Naturstoffhybride als neue Leitstrukturen bei der Wirkstoffsuche

Abstract

Bei der Entwicklung neuer Wirkstoffe spielen Naturstoffe eine wichtige Rolle. Besondere Bedeutung kommt ihnen auf den Gebieten Antiinfektiva, Krebstherapeutika und Immunsuppressiva zu. Die Zahl der natürlich vorkommenden Substanzen ist jedoch begrenzt, wohingegen durch die Kombination von Teilen unterschiedlicher Naturstoffe Millionen von Naturstoffhybriden mit vielfältigen und verschiedenartigen Eigenschaften zugänglich sein sollten. Dieser Ansatz ist für die Entwicklung neuer Leitstrukturen für sowohl medizinische als auch agrochemische Anwendungen sehr vielversprechend, da die biologische Aktivität dieser Hybride in vielen Fällen diejenige der entsprechenden Mutterverbindungen übersteigt. Der Vorteil dieses Konzepts gegenüber einem auf dem Zufall beruhenden kombinatorischen Ansatz besteht in der Vielfalt und der inhärenten biologischen Aktivität der gebildeten Hybride.

Design and Synthesis of 12‐Aza‐Epothilones (Azathilones)—“Non‐Natural” Natural Products with Potent Anticancer Activity

“…In this context we have also investigated the biological activity of 12‐aza‐epothilones, which are characterized by the replacement of a backbone carbon atom by nitrogen in the epothilone macrocycle 6c,d. 7 The resulting analogues may best be described as “non‐natural” natural products,8 as they still retain most of the (two‐dimensional) structural features of the natural product lead; at the same time they are structurally unique, as they are outside of the general scope of nature's biosynthetic machinery for polyketide biosynthesis, which is not programmed for the incorporation of single nitrogen atoms in a regular polyketide backbone 9. As a result of these studies we discovered that 12‐aza‐epothilones 1 (termed “azathilones”) can retain much of the antiproliferative activity of natural epothilones, depending on the nature of the acyl substituent attached to the backbone nitrogen atom 6d.…”

From Conjugated Tertiary Skipped Diynes to Chain‐Functionalized Tetrasubstituted Pyrroles

“…[14] Chain-functionalized pyrroles constitute a structural motif of particular interest in synthetic and medicinal chemistry, as it is the foundation of important medicines, natural products and synthetic materials. [15] In particular, tetrasubstituted pyrroles 5 can be considered as hybrid scaffolds [16] comprising a structurally privileged pyrrole ring and a naturally occurring a-hydroxy acid motif. [17] The hybrid features five points of diversity (two chemodifferentiated ester groups, two chemodifferentiated R groups and one N À R 1 group) and two differentiated points for complexity generation, one in the ring (sp 2 -linking point; C4-H) and the other in the chain (sp 3 These hybrid structures are usually synthesized by Friedel-Crafts reaction between the substituted pyrrole and the corresponding alkyl glyoxylate.…”

Natural Product Synthesis: Changes over Time

“…With the advent of the 21 st century, the targets of natural product synthesis have become even more complex. While palytoxin, [41] polypeptides such as fuzeon, [58] or branched oligosaccharides [59] marked the frontiers of synthesis until recently, even more complex structures [60] such as glycoproteins have been conquered in the past decade. Thus, a glycoprotein with a molecular mass of 17 868 has been obtained by Danishefsky through targeted synthesis, [61] setting a new benchmark for natural product synthesis.…”