Synthesis, biological evaluation, and quantitative structure-activity relationship analysis of new Schiff bases of hydroxysemicarbazide as potential antitumor agents
Synthesis, biological evaluation, and quantitative structure-activity relationship analysis of new Schiff bases of hydroxysemicarbazide as potential antitumor agents
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DOI：
10.1021/jm010252q
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发表时间：
2002-01-17
影响因子：
7.3
通讯作者：
Lien, EJ
中科院分区：
文献类型：
--
作者：
Ren, SJ;Wang, R;Lien, EJ
合成了30个羟基辛酰肼席夫碱（Ar-CH=NNHCONHOH），并对小鼠白血病细胞L1210进行了抗肿瘤活性的测定。发现IC 50值在2.7 x 10（-6）至9.4 x 10（-4）M范围内。在30种化合物中，共有17种化合物对L1210细胞的抑制活性高于羟基脲（目前用于治疗黑色素瘤、白血病和卵巢癌的抗癌药物）。IC 50值在微摩尔范围内的6种化合物的效力是羟基脲的11至30倍（IC 50 = 8.2 x 10（-5）M）。用摇瓶法测定了模型化合物[1-（3-三氟甲基苯亚甲基）-4-羟基乙酰氨基肼，1]的分配系数（log P）和电离常数（pK（a）），并将测得的log P用于推导-CH=NNHCONHOH的Hansch-Fujita pi常数。在新推导的pi和其他部分的pi的基础上，通过pi值的总和计算其他29种化合物的分配系数（SlogP）。定量构效关系（QSAR）分析表明，除了必需的药效基团（-NHCONHOH）外，疏水性（SlogP）、分子大小/极化率（计算的摩尔活性）和邻位含氧基团（I）的存在是决定其抗肿瘤活性的重要因素。总之，在这项研究中获得的结果表明，几个席夫碱的羟基emismbazide是有效的抑制肿瘤细胞，值得进一步研究作为癌症化疗药物。
Thirty Schiff bases of hydroxysemicarbazide (Ar-CH=NNHCONHOH) have been synthesized and tested against L1210 murine leukemia cells. The IC50 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 IC50 values in micromolar range were 11- to 30-fold more potent than hydroxyurea (IC50 = 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.