Design and Synthesis of Cellular Signal Transduction Modulator, Benzolactam Derivatives and Related Compounds

已知佛波酯（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）来激活该酶。我们合成的（-）-苯并内酰胺-V8 -310，较好地再现了杀鱼素的活性构象和活性。在这个项目中，我们进行了合成苯并内酰胺与疏水取代基在不同的位置。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型苯并内酰胺分子与PKCδ与佛波醇13-乙酸酯的晶体复合物中观察到的cys 2结构域结构的对接。在此基础上，我们设计了含七元内酰胺和羟甲基的新型PKC激动剂。这些化合物显示出显著的PKC激动活性，抑制常数为低纳摩尔级。我们还开发了一种新的疏水性药效团，碳硼烷（dicarba-closo-dodecaborane），并应用于设计的PKC激动剂。以碳硼烷为疏水基团的苯并内酰胺类化合物对PKC具有较强的亲和性，这一结果为我们设计和合成其他以碳硼烷为疏水药效团的受体配体提供了理论依据。与天然配体相比，设计的合成类维生素A和雌激素与碳硼烷显示出显着的激动活性。

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. (-)-Benzolactam-V8-310, which we have been synthesized, reproduces well the active conformation and activities of teleocidins. In this project, 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 PKCδ with phorbol 13-acetate. On the basis of these investigation, we designed new PKC agonists having 7-membered lactam moiety and hydroxymethyl group. The compounds showed significant PKC agonistic activity, with inhibition constants of low nanomolar order. We also developed a new hydrophobic pharmacophore, carborane (dicarba-closo-dodecaborane), and applied in design of the PKC agonist. The compound with carborane as a hydrophobic component on benzolactam sleleton, showed potent affinity for PKC.The results lead us to design and synthesis of the other receptor ligands with carborane as a hydrophobic pharmacophore. Designed synthetic retinoids and estrogens with carborane showed significant agonistic activities, compared with native ligands.