Abstract
For imaging herpes simplex virus thymidine kinase, syntheses of 5-substituted arabinosyl uridine analogs were highly desirable. 5-[125I]Iodo arabinosyl uridine analog was prepared from 2,2'-cyclouridine via ring opening and destannyl radioiodination in 77% yield and in 99% yield respectively. 2',3',5'-O-acetyl N1-arabinosyl 5-trimethylstannyl uracil was prepared via deiodostannylation using hexamethylditin under catalysis of bis(triphenylphosphine)palladium dichloride in 75% yield. Cold target compounds, eg. 5-fluoro and (E)-5-(2-fluorovinyl) arabinosyl uridine analogs, were prepared via halodestannylation with selectfluorTM in 28% and 7% yield, respectively. Our other research goal regarding the development of cancer chemotherapy and tumor imaging agents has been realized through parallel solution-phase synthesis approach. We constructed a library of n-butyl amides under HBTU catalysis followed by 3-(4,5-cimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) screening. Unexpectedly, n-butyl amides of two common pharmaceuticals: ethacrynic acid and fenbufen revealed substantial toxicities against both A549 and MCF7 cell lines. For preparing radiofluoro substituted compounds, the required precursor, a tosylate, needed to be prepared first. N-Boc-4-hydroxy-n-butyl ethacrynic amide was used to generate the tosylate with TsCl in 20% yield. In addition, the authentic standard, N-Boc-4-fluoro-n-butyl ethacrynic amide, was prepared from the alcohol in 45% yield. For preventing the ring closure during radionucleophilic fluorination, the proton of amido group should be protected via three steps of reactions in 40% yield via t-butyldimethylsilyl chloride, di(t-butyl carbonate) anhydride and tetrabutylammonium fluoride/AcOH, sequentially. 8-Fluoro-n-octyl azide was prepared via di-tosylation of 1,8-n-octan-diol with TsCl, followed by azide-transfer reaction and nucleophilic fluoro substitution. The yield via three steps was 28%. Followed by hydrogenation with triphenylphosphine, the desired core amino compound, 8-fluoro-n-octyl amine, was obtained in 58% yield. Another library of 1-amino-1-deoxy phytosphingosine analogs for targeting nature killer T cell proliferation was screened for their anti-cellular growth activity with MTT assay as well.