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

佛波酯(TPA)和杀线菌素是已知的有效的肿瘤促进剂，并通过竞争性地与酶结合来激活蛋白激酶C(PKC)。我们合成的(-)-苯并内酰胺-V8-310很好地再现了线虫毒素的活性构象和活性。在本项目中，我们进行了不同位置上带有疏水取代基的苯内酰胺的合成。构效关系数据表明，C-2和C-9之间疏水区的存在和C-8位的空间构型因子的存在对生物活性的出现起着至关重要的作用。我们还模拟了这些端杀素型苯内酰胺分子与PKCδ与佛波醇13-乙酸酯晶体复合物中观察到的cys2结构域结构的对接。在这些研究的基础上，我们设计了具有7元内酰胺基团和羟甲基的新型PKC激动剂。这些化合物具有显著的PKC激动活性，其抑制常数为低纳摩尔数量级。我们还开发了一种新的疏水药效团Carborane(二碳杂环十二硼烷)，并将其应用于PKC激动剂的设计。以碳硼烷为疏水基团的化合物对PKC表现出很强的亲和力，这一结果引导我们设计合成了以碳硼烷为疏水药效基团的其他受体配体。与天然配体相比，设计合成的含碳硼烷的维甲酸和雌激素具有显著的激动剂活性。

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.