β-锗代α-氨基酸衍生物的合成、抗肿瘤活性及构效关系研究

Synthesis,antitumor activity and QSAR of β-germanyl-α-amino acid sesquioxide derivatives

目的设计合成具有不同取代基的锗代α-氨基酸衍生物,研究它们的抑瘤活性及构效关系。方法根据有机锗衍生物的抑瘤作用原理,设计合成了9个锗代α-氨基酸衍生物,测试了所合成的化合物对于小鼠H22肿瘤生长的抑制活性,利用C2的QSAR+和Catalyst进行构效关系研究和建立药效团模型。结果合成9个目标化合物,其结构利用1H-NMR、13C-NMR、红外光谱、元素分析等方法进行了确证,含有不同取代基的化合物[Ⅰ]均具有一定的抑瘤活性;无论是高剂量(150 mg.kg-1.d-1)还是低剂量(75 mg.kg-1.d-1),含硝基的[Ⅰ-2]和[Ⅰ-7]以及高剂量的溶肉瘤素衍生物[Ⅰ-6]与含羟基的衍生物[Ⅰ-3]和[Ⅰ-4]对小鼠H22肿瘤生长的抑制率(灌胃)均超过阳性对照5-FU(皮下注射,15 mg.kg-1.d-1)。将低剂量组的抑瘤活性实验结果利用C2的QSAR+和Catalyst进行处理,得合适的QSAR方程Activity%=-18.122 7-12.032×AlgP98-3.127 14×Hd-4.337 015×HOMO+0.011 247×Wiene和药效团模型。结论含有不同取代基的锗代α-氨基酸衍生物的抗肿瘤活性与苯环上取代基的性质有关,吸电子基团的存在通过影响分子的HOMO增强抗肿瘤活性。

OBJECTIVE To determine the antitumor activity and QSAR of the substituting groups of β-gerrnanyl-α-amino acid sesquioxide eompounds. METHODS Based on the antitumor mechanism of organogermanium, 9 compounds of β-germanyl-α-amino acid sesquioxide derivatives [ Ⅰ ] containing various substituting groups were prepared. Their inhibition to the growth of H22 in rats was tested and 3D-QSAR equations and pharmaeophore models were obtained using C^2 QSAR and catalyst program respectively. RESULTS Nine compounds were prepared and their structure confirmed by ^1H NMR,^13C-NMR, IR spectra and Ge elementary analysis. All exhibited antitumor activity. No matter in low dose （75 mg·kg^-1· d^-1） or in high-dose （150 mg · kg^-1 · d^-1 ）, the inhibition to the growth of H22 in rats in compound containing nitryl group （ Ⅰ-2 and Ⅰ-7）, sarcolysine derivative （ Ⅰ -6）, phenolic hydroxylic derivatives （ Ⅰ-3 and Ⅰ-4） and fluorin derivative （Ⅰ-8） in high dose was higher than that of the control 5-FU （sc, 15 mg · kg^-1·d^-1） under the same condition. The optimized 3D-QSAR equation （r=1. 000, r^2 =0. 998, ftest = 493.7, n= 9, Lse= 0. 314） was; Activity% =- 18. 122 7- 12. 032 × AlgP98 - 3. 127 14 × Hd- 4. 337 015 × HOMO＋ 0. 011 247XWiene. The best pharmacophore model （correl=0. 97） showed that they had two hydrogen bonding donors： one hydrogen bonding aceeptor and one bydrophober group. CONCLUSIONS; The antitumor activity of [Ⅰ] is affected by the substituting group on the phenyl ring of the compounds. The existence of electron withdrawing group will enhance the antitumor activity through influencing the HOMO of the compounds.