Li-Wu Chiang

Solution-phase parallel synthesis and screening of anti-tumor activities from fenbufen and ethacrynic acid libraries.

The derivatives with fenbufen and ethacrynic acid core compounds was synthesized through a facial preparation of 1-amino-4-azidobutane. The subsequent coupling with 102 members of carboxylic acids afforded amide products. The in situ screening using colorimetric assay with 3-(4.5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide showed that fenbufen but not ethacrynic acid butyl amide members displayed the cytotoxicities to tumor cells substantially, including two human cell lines (MCF7 and A549) and two murine cell lines (C26 and TRAMP-C1). Three fenbufen analogs were found to have a good anti-tumor activity comparable to cisplatin.

Synthesis and evaluation of [18F]Fluorobutyl ethacrynic amide: a potential PET tracer for studying glutathione transferase.

[(18)F]Flurobutyl ethacrynic amide ([(18)F]FBuEA) was prepared from the precursor tosylate N-Boc-N-[4-(toluenesulfonyloxy)butyl]ethacrynic amide with a radiochemical yield of 3%, a specific activity of 48 GBq/μmol and radiochemical purity of 98%. Chemical conjugation of [(18)F]FBuEA with glutathione (GSH) via a self-coupling reaction and enzymatic conjugation under catalysis of glutathiontransferase alpha (GST-α) and π provided about 41% yields of radiochemical conjugated product [(18)F]FBuEA-GSH, 85% and 5-16%, respectively. The catalytic selectivity of this tracer toward GST-alpha was addressed. Positron emission tomography (PET) imaging of [(18)F]FBuEA in normal rats showed that a homogeneous pattern of radioactivity was distributed in the liver, suggesting a catalytic role of GST. By contrast, PET images of [(18)F]FBuEA in rats with thioacetamide-induced cholangiocarcinoma displayed a heterogeneous pattern of radioactive accumulation with cold spots in tumor lesions. PET imaging with [(18)F]FBuEA could be used for early diagnosis of hepatic tumor with a low GST activity as well as liver function.

Synthesis of amino core compounds of galactosyl phytosyl ceramide analogs for developing iNKT-cell inducers.

1-Aminophytosphingosine and 6-aminogalactosyl phytosphingosine were prepared in 61% and 40% yield libraries with 44 carboxylic acids showed that a 4-butylbenzoic acid-derived product exe, respectively. Glycosylation using benzoyl-protected lipid resulted in better α-selectivity for ceramide analogs, but the yield was less than that obtained with benzyl moieties. Screening the amide rted less cytotoxicity. These analogs were purified for validation of immunological potencies and the α-GalCer analog but not the sphingosine analog stimulated human iNKT cell population.

Evaluation of 5-[123I] Iodo-arabino-uridine (123I-IaraU) as a Gene Probe for Tramp-C1/HSV1-sr39tk System

Background: 5-Iodo-arabino-uridine (IaraU) is a less toxic analogue of FIAU and may not be potential as a drug for suicide gene therapy. The purpose of this study was to evaluate the possibility of radioiodine labeled IaraU as a candidate for imaging HSV1-sr39tk report gene expression in tumor cells and animal model. Methods: The rat prostate cancer cell line Tramp-C1 was transduced with HSV1-sr39tk and IL-3. Uptake of 123I-IaraU in the transduced Tramp-C1 referred as Tramp-C1/IL3-tk and in the parental Tramp-C1 as a control was tested. The Tramp-C1/IL3-tk cells as well as the Tramp-C1 cells were inoculated subcutaneously into the left flank and the right flank of C57BL/6J mice separately to produce the prostate tumor xenografts. Biodistribution study in the tumor-implanted animals was carried out after intravenous injection of 123I-IaraU at 6 h and 24 h. The animals were imaged by 123I-IaraU using micro SPECT/CT at 1, 3, 6, and 24 h postinjection. Results: The biodistribution study showed intensive retention of the radioactivity in gastrointestinal tract at 6 h, and excreted almost exhaustively from the body at 24 h. The micro SPECT/CT imaging showed only trace uptake of 123I-IaraU in Tramp-C1/IL3-tk xenograft, and negligible uptake in the Tramp-C1 xenograft. Conclusion: 123I-IaraU was deficiently evidenced as a probe to monitor gene expression in the Tramp-C1/HSV1-sr39tk system.