AMIFOSTINE ESTERS FOR CYTOTOXIC CHEMOPROTECTION

Xavier University Of Louisiana, New Orleans LA

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Abstract

Amifostine 1, WR-2721, Ethyol) is used as a cytoprotector adjuvant agent with the therapy of cancer drugs such as cisplatin, cyclophosphonamide, carboplatin and mitomycin for the treatment of diverse range of solid tumors in cancer patients. Amifostine protects normal tissues against the hematological, neurological, nephrological and other cytotoxic effects of anti-cancer agents without any protection to cancer cells. Amifostine (1) is a phosphorothioic acidic molecule and it exists as a charged (ionized) molecule at a physiological Ph 7.4 which results in its poor distribution and rapid clearance in urine. Therefore, amifostine must be administered intravenously in high doses minutes before the cancer therapy. We hypothesized that the chemical masking of these acidic protons of amifostine (1) with labile (easily hydrolizable) 'R' groups will provide the ester pro-drugs of amifostine which will not ionize at physiological pH but can be hydrolyzed by esterase or phosphatase or phosphodiesterase enzymes in vivo over a period of time. These ester pro- drugs of amifostine, thus will improve the amifostine absorption/distribution and upon hydrolysis will improve the cytoprotection of normal cells due to gradual release of amifostine over a period of time. The goals of this proposal, therefore, are to design and synthesize several R=alkyl, acyloxyalkyl, alkoxycarbonyl, amidomethyl and benzyl amifostine pro-drugs with varying degree of hydrolytic ability/stability; to determine log P values of these pro-drugs to evaluate lipophilicity to study in vitro hydrolytic stability of these pro-drugs to characterize the release of amifostine at the physiological pH 7:4; and to study in vitro cytotoxic chemoprotection of these pro-drugs in human colon cell line to evaluate their efficacy as cytoprotector agents. The outcome of these studies is expected to provide valuable information about the potential usefulness of these agents as pro-drugs of amifostine in cancer therapy.