Institute of Problems of Chemical Physics, Russian Academy of Sciences, Chernogolovka, 142432, Russian Federation.
Moscow Region State University, 105005, Moscow, Russian Federation.
Curr Cancer Drug Targets. 2018;18(4):365-371. doi: 10.2174/1568009617666170623104030.
Anti-tumor effect of hydroxamic acid derivatives is largely connected with its properties as efficient inhibitors of histone deacetylases, and other metalloenzymes involved in carcinogenesis.
The work was aimed to (i) determine the anti-tumor and chemosensitizing activity of the novel racemic spirocyclic hydroxamic acids using experimental drug sensitive leukemia P388 of mice, and (ii) determine the structure-activity relationships as metal chelating and HDAC inhibitory agents.
Outbreed male rat of 200-220 g weights were used in biochemical experiments. In vivo experiments were performed using the BDF1 hybrid male mice of 22-24 g weight. Lipid peroxidation, Fe (II) -chelating activity, HDAC fluorescent activity, anti-tumor and anti-metastatic activity, acute toxicity techniques were used in this study.
Chemosensitizing properties of water soluble cyclic hydroxamic acids (CHA) are evaluated using in vitro activities and in vivo methods and found significant results. These compounds possess iron (II) chelating properties, and slightly inhibit lipid peroxidation. CHA prepared from triacetonamine (1a-e) are more effective Fe (II) ions cheaters, as compared to CHA prepared from 1- methylpiperidone (2a-e). The histone deacetylase (HDAC) inhibitory activity, lipophilicity and acute toxicity were influenced by the length amino acids (size) (Glycine < Alanine < Valine < Leucine < Phenylalanine). All compounds bearing spiro-N-methylpiperidine ring (2a-e) are non-toxic up to 1250 mg/kg dose, while compounds bearing spiro-tetramethylpiperidine ring (1a-e) exhibit moderate toxicity which increases with increasing lipophility, but not excite at 400 mg/kg.
It was shown that the use of combination of non-toxic doses of cisplatin (cPt) or cyclophosphamide with CHA in most cases result in the appearance of a considerable anti-tumor effect of cytostatics. The highest chemosensitizing activity with respect to leukemia Р388 is demonstrated by the CHA derivatives of Valine 1c or 2c.
羟肟酸衍生物的抗肿瘤作用在很大程度上与其作为组蛋白去乙酰化酶和其他参与致癌作用的金属酶有效抑制剂的特性有关。
本工作旨在：（i）使用实验性药物敏感白血病 P388 的小鼠，确定新型手性螺环羟肟酸的抗肿瘤和化疗增敏活性；（ii）确定作为金属螯合剂和 HDAC 抑制剂的结构-活性关系。
使用 200-220 克体重的杂交雄性大鼠进行生化实验。使用 22-24 克体重的 BDF1 杂交雄性小鼠进行体内实验。本研究采用脂质过氧化、Fe（II）螯合活性、HDAC 荧光活性、抗肿瘤和抗转移活性、急性毒性技术。
通过体外活性和体内方法评价水溶性环状羟肟酸（CHA）的化疗增敏特性，结果显著。这些化合物具有铁（II）螯合特性，并且轻微抑制脂质过氧化。与由 1-甲基哌啶酮（2a-e）制备的 CHA 相比，由三乙酮胺（1a-e）制备的 CHA 是更有效的 Fe（II）离子螯合剂。组蛋白去乙酰化酶（HDAC）抑制活性、亲脂性和急性毒性受氨基酸（大小）（甘氨酸<丙氨酸<缬氨酸<亮氨酸<苯丙氨酸）的影响。所有带有螺-N-甲基哌啶环（2a-e）的化合物在高达 1250mg/kg 剂量时均无毒性，而带有螺-四甲基哌啶环（1a-e）的化合物则具有中等毒性，随着亲脂性的增加而增加，但在 400mg/kg 时不会引起兴奋。
结果表明，联合使用非毒性剂量顺铂（cPt）或环磷酰胺与 CHA，在大多数情况下可使细胞抑制剂的抗肿瘤作用明显增强。具有 Valine 1c 或 2c 的 CHA 衍生物对白血病 P388 表现出最高的化疗增敏活性。
