation-controlled Keck allylation, whereas the intraring cis or trans relative stereochemistry was controlled by a stereoselective internal alkylation.