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首页> 外文学位 >Design, synthesis and biological evaluation of human inosine 5'-monophosphate dehydrogenase inhibitors: 1,5-diazabicyclo(3.1.0)hexane-2,4-diones, as novel isozyme-selective cancer chemotherapeutic agents.
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Design, synthesis and biological evaluation of human inosine 5'-monophosphate dehydrogenase inhibitors: 1,5-diazabicyclo(3.1.0)hexane-2,4-diones, as novel isozyme-selective cancer chemotherapeutic agents.

机译：人肌苷5'-单磷酸脱氢酶抑制剂的设计，合成和生物学评估：1,5-二氮杂双环（3.1.0）己烷-2,4-二酮，作为新型的同工酶选择性癌症化学治疗剂。

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摘要

IMP dehydrogenase (IMPDH, EC 1.1.1.205) controls a critical junction in the metabolism of purine nucleotides. IMPDH catalyzes the formation of XMP from IMP and is one of the rate-limiting enzymes in de novo guanine nucleotide biosynthesis. IMPDH has long been recognized as a target for cancer and viral chemotherapy and has recently emerged as a target for immunosuppression. The IMPDH enzyme is coded by two distinct genes termed Type I and Type II. IMPDH Type II is expressed at high levels in dividing and neoplastic cells, whereas IMPDH Type I is constitutively expressed at low levels. Thus, human IMPDH Type II is a major target for cancer chemotherapy. This study has focused on the design and synthesis of the 1,5-diazabicyclo[3.1.0]hexane-2,4-diones as novel inhibitors of human IMPDH activity. The 1,5-diazabicyclo[3.1.0]hexane-2,4-diones demonstrated effective inhibition of IMPDH activity in human Tmolt4 lymphoblastic leukemia cells. In addition to decreasing IMPDH activity, the agents decreased purine de novo synthesis, DNA and RNA syntheses, and pools of dGTP and dATP. The agents demonstrated potent inhibition of human Tmolt4 leukemia growth and proved to be cytotoxic (ED50 ≤ 4 mug/ml) in all human hematopoeitic leukemias and lymphomas studied. Significant reductions in cell growth from many selected solid tumors were observed by the agents. Noteworthy reductions in breast MCF-7 and glioma U-87MG growth occurred in the presence of the agents. Anticancer activity of the 1,5-diazabicyclo[3.1.0]hexane-2,4-diones was due to specific inhibition of IMPDH activity since their effects on cell growth and DNA synthesis could be reversed by the addition of exogenous guanosine. The biochemical action of these agents was due to the specific inhibition of human recombinant Type II IMPDH compared to the Type I isoform. The higher sensitivity of Type II IMPDH to the 1,5diazabicyclo[3.1.0]hexane-2,4-diones represents an exploitable difference between the two isoforms. The differential sensitivities of the agents on Type I and II IMPDH may allow for their utilization as cancer chemotherapeutic agents without compromising the metabolism of normal cells. Altogether, these studies confirm a positive correlation between the specific inhibition of human IMPDH Type II activity and the antitumor properties of these agents in Tmolt4 cells.
机译：IMP脱氢酶（IMPDH，EC 1.1.1.205）控制嘌呤核苷酸代谢中的关键连接。 IMPDH催化由IMP形成XMP，并且是从头鸟嘌呤核苷酸生物合成中的限速酶之一。 IMPDH长期以来被认为是癌症和病毒化学疗法的靶标，并且最近已经成为免疫抑制的靶标。 IMPDH酶由称为I型和II型的两个不同基因编码。 IMPDH II型在分裂和赘生性细胞中高水平表达，而IMPDH I型在低水平中组成性表达。因此，人类IMPDH II型是癌症化疗的主要靶标。这项研究的重点是作为人IMPDH活性的新型抑制剂的1,5-二氮杂双环[3.1.0]己烷-2,4-二酮的设计和合成。 1,5-二氮杂双环[3.1.0]己烷-2,4-二酮证明有效抑制人Tmolt4淋巴细胞白血病细胞中的IMPDH活性。除了降低IMPDH活性外，这些试剂还减少了嘌呤从头合成，DNA和RNA合成以及dGTP和dATP的库。该药物对人类Tmolt4白血病的生长具有有效的抑制作用，并且在所有研究的人类造血细胞白血病和淋巴瘤中被证明具有细胞毒性（ED50≤4杯/毫升）。药剂观察到许多选择的实体瘤的细胞生长显着减少。在存在药剂的情况下，乳腺MCF-7和神经胶质瘤U-87MG的生长显着降低。 1,5-二氮杂双环[3.1.0]己烷-2,4-二酮的抗癌活性是由于对IMPDH活性的特异性抑制，因为它们对细胞生长和DNA合成的影响可以通过添加外源鸟苷来逆转。与I型同工型相比，这些试剂的生化作用是由于人类重组II型IMPDH的特异性抑制。 II型IMPDH对1,5二氮杂双环[3.1.0]己烷-2,4-二酮的较高敏感性表示这两种同工型之间存在可利用的差异。药物对I型和II型IMPDH的敏感性不同，可能会使其用作癌症化学治疗剂而不会损害正常细胞的代谢。总而言之，这些研究证实了对人类IMPDH II型活性的特异性抑制与这些药物在Tmolt4细胞中的抗肿瘤特性之间呈正相关。

著录项

  • 作者

    Barnes, Betsy Jo.;

  • 作者单位

    The University of North Carolina at Chapel Hill.;

  • 授予单位 The University of North Carolina at Chapel Hill.;
  • 学科 Chemistry Biochemistry.; Chemistry Pharmaceutical.; Chemistry Organic.; Health Sciences Oncology.
  • 学位 Ph.D.
  • 年度 1999
  • 页码 173 p.
  • 总页数 173
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 生物化学;药物化学;有机化学;肿瘤学;
  • 关键词

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