Design, Synthesis and Biological Activity of Anti-HIV Compounds Derived from Teleocidins

开发针对人类免疫缺陷病毒（HIV）的化疗药物是目前一个具有挑战性的问题。虽然12-O-十四酰基佛波醇-13-乙酸酯（TPA）具有抗HIV活性，但由于其毒性太大而不适合在体内使用。然而，prostratin已被报道为具有蛋白激酶C（PKC）结合活性的抗HIV细胞保护佛波醇，并且没有明显的肿瘤促进活性。Teleocidin是众所周知的TPA型肿瘤促进剂。prostratin的发现促使我们研究teleocidins的抗HIV活性。佛波酯（TPA）和teleocidin是有效的肿瘤促进剂，并通过竞争性结合蛋白激酶C（PKC）激活PKC。由于这些化合物结构上的显著差异，它们的化学结构与活性之间的关系引起了人们的广泛关注。(-)-B ...更多信息 enzolactam-V8-310是一种有效的抗HIV化合物，在所检测的teleocidin相关衍生物中具有最高的选择性指数，它再现了teleocidin的活性构象和其他生物活性。我们已经完成了在不同位置上具有疏水取代基的苯并内酰胺的合成。构效关系数据表明，C-2和C-9之间的疏水区域和C-8位阻因子的存在对生物活性的出现起着关键作用。我们还模拟了这些teleocidin型苯并内酰胺分子的cys 2结构域结构中观察到的PKCd与佛波醇13-乙酸酯的晶体复合物的对接。Teleocidins和benzolactams与佛波醇-13-乙酸酯很好地配合到同一腔中。三个与蛋白质结合的官能团中，两个与13-佛波醇乙酸酯中的蛋白质原子结合，而第三个与13-佛波醇乙酸酯中的蛋白质原子结合。该模型很好地解释了（-）-BL-V8-310与其在C-8位具有大取代基的类似物之间活性的显著差异。少

Development of chemotherapy against human immunodeficiency virus (HIV) is currently a challenging problem. Though 12-O-tetradecanoylphorbol-13-acetate(TPA) has anti-HIV activity, it is not suitable for use in vivo as it is too toxic. However, prostratin has been reported as an anti-HIV cytoprotective phorbol with protein kinase C (PKC) binding activity and without apparent tumor promotion activity. Teleocidins are well-known TPA-type tumor promoters. The discovery of prostratin prompted us to investigate the anti-HIV activity of teleocidins. We havefound the anti-HIV activity of teleocidin and of designed molecules that reproduce the stereochemistry of teleocidins.Phorbol esters (TPA) and teleocidins are known to be potent tumor promoters and to activate protein kinase C (PKC) by binding competitively to the enzyme. The relationship between the chemical structures and the activities of these compounds has attracted much attention because of the marked structural dissimilarities. (-) -B … More enzolactam-V8-310 which is a potent anti-HIV compound with the highest selectivity index among the teleocidin-related derivatives examined, reproduces the active conformation and the other biological activities of teleocidins. We have performed the synthesis of benzolactams with hydrophobic substituents at various positions. Structure-activity data indicate that the existence of a hydrophobic region between C-2 and C-9 and the steric factor at C-8 play critical roles in the appearance of biological activities. We also simulated the docking of these teleocidin-type benzolactam molecules to the cys2 domain structure observed in the crystalline complex of PKCd with phorbol 13-acetate. Teleocidins and benzolactams fitted well into the same cavity as phorbol-13-acetate. 0f the three functional groups hydrogen-honding to the protein, two hydrogen-bonded with protein atoms in cmmon with phorbol 13-acetate, but the third one hydrogen-bonded with a different protein atom from that in the case of phorbol-13-acetale. The model explains well the remarkable difference in activity between (-) -BL-V8-310 and its analog having a bulky substituent at C-8. Less