Coumarin Acetylenes & Propargyl Ethers, a New Class of Cytochrome P450 Inhibitors

细胞色素P450酶是血红素蛋白的超家族，其参与细胞色素P450的代谢。 内源性和外源性化合物。本项目的目标是合成和研究一些新的潜在的选择性机制为基础的灭活剂的某些P450酶参与致癌作用。在我们以前的研究中，我们已经确定了一些芳香乙炔和某些炔丙基醚是细胞色素P450依赖性单加氧酶的选择性自杀抑制剂。在本计画中，我们提出合成一类新的含香豆素环结构的化合物，其中含有炔丙基醚或乙炔基。我们正计划合成炔丙基取代的香豆素，以及乙炔基取代的香豆素，并在体外测定它们对P450酶的数量，以研究其相对潜在的抑制作用的基础上的类型，位置和数量的取代基的环系统。由于它们与香豆素、7-乙氧基香豆素和7-乙氧基-4-三氟甲基香豆素（已知的香豆素P450底物）的结构相似性，这些化合物应该与人P450酶2A 6、1A 2、2B 1和2 E1以及大鼠P450酶2A 6、1A 2、2B 1和2 E1相互作用。 P450为1A 1、1A 2和2B 1。然而，在含有三键的取代基上存在或不存在氧应改变极性和分支的形状，导致与各种P450酶活性位点的相互作用的一些差异，并有望引起基于选择性机制的（自杀）抑制。上述P450酶在药物和环境化学品（包括原致癌物）的代谢中极其重要。由于自杀抑制剂的特殊性质，这些化合物是 癌症发展和治疗研究中的有用工具。此外，这些抑制剂的作用机制使得有可能使用它们作为探针进入P450酶的活性位点，促进重要氨基酸残基的鉴定，从而更好地理解参与P450依赖性反应的结构-活性关系。

Cytochrome P450 enzymes are a superfamily of hemoproteins involved in the metabolism of endogenous and xenobiotic compounds. The goal of this project is to synthesize and study a number of new potentially selective mechanism-based inactivators for certain P450 enzymes involved in carcinogenesis. In our previous studies, we have established that a number of aromatic acetylenes and certain propargyl ethers are selective suicide inhibitors of cytochrome P450-dependent monooxygenases. In this project, we propose to synthesize a new class of compounds containing a coumarin ring structure, with a propargyl ether or ethynyl moiety. We are planning to synthesize propargyl substituted coumarins, as well as ethynyl substituted coumarins, and assay them in-vitro on a number of P450 enzymes in order to study their relative potential inhibitory effects based on the type, placement, and number of the substituents on the ring system. Due to their structural similarities to coumarin, 7-ethoxycoumarin, and 7-ethoxy-4-trifluoromethylcoumarin (known coumarin P450 substrates), these compounds should interact with human P450 enzymes 2A6, 1A2, 2B1, and 2E1, as well as rat P450s 1A1, 1A2, and 2B1. However the presence or absence of an oxygen on the substituent containing the triple bond should change the polarity, and the shape of the branch, leading to some differences in the interaction with various P450 enzymes' active sites, and hopefully causing selective mechanism-based (suicide) inhibition. The above-mentioned P450 enzymes are extremely important in the metabolism of pharmaceuticals and environmental chemicals including procarcinogens. Due to the special properties of suicide inhibitors, these compounds are useful tools in the studies of cancer development and treatment. Additionally, The mechanism of action of these inhibitors makes it possible to use them as probes into the active sites of P450 enzymes, facilitating the identification of important amino acid residues, leading to better understanding of the structure-activity relationships involved in the P450-dependent reactions.