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

佛波酯（TPA）和远杀菌素被认为是有效的肿瘤促进剂，并通过与激酶C （PKC）的竞争性结合激活PKC。我们合成的(-)-苯内酰胺v8 -310具有较好的活性构象和活性。在这个项目中，我们合成了在不同位置具有疏水取代基的苯内酰胺。结构-活性数据表明，C-2和C-9之间疏水区域的存在以及C-8上的位阻因子在生物活性的表现中起关键作用。我们还模拟了这些远杀虫素型苯内酰胺分子与PKCδ与phorbol 13-acetate晶体配合物中观察到的cys2结构域结构对接。在此基础上，我们设计了具有7元内酰胺和羟甲基的新型PKC激动剂。化合物表现出明显的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药效团——碳硼烷，并将其应用于PKC激动剂的设计。该化合物在苯内酰胺骨架上以碳硼烷为疏水组分，对PKC具有较强的亲和力。这些结果引导我们设计和合成了以碳硼烷为疏水药效团的其他受体配体。与天然配体相比，设计的含碳硼烷的合成类维生素a和雌激素具有显著的激动作用。

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.