AMIFOSTINE ESTERS FOR CYTOTOXIC CHEMOPROTECTION

用于细胞毒性化学保护的氨磷汀酯

• 批准号: 6450667
• 负责人: Shashikant K Phadtare
• 金额: $ 3.85万
• 依托单位: XAVIER UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6450667
• 关键词: cell line; cytoprotection; drug design /synthesis /production; drug screening /evaluation; esters; neoplasm /cancer chemotherapy; prodrugs; thiophosphate

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.

氨fostine 1， WR-2721, Ethyol)作为细胞保护佐剂与顺铂、环磷酰胺、卡铂、丝裂霉素等抗癌药物一起用于治疗多种肿瘤患者的实体瘤。氨磷汀保护正常组织免受血液学、神经学、肾学和其他抗癌药物的细胞毒性作用，而对癌细胞没有任何保护作用。氨磷汀(1)是一种磷硫酸分子，它以带电（电离）分子的形式存在，生理Ph值为7.4，这导致其在尿液中的分布不佳，清除迅速。因此，氨磷汀必须在癌症治疗前几分钟静脉注射高剂量。我们假设氨fofostine(1)的这些酸性质子被不稳定的（容易水解的）R基团化学掩膜将提供氨fofostine的酯前药物，这些药物在生理pH下不会电离，但可以在体内被酯酶或磷酸酶或磷酸二酯酶水解一段时间。这些氨磷汀的酯类前药，因此会改善氨磷汀的吸收/分布，水解后由于氨磷汀在一段时间内逐渐释放，会改善正常细胞的细胞保护作用。因此，本课题的目标是设计并合成几种具有不同程度水解能力/稳定性的R=烷基、酰基氧基烷基、烷氧羰基、氨基甲基和苯基氨fostine前药；测定这些前药的log P值，评价其亲脂性；研究这些前药的体外水解稳定性，表征生理pH值7:4时氨磷汀的释放；并研究这些前药对人结肠癌细胞系的体外细胞毒化学保护作用，评价其作为细胞保护剂的作用。这些研究的结果有望为这些药物作为氨磷汀的前药在癌症治疗中的潜在有用性提供有价值的信息。