ABSTRACT
The buffered permanganate oxidation of (-)-myternal, a member of the pinene family, provides the α-hydroxyketone (-)-(1R,3S,5R)-3-hydroxy-6,6-dimethylbicyclo[3.1.1]heptan-2-one in preparative yield (65% on a multigram scale). This α-hydroxyketone is oxidized, in a second reaction, to the α,ß-diketone (1R,5R)-6,6-dimethylbicyclo[3.1.1]heptane-2,3-dione ("PinDione"). As both oxidations are fast, simple, safe, inexpensive, good-yielding, and multigram scalable, these transformations are a preparative expansion of the pinane family.
ABSTRACT
The RAS-RAF-MEK-MAPK cascade is an essential signaling pathway, with activation typically mediated through cell surface receptors. The kinase inhibitors vemurafenib and dabrafenib, which target oncogenic BRAF V600E, have shown significant clinical efficacy in melanoma patients harboring this mutation. Because of paradoxical pathway activation, both agents were demonstrated to promote growth and metastasis of tumor cells with RAS mutations in preclinical models and are contraindicated for treatment of cancer patients with BRAF WT background, including patients with KRAS or NRAS mutations. In order to eliminate the issues associated with paradoxical MAPK pathway activation and to provide therapeutic benefit to patients with RAS mutant cancers, we sought to identify a compound not only active against BRAF V600E but also wild type BRAF and CRAF. On the basis of its superior in vitro and in vivo profile, compound 13 was selected for further development and is currently being evaluated in phase I clinical studies.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Phenylurea Compounds/chemistry , Phenylurea Compounds/pharmacology , Proto-Oncogene Proteins B-raf/genetics , Pyrimidines/chemistry , Pyrimidines/pharmacology , ras Proteins/metabolism , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacokinetics , Biological Availability , Cell Line, Tumor/drug effects , Chemistry Techniques, Synthetic , Dogs , Female , Half-Life , Humans , Male , Mice, Nude , Molecular Targeted Therapy , Mutation , Phenylurea Compounds/chemical synthesis , Phenylurea Compounds/pharmacokinetics , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Proto-Oncogene Proteins B-raf/metabolism , Proto-Oncogene Proteins c-raf/metabolism , Pyrimidines/chemical synthesis , Pyrimidines/pharmacokinetics , Rats, Sprague-Dawley , Structure-Activity Relationship , Xenograft Model Antitumor Assays , ras Proteins/geneticsABSTRACT
Treatment of pyridine borane (Py.BH3) with iodine, bromine, or strong acids affords activated Py.BH2X complexes that are capable of hydroborating alkenes at room temperature. Evidence is presented for an unusual hydroboration mechanism involving leaving group displacement. In contrast to THF.BH3, hydroboration with Py.BH2I selectively affords the monoadducts. The crude hydroboration products are converted into synthetically useful potassium alkyltrifluoroborate salts upon treatment with methanolic KHF2.
