Hall I H, Izydore R A, Zhou X, Daniels D L, Woodard T, Debnath M L, Tse E, Muhammad R A
Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina, Chapel Hill 27599-7360, USA.
Arch Pharm (Weinheim). 1997 Mar;330(3):67-73. doi: 10.1002/ardp.19973300306.
The 3,5-isoxazolidinediones and 2-isoxazolin-5-ones demonstrated potent cytotoxicity against the growth of human Tmolt3 T cell leukemia, murine P388 and L1210 leukemias, as well as human HeLa-S3 uterine carcinoma and glioma tumor cell growth. The specificity of the 3,5-isoxazolidinedione and 2-isoxazoline-5-one derivatives as cytotoxic agents varied with the histological type of tumor cell. Selected compounds were active against solid HeLa uterine. KB nasopharynx, skin A431, SW-480 adenocarcinoma, osteosarcoma and glioma growth. Selected compounds demonstrated in vivo antineoplastic activity against Ehrlich ascites carcinoma growth. In L-1210 leukemia cells, the agents blocked DNA and protein synthesis at 25, 50 and 100 microM over 60 min. The agents were effective in reducing rate limiting enzymes in the de novo purine and pyrimidine pathways. In addition they suppressed dihydrofolate reductase and ribonucleoside reductase activities with moderate inhibition of DNA and RNA polymerase activities. DNA itself was not a target of the agents.
3,5-异恶唑烷二酮和2-异恶唑啉-5-酮对人Tmolt3 T细胞白血病、小鼠P388和L1210白血病以及人HeLa-S3子宫癌和胶质瘤肿瘤细胞的生长表现出强大的细胞毒性。3,5-异恶唑烷二酮和2-异恶唑啉-5-酮衍生物作为细胞毒性剂的特异性因肿瘤细胞的组织学类型而异。所选化合物对实体HeLa子宫癌、KB鼻咽癌、皮肤A431癌、SW-480腺癌、骨肉瘤和胶质瘤的生长具有活性。所选化合物对艾氏腹水癌的生长表现出体内抗肿瘤活性。在L-1210白血病细胞中，这些药物在60分钟内以25、50和100微摩尔的浓度阻断DNA和蛋白质合成。这些药物有效地降低了从头嘌呤和嘧啶途径中的限速酶。此外，它们抑制二氢叶酸还原酶和核糖核苷还原酶的活性，对DNA和RNA聚合酶的活性有中等程度的抑制。DNA本身不是这些药物的作用靶点。
