jo7b03284_si_001.pdf (1.47 MB)
Synthesis of a Next-Generation Taxoid by Rapid Methylation Amenable for 11C‑Labeling
journal contribution
posted on 2018-02-14, 00:00 authored by Joshua
D. Seitz, Tao Wang, Jacob G. Vineberg, Tadashi Honda, Iwao OjimaNext-generation
taxoids, such as SB-T-1214, are highly potent cytotoxic
agents that exhibit remarkable efficacy against drug-resistant tumors
in vivo, including those that overexpress the P-glycoprotein (Pgp)
efflux pump. As SB-T-1214 is not a substrate for Pgp-mediated efflux,
it may exhibit a markedly different biodistribution and tumor-accumulation
profile than paclitaxel or docetaxel, which are both Pgp substrates.
To investigate the biodistribution and tumor-accumulation levels of
SB-T-1214 using positron emission tomography (PET), a new synthetic
route has been developed to allow the incorporation of 11C, a commonly employed positron-emitting radionucleide, via methyl
iodide at the last step of chemical synthesis. This synthetic route
features a highly stereoselective chiral ester enolate–imine
cyclocondensation, regioselective hydrostannation of the resulting
β-lactam, and the Stille coupling of the novel vinylstannyl
taxoid intermediate with methyl iodide. Conditions have been established
to allow the rapid methylation and HPLC purification of the target
compound in a time frame amenable to 11C-labeling for applications
to PET studies.