Ren Shijun, Wang Rubin, Komatsu Kenichi, Bonaz-Krause Patricia, Zyrianov Yegor, McKenna Charles E, Csipke Csaba, Tokes Zoltan A, Lien Eric J
Department of Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, CA 90089-9121, USA.
J Med Chem. 2002 Jan 17;45(2):410-9. doi: 10.1021/jm010252q.
Thirty Schiff bases of hydroxysemicarbazide (Ar-CH=NNHCONHOH) have been synthesized and tested against L1210 murine leukemia cells. The IC(50) values were found to be in a range from 2.7 x 10(-6) to 9.4 x 10(-4) M. A total of 17 out of the 30 compounds had higher inhibitory activities than hydroxyurea (an anticancer drug currently used for the treatment of melanoma, leukemia, and ovarian cancer) against L1210 cells. Six compounds with IC(50) values in micromolar range were 11- to 30-fold more potent than hydroxyurea (IC(50) = 8.2 x 10(-5) M). The partition coefficient (log P) and ionization constants (pK(a)) of a model compound [1-(3-trifluoromethylbenzylidene)-4-hydroxysemicarbazide, 1] were measured by the shake-flask method, and the measured log P was used to derive Hansch-Fujita pi constant of -CH=NNHCONHOH. On the basis of the newly derived pi and those of other moieties, the partition coefficients (SlogP) of the other 29 compounds were calculated by the summation of pi values. Quantitative structure-activity relationship (QSAR) analysis showed that, besides the essential pharmacophore (-NHCONHOH), hydrophobicity (SlogP), molecular size/polarizability (calculated molar refractivity), and the presence of an oxygen-containing group at the ortho position (I) were important determinants for the antitumor activities. In conclusion, the results obtained in this study show that several Schiff bases of hydroxysemicarbazide are potent inhibitors of tumor cells and warrant further investigation as cancer chemotherapeutic agents.
已合成了30种羟基氨基脲席夫碱（Ar-CH=NNHCONHOH），并对L1210小鼠白血病细胞进行了测试。发现其半数抑制浓度（IC50）值在2.7×10⁻⁶至9.4×10⁻⁴ M范围内。30种化合物中有17种对L1210细胞的抑制活性高于羟基脲（一种目前用于治疗黑色素瘤、白血病和卵巢癌的抗癌药物）。6种IC50值在微摩尔范围内的化合物比羟基脲（IC50 = 8.2×10⁻⁵ M）的效力高11至30倍。通过摇瓶法测量了一种模型化合物[1-(3-三氟甲基亚苄基)-4-羟基氨基脲，1]的分配系数（log P）和电离常数（pK(a)），并使用测得的log P推导出-CH=NNHCONHOH的Hansch-Fujita π常数。根据新推导的π值和其他部分的π值，通过π值求和计算出其他29种化合物的分配系数（SlogP）。定量构效关系（QSAR）分析表明，除了必需药效团（-NHCONHOH）外，疏水性（SlogP）、分子大小/极化率（计算摩尔折射率）以及邻位（I）含氧基团的存在是抗肿瘤活性的重要决定因素。总之，本研究获得的结果表明，几种羟基氨基脲席夫碱是肿瘤细胞的有效抑制剂，值得作为癌症化疗药物进一步研究。
