Adriamycin analogues. rationale, synthesis, and preliminary antitumor evaluation of highly active DNA-nonbinding N-(trifluoroacetyl)adriamycin 14-O-hemiester derivatives.
Adriamycin analogues. rationale, synthesis, and preliminary antitumor evaluation of highly active DNA-nonbinding N-(trifluoroacetyl)adriamycin 14-O-hemiester derivatives.
复制标题
阿霉素类似物。
DOI：
10.1021/jm00147a017
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发表时间：
1985
影响因子：
7.3
通讯作者：
Seshadri,R
中科院分区：
文献类型：
--
作者：
Israel,M;Potti,PG;Seshadri,R
N-（三氟乙酰基）阿霉素14-戊酸（ad32）是一种新型的阿霉素DNA非结合类似物，具有良好的抗肿瘤活性，经过广泛的临床试验，具有抗肿瘤活性和低毒性。然而，由于该药物水溶性差，需要在含有表面活性剂的配方中以高稀释度持续静脉输注给药，并使用类固醇预防与载药相关的胸痛综合征。基于药理学的考虑，本论文所述化合物已被制备为改善水溶性的N-（三氟乙酰）阿霉素14-戊酸的第二代类似物；利用可用的羧酸功能使产品在稀碱性水介质中溶解。用二碱性酸（丙二酸、丁二酸、戊二酸、己二酸、戊二酸、壬二酸、癸二酸）的钠盐在丙酮水溶液中处理JV-（三氟乙酰基）-14-卤代柔红霉素（溴或碘）制备目标化合物。所有产品对小鼠P388白血病（ip肿瘤，ip治疗1天，2天，3天，4天，每天1次）均有显著的体内抗肿瘤活性；大多数化合物都优于阿霉素（最佳剂量为每天3.0 mg/kg），阿霉素是两种用作阳性对照的药物之一，可使寿命增加181%。几种被试化合物在该体系中表现出很高的治疗活性，与另一阳性对照剂JV-（三氟乙酰基）阿霉素14-戊酸相似。半己二酸产物表现出最理想的特性：高抗肿瘤功效（在40-70 mg/kg的剂量反应范围内，所有P388荷瘤动物的治愈率为86%）、水溶性（在pH 7.4的磷酸盐缓冲液中为60 mg/mL）和溶液稳定性（在4℃下不分解，27℃下水解0.5%,pH 7.4下24小时）。
N-(Trifluoroacetyl) adriamycin 14-valerate (AD 32), a novel DNA nonbinding analogue of adriamycin with superior experimental antitumor activity, has undergone extensive clinical trial, with documentation of antitumor activity and low toxicity in human subjects. However, poor water solubility necessitates that the drug be administered to patients by continuous intravenous infusion at high dilution in a surfactant-containing formulation, with steroid prophylaxis to protect against a chest pain syndrome associated with the vehicle. On the basis of pharmacologic considerations, the title compounds have been prepared as second-generation analogues of N-(trifluoroacetyl) adriamycin 14-valerate with improved aqueous solubility; use is made of the available carboxylic acid function to solubilize the products in dilute aqueous alkaline medium. Target compounds were made by treating JV-(trifluoroacetyl)-14-halodaunorubicin (bromo or iodo) with monosodium salts of dibasic acids (malonic, succinic, glutaric, adipic, pimelic, azelaic, sebacic) in aqueous acetone. All of the products showed significant in vivo antitumor activity against the murine P388 leukemia (ip tumor, ip treatment once daily on days 1, 2, 3, and 4); most compounds were superior to the+ 181% increase in life span afforded by adriamycin (optimal dose 3.0 mg/kg per day), one of two drugs used as positive controls for the assays. Several of the test compounds showed highly curative activity in this system, similar to JV-(trifluoroacetyl) adriamycin 14-valerate, the other positive control agent. The hemiadipate product exhibited the most desirable properties of high antitumor efficacy (86% cure rate of all P388 tumor-bearing animals through four levels of a 40-70 mg/kg dose-response range), aqueous solubility (60 mg/mL in pH 7.4 phosphate buffer), and solution stability (no decomposition at 4 C, 0.5% hydrolysis at 27 C, over 24 h at pH 7.4).