Masaaki Suzuki

Potent Prostaglandin A1 Analogs That Suppress Tumor Cell Growth through Induction of p21 and Reduction of Cyclin E

Although the cyclopentenone prostaglandin A1 (PGA1) is known to arrest the cell cycle at the G1 phase in vitro and to suppress tumor growth in vivo, its relatively weak activity limits its usefulness in cancer chemotherapy. In an attempt to develop antitumor drugs of greater potency and conspicuous biological specificity, we synthesized novel analogs based on the structure of PGA1. Of the newly synthesized analogs, 15-epi-Δ7-PGA1 methyl ester (NAG-0092), 12-iso-Δ7-PGA1 methyl ester (NAG-0093), and ent-Δ7-PGA1methyl ester (NAG-0022) possess a cross-conjugated dienone structure around the five-member ring with unnatural configurations at C(12) and/or C(15) and were found to be far more potent than native PGA1 in inhibiting cell growth and causing G1arrest in A172 human glioma cells. These three analogs induced the expression of p21 at both RNA and protein levels in a time- and dose-dependent fashion. Kinase assays with A172 cells treated with these analogs revealed that both cyclin A- and E-dependent kinase activities were markedly reduced, although cyclin D1-dependent kinase activity was unaffected. Immunoprecipitation-Western blot analysis showed that the decrease in cyclin A-dependent kinase activity was due to an increased association of p21 with cyclin A-cyclin-dependent kinase 2 complexes, whereas the decrease in cyclin E-dependent activity was due to a combined mechanism involving reduction in cyclin E protein itself and increased association of p21. Thus, these newly synthesized PGA1analogs may prove to be powerful tools in cancer chemotherapy as well as in investigations of the structural basis of the antiproliferative activity of A series prostaglandins.

Pd0–Mediated Rapid C–[11C]Methylation and C–[18F]Fluoromethylation: Revolutionary Advanced Methods for General Incorporation of Short–Lived Positron–Emitting 11C and 18F Radionuclides in an Organic Framework

The study of in vivo bioscience and medical treatment from molecular point of view requires the precise evaluation of molecule behavior in living systems, especially involving the human body. Positron emission tomography (PET) is a non–invasive imaging technology with a good resolution, high sensitivity, and accurate quantification, which makes it possible to timely and spatially analyze the dynamic behavior of molecules in in vivo systems using a specific molecular probe labeled with positron–emitting radionuclides such as 11C, 13N, 18F, and 76Br (Phelps, 2004). PET has been extensively used for the diagnosis of diseases such as cancers, cerebral dysfunction, and etc., and recently, in medical checkups as an early detection approach. In the current paradigm shift to drug discovery, PET molecular imaging will provide an important new scientific platform to execute human microdosing trials during the early stage of drug development, especially from the viewpoint of promoting evidence–based medicine (Lappin & Garner, 2003; Bergström et al., 2003). A core concept and the driving force of molecular imaging would truly be “Seeing is Believing”. It is of significant value to unveil the vital functions and phenomena of living systems by molecular imaging the in vivo behavior of a ligand and the localization of a biologically significant target molecule. The potential of PET molecular imaging in an interdisciplinary scientific area strongly depends on the availability of suitable radioactive molecular probes with specific biological functions. The development of biologically significant novel PET probes will be accomplished by the combination of an efficient synthetic strategy for designed molecules and new advances in the field of labeling chemistry (Schubiger et al., 2007).