형광특성을 갖는 수용성 파클리탁셀의 합성 및 특성

Abstract

Paclitaxel(Taxol) is a antineoplastic agent that is derived from the bark of the Pacific yew tree (Taxus brevifolia) (Wani et al., 1971). It has been used to ovarian carcinoma, breast carcinoma, leukemia, melanoma, prostate carcinoma and so on, and has become especially important for the management of ovarian and breast carcinoma (Sarosy et al., 1992, Holmes et al., 1991). But, the application of some pharmaceutically active substances such as an anti-cancer drug, paclitaxel, suffer from their low solubility in body fluids and serious side effects. There were several ways to overcome this problem. One possible way is substitution at the reactive sites on the carbon 2' and/or 7 position of the chemical structure of paclitaxel. The conventional such derivatives of paclitaxel with poly(ethylene-glycol) PEG, however, were too stable so that a high percentage of the polymer drug could be excreted before the drug made bio-available parent drug by esterases with their intended interaction. Jo. et al.17~27) solved this problem by the development of a prodrug, so called PP7 which introduces a hydrophilic PEG, succinic acid mono-ester of poly(ethylene-glycol) monomethylether, with a self-immolating linker(L) at the carbon 7 position. A patented self-immolating link17~19) between PEG and the drug which provides a hydrolytic stability of the drug-polymer link in the body liquid of only a few minutes, just sufficient to transport the major amount of the drug to the site where its activity is required. Fluorescent analogues of drugs, with a high quantum yield, are widely used as important tools in studies of the elucidation of structures and the mechanisms of drug binding to proteins and nucleic acids. The molecular mechanism(s) by which paclitaxel binds to and stabilizes microtubules is currently unclear. To get a better understanding the mechanism of action of paclitaxel and the environment of the paclitaxel-binding site, incorporation of fluorescent 1-pyrenbutyrate onto the carbon 2’ of paclitaxel and a paclitaxel prodrug(PP7)17~19) has been successfully carried out. These compounds synthesized were characterized by FT-NMR, high performance liquid chromatography (HPLC), UV and photo luminescence spectrometry. The paclitaxel analogues synthesized showed high fluorescent susceptibility with concentration dependency in both excitation and emission spectra. It could be used for in-vivo studying the mechanism of the bioactivities and efficacy of paclitaxel.