ABSTRACT
Dasatinib was identified as a potent orally administered Src/Abl kinase inhibitor with excellent antiproliferative activity against Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase. The low bioavailability of Dasatinib may be due to both incomplete oral absorption and first-pass metabolism. A prodrug, JLTN, was synthesized to minimize the first-pass effect of Dasatinib and improve the oral bioavailability following oral administration via targeting intestinal peptide transporter and enhancing chemical stability. Biological evaluation data indicated that there was a 150%-fold increase in oral bioavailability of this prodrug compared to the parent drug Dasatinib in monkeys.
Subject(s)
Prodrugs/chemical synthesis , Prodrugs/pharmacokinetics , Pyrimidines/chemical synthesis , Pyrimidines/pharmacokinetics , Thiazoles/chemical synthesis , Thiazoles/pharmacokinetics , Animals , Dasatinib , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Macaca mulatta , Male , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokineticsABSTRACT
Indoleamine 2,3-dioxygenase (IDO) is an enzyme that suppresses adaptive T-cell immunity by catabolizing tryptophan from the cellular microenvironment. Inhibition of IDO pathway might enhance the efficacy of immunotherapeutic strategies for cancer. We synthesized 1-alkyl-tryptophan targeted IDO inhibitors and compared their effects on IDO expression and activity in dendritic cells (DCs) with the common IDO inhibitor 1-methyl-DL-tryptophan (1-MT). The IDO gene expression was examined by RT-PCR and realtime PCR. The toxicity of these analogs on the proliferation of DCs was detected by MTT assay. All of these analogs inhibited IDO expression and activity induced by IFN-gamma and showed no cytotoxicity to DCs at 100 microM. 1-MT intensively suppressed IDO1 expression and activity in DCs, and 1-propyl-tryptophan (1-PT) and 1-isopropyl-tryptophan (1-isoPT) moderately inhibited them. 1-Butyl-tryptophan (1-BT) and 1-ethyl-tryptophan (1-ET) mainly inhibited IDO2 expression. Our results suggest that those analogs differed in their inhibitory activity on IDO expression may give us a clue for developing active IDO inhibitors.
Subject(s)
Dendritic Cells/drug effects , Gene Expression Regulation, Enzymologic , Indoleamine-Pyrrole 2,3,-Dioxygenase/genetics , Interferon-gamma/pharmacology , RNA, Messenger/genetics , Animals , Cell Proliferation , Cells, Cultured , Dendritic Cells/enzymology , Down-Regulation , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Mice , Recombinant Proteins , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
A convenient remote controlled synthesis of a new tryptophan analog, l-5-(2-[(18)F] fluoroethoxy)-tryptophan (5-(18)FEHTP) was described. The radiochemical yield within 65min was about 12-16% without decay correction, the radiochemical purity was over 98%, and 5-(18)FEHTP dissolved in saline was stable over 6h at room temperature. The biodistribution of 5-(18)FEHTP in mice and the high uptake of 5-(18)FEHTP in tumor demonstrated that it is very likely a new PET tracer for tumor imaging.
Subject(s)
Brain Neoplasms/diagnostic imaging , Inflammation/diagnostic imaging , Positron-Emission Tomography/methods , Radiopharmaceuticals/pharmacokinetics , Tryptophan/analogs & derivatives , Animals , Brain Neoplasms/metabolism , Image Enhancement/methods , Inflammation/metabolism , Isotope Labeling/methods , Metabolic Clearance Rate , Mice , Organ Specificity , Radiopharmaceuticals/chemical synthesis , Tissue Distribution , Tryptophan/chemistry , Tryptophan/pharmacokineticsABSTRACT
To seek novel antitumor agents, we designed and synthesized new 1-tryptophan analogs based on tryptophan catabolism. 1-Alkyl-tryptophan analogues including 1-ethyltryptophan (1-ET), 1-propyltryptophan (1-PT), 1-isopropyltryptophan (1-isoPT) and 1-butyltryptophan (1-BT) were synthesized from tryptophan. We examined whether those compounds had the antiproliferative effects on SGC7901 and HeLa cells line by using MTT assay in vitro, respectively. Compared to tryptophan, all targeted compounds efficiently inhibited proliferation of two cancer cell lines at 2 mmol/L for 48 hours. Among these tryptophan analogs, 1-BT showed the most powerful cytotoxicity against SGC7901 and HeLa cells at 1 mmol/L and 2 mmol/L concentration. These data suggest that some specific tryptophan analogs could be developed as potential anti-neoplastic agents.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Tryptophan/analogs & derivatives , Cell Line, Tumor , Drug Screening Assays, Antitumor , Enzyme-Linked Immunosorbent Assay , Humans , Magnetic Resonance Spectroscopy , Tryptophan/chemical synthesis , Tryptophan/pharmacologyABSTRACT
This paper outlines briefly the role of nuclear medicine in life sciences and health care. Molecular imaging by using isotopic tracers can noninvasively visualize the chemistry or hidden process in the cells and tissues inside the body, obtaining "functional" images to provide early information of any disease and revealing the secrets of life. The vitality of nuclear medicine is its ability to translate bench into new clinical application that can benefits the patients. Although nuclear medicine community in China has made significant achievement with a great effort since 1950s, there are many obstacles to future development. Recommended measures are proposed here in an attempt to solve our existing problems.
