Prasad J V, Loo J A, Boyer F E, Stier M A, Gogliotti R D, Turner W J, Harvey P J, Kramer M R, Mack D P, Scholten J D, Gracheck S J, Domagala J M
Department of Chemistry, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, MI 48105, USA.
Bioorg Med Chem. 1998 Oct;6(10):1707-30. doi: 10.1016/s0968-0896(98)00118-7.
Nucleocapsid protein (NCp7), which contains highly conserved retroviral zinc fingers, is essential in the early as well as the late phase of human immunodeficiency virus (HIV) life cycle and constitutes a novel target for AIDS therapy. HIV-1 NCp7 is a basic 55 amino acid protein containing two C(X)2C(X)4H(X)4C motif zinc fingers flanked by basic amino acids on each side. 2,2'-dithiobisbenzamides have previously been reported to release zinc from these NCp7 zinc fingers and also to inhibit HIV replication. Specifically, 2,2'-dithiobisbenzamides derived from simple amino acids showed good antiviral activities. The benzisothiazolone 3, the cyclic derivative of 2, was selected for clinical trials as an agent for AIDS therapy. Herein we report the syntheses and antiviral activities, including therapeutic indices, of 2,2'-dithiobisbenzamides derived from alpha-, beta- and gamma-amino acids. Electrospray ionization mass spectrometry was used to study the zinc-ejection activity of these compounds. Among the alpha-amino acid derived 2,2'-dithiobisbenzamides, analogues containing alkyl side chains were found to be antivirally active with good therapeutic indices. 2,2'-Dithiobisbenzamides, derived from beta- and gamma-amino acids, were found to possess better antiviral and therapeutic efficacies than the alpha-amino acid analogues. Thus compound 59 was found to possess an EC50 of 1.9 microM with a therapeutic index of > 50. Interestingly, 2,2'-dithiobisbenzamides derived from alpha-amino acids containing a protected acid function and polar side chains also exhibited very good antiviral activity.
核衣壳蛋白（NCp7）含有高度保守的逆转录病毒锌指结构，在人类免疫缺陷病毒（HIV）生命周期的早期和晚期均至关重要，是艾滋病治疗的一个新靶点。HIV-1 NCp7是一种由55个氨基酸组成的碱性蛋白，含有两个C(X)2C(X)4H(X)4C基序锌指结构，两侧均有碱性氨基酸。此前有报道称，2,2'-二硫代双苯甲酰胺可从这些NCp7锌指结构中释放锌，还能抑制HIV复制。具体而言，由简单氨基酸衍生的2,2'-二硫代双苯甲酰胺具有良好的抗病毒活性。苯并异噻唑酮3（2的环状衍生物）被选作艾滋病治疗药物进行临床试验。在此，我们报告了由α-、β-和γ-氨基酸衍生的2,2'-二硫代双苯甲酰胺的合成及其抗病毒活性，包括治疗指数。采用电喷雾电离质谱法研究了这些化合物的锌释放活性。在由α-氨基酸衍生的2,2'-二硫代双苯甲酰胺中，发现含有烷基侧链的类似物具有抗病毒活性，且治疗指数良好。由β-和γ-氨基酸衍生的2,2'-二硫代双苯甲酰胺的抗病毒和治疗效果优于α-氨基酸类似物。因此，发现化合物59的半数有效浓度（EC50）为1.9微摩尔，治疗指数大于50。有趣的是，由含有受保护酸功能和极性侧链的α-氨基酸衍生的2,2'-二硫代双苯甲酰胺也表现出非常好的抗病毒活性。
