Synthesis of natural product inspired compound library of tetrahydroindolo[2,3-a]quinolizines


One of the important obstacles to the discovery of hit and lead structures from pharmaceutical industry compound collections undergoing high throughput screening (HTS) campaigns is the redundancy of the core-structures or scaffolds of the libraries. Moreover, often the library synthesis efforts are driven by the availability of inexpensive substrates or synthesis routes and that often has the structural features heavily compromised yielding relatively flat heterocycles which often fail to provide desired starting points for drug discovery. Biological relevance of the molecular frameworks or scaffolds used in the synthesis of a compound collection bequeaths them ability to modulate different biological functions. Scaffolds of natural products for instance, encode evolutionary selected properties for interacting with proteins and, therefore, represent biologically prevalidated frameworks. Natural product based synthesis thus employs the core structures of natural products as scaffolds for compound collections. Natural product derived molecules behold the frameworks identical with the core structure of a natural product in which different substituents are introduced at exactly the same positions as predetermined by nature. However, in natural-product-inspired synthesis, closely related structural frameworks of natural products may be used for library synthesis(1). In this approach, not only the relative positions and nature of substituents can be varied but also different relative stereochemistry patterns can be generated covering a broader chemical space of a particular structural class.
In order to enrich the compound collection in the consortium European Lead Factory (ELF) with natural product based structural features, we set out to develop synthetic access to indole alkaloids inspired tetrahydroindolo[2,3-a]quinolizine scaffold and a compound collection based on this framework. Many natural products embodying indolo[2,3-a]quinolizidine framework had displayed a wide range of biological activities such as antibacterial (Lercheine), antiviral (Hirsutine), the cytotoxic (10-hydroxyngustine), as well as antiplasmodial agent (Glabratine)(2). We too have recently reported synthesis and biology of anticancer centrocountins- the indoloquinolizines and related phosphatase inhibitors (3-4). These findings provide further validation to the employing indolo[2,3-a]quinolizidine scaffold as a promising structural framework to build compound library for drug discovery endeavors.

(1) K. Kumar, H. Waldmann, Angew. Chem. Int. Ed. 2009, 48, 3224 – 3242.
(2) M. Ishikura, K. Yamada, T. Abe, Nat. Prod. Rep. 2010, 27, 1630 – 1680.
(3) V. E. Lux, P. Küchler, S. Ziegler, K. Kumar, H. Waldmann Angew. Chem. Int. Ed. 2014, 53, 2134 – 2137.
(4) V. E. Lux, H. Dückert, V. Khedkar, H. Bruss, H. Waldmann, K. Kumar, Chem. Eur. J. 2013, 19, 2294 – 2304.

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