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本文发展一个实用改进方法以合成具有抗人免疫缺陷病毒(HIV-1)的天然产物的类似物11-去甲胡桐素A[(±)-1],方法改进包括以间苯三酚为起始原料与正丁酰乙酸乙酯在饱和氯化氢甲醇存在下,经过Pechmann反应生成5,7-双羟基-4-正丙基香豆素(3),再与巴豆酸用多聚磷酸作溶剂及催化剂进行酰化,同时分子内环合得到收率为70%关键中间体苯并二氢吡喃酮(4),并与缩醛1,1-二乙氧基-3-甲基-2-丁烯用微波辅助催化得到苯并吡喃(6),最后用Luche还原以CeCl3.7H2O作催化剂,在低温下经NaBH4选择性还原化合物(6)得到目标产物即消旋11-去甲胡桐素A(±)-1。上述4步反应总收率32%,比原方法提高1倍。体外研究表明(±)-1对HIV-1(野株)及耐药株均有明显抑制逆转录酶和P24抗原的活性,(±)-1在细胞培养内分别与作用机制不同的3种治疗艾滋病药物(AZT、T-20、Indinavir)都有明显的协同作用。小鼠急性毒性,(±)-1的LD50灌胃给药为735.65 mg.kg-1,腹腔给药为525.10 mg.kg-1。小鼠灌胃给与(±)-1血浆峰浓度(Cmax)与药时曲线面积AUC0-∞分别为0.54μg.mL-1及1.08(μg.mL-1).h。为了初步观察(±)-1的体内药效,采用血清药理学方法,小鼠腹腔注射1次(±)-1或临床有效对照药奈韦拉平,30 min和60 min后血清有相似的抑制HIV-1逆转录酶活性。实验结果提示去甲11-胡桐素A值得进一步研究。
In this paper, we develop a practical and improved method to synthesize 11-desuperhornin A [(±) -1], an analogue of the natural product of human immunodeficiency virus (HIV-1). The improvements include starting with phloroglucinol Raw materials and n-butylacetoacetate in the presence of saturated hydrogen chloride methanol, Pechmann reaction to generate 5,7-dihydroxy-4-n-propyl coumarin (3), and then crotonic acid with polyphosphoric acid as a solvent and catalyst Acylation, and intramolecular cyclization to yield the key intermediate chromanone (70% yield) (70%), and with acetal 1,1-diethoxy-3-methyl- (6) with microwave-assisted catalysis and finally with Luche reduction using CeCl3.7H2O as a catalyst. The compound (6) is selectively reduced by NaBH4 at low temperature to obtain the target product, ie racemic 11-nortriptyline A ±) -1. The above 4-step reaction total yield of 32%, 1 times higher than the original method. In vitro studies showed that (±) -1 inhibited the activity of reverse transcriptase and P24 antigens on both HIV-1 (wild-type) and drug-resistant strains. The activity of (±) AIDS drugs (AZT, T-20, Indinavir) have a clear synergy. Mice acute toxicity, (±) -1 LD50 gavage administration of 735.65 mg.kg-1, intraperitoneal administration of 525.10 mg.kg-1. The plasma concentration of (±) -1 and the curve of drug concentration (AUC0-∞) were 0.54μg.mL-1 and 1.08 (μg.mL-1) Serum pharmacology was used to observe the in vivo efficacy of (±) -1. The mice were injected intraperitoneally with (±) -1 or clinically effective control drug nevirapine for 30 min and 60 min, respectively. Similar serum levels of HIV- 1 reverse transcriptase activity. The experimental results suggest that noradrenaline A is worth further study.