Drug-Oriented Synthesis of Cardiotonic Steroids

[摘要] Steroids are a structurally privileged class of bioactive natural products whose architecture has served as the bedrock for many valuable therapeutics throughout human history. In particular, the cardenolide sub-class of steroids, typified by ouabain and digoxin, has been used clinically since the late 18th century for the treatment of congestive heart failure; a widespread and detrimental affliction. In addition, the recently discovered anticancer activity of cardenolides has brought them back into focus as highly valuable therapeutic agents, although the mechanism of their anticancer activity is not fully understood. Moreover, cardenolides are well known for their low therapeutic windows. The design and construction of novel cardenolide analogues for biological evaluation is highly sought after. However, the chemical complexity of cardenolides makes the synthesis of new analogues a long process which is economically unjustifiable in an industrial setting. Herein we describe our efforts toward the development of a drug-oriented, concise, and stereodivergent synthetic approach to the cardenolide class of steroids culminating in the total synthesis of several natural cardenolides and analogues.Chapter 1 delves into the relevant background and history of cardenolides as well as their structure and bioactivity. The mechanism of action leading to a positive inotropic response is explained and the mode of binding to the Na+/K+ATPase is discussed. Some previously reported structure-activity relationship studies are described and evaluated. Chapter 2 describes several landmark efforts towards the total synthesis and semi-synthesis of cardenolides. A comparison of these two approaches is discussed and various semi-synthetic and totally synthetic routes aimed at cardenolides are described. Special attention is paid toward butenolide installation, stereochemical control, and introduction of key sites of oxygenation.Chapter 3 provides a detailed overview of the design and development of a conceptually new two-step synthetic approach to oxygenated steroidal cores. Chiral Cu(II)-BOX catalysts are successfully investigated for their ability to promote the enantio- and diastereoselective Michael addition of cyclic β-ketoesters and functionalized enones. A library of Michael adducts with unique A and D ring sizes, as well as C13 substitution is produced with high selectivities and yields (82–95% yield, 90–96% ee, and 4:1 to >20:1 dr). The Michael adducts then undergo stereodivergent intramolecular double aldol cyclization to afford a library of natural and unnatural steroidal cores. The factors controlling the diastereoselective cyclization are discussed.Chapter 4 describes the elaboration of the aforementioned methodology to allow the total synthesis of four targets: 19-hydroxysarmentogenin, trewianin aglycone, panogenin, and cis-panogenin. Modifications allow the pre-installation of oxygenation at the key positions C3 and C11. These functional handles are carried through the Michael addition/cyclization sequence to afford a heavily functionalized steroid intermediate with 7 stereocenters in a fused tetracyclic array with oxygenation installed at C3, C11, C14, C17, and C19 in only 7 linear steps. This intermediate is then elaborated in a stereodivergent fashion into the four target cardenolides in only 9-11 linear steps. Finally, a biochemical Na+/K+ATPase inhibition assay was developed and concentration-response curves were generated for the synthesized steroids. The resulting data corroborates the importance of the orientation at C17 and C11, while suggesting that the configuration at C5 is of little importance for aglycones.

[发布机构] University of Michigan

[效力级别] synthetic organic chemistry

[关键词] cardiotonic steroids;synthetic organic chemistry;medicinal chemistry;total synthesis;cardenolide;Chemistry;Science;Medicinal Chemistry