AMIFOSTINE ESTERS FOR CYTOTOXIC CHEMOPROTECTION

Amifostine 1，WR-2721，Ethyol）作为细胞保护剂辅助剂，与顺铂、环磷酰胺、卡铂和丝裂霉素等癌症药物一起用于治疗癌症患者的各种实体瘤。氨磷汀保护正常组织免受抗癌剂的血液学、神经学、肾脏学和其他细胞毒性作用，而对癌细胞没有任何保护作用。氨磷汀（1）是一种硫代磷酸分子，在生理pH 7.4时以带电（离子化）分子形式存在，导致其在尿液中分布不良和清除迅速。因此，氨磷汀必须在癌症治疗前几分钟以高剂量静脉内给药。我们假设，用不稳定的（容易水解的）“R”基团化学掩蔽氨磷汀（1）的这些酸性质子将提供氨磷汀的酯前药，其在生理pH下不会水解，但可以在体内一段时间内被酯酶或磷酸酶或磷酸二酯酶水解。因此，氨磷汀的这些酯前药将改善氨磷汀的吸收/分布，并且在水解时，由于氨磷汀在一段时间内的逐渐释放，将改善正常细胞的细胞保护。因此，本发明的目的是设计和合成几种具有不同程度水解能力/稳定性的R=烷基、酰氧基烷基、烷氧基羰基、酰胺甲基和苄基氨磷汀前药;测定这些前药的log P值以评价亲脂性，研究这些前药的体外水解稳定性，以表征氨磷汀在生理pH 7：4下的释放;并研究这些前体药物在人结肠细胞系中的体外细胞毒性化学保护，以评估它们作为细胞保护剂的功效。这些研究的结果有望提供有关这些药物作为氨磷汀前药在癌症治疗中的潜在有用性的有价值的信息。

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.