Kamal Kumar
Synthesemethoden zur Entwicklung von strukturell diversen und naturstoff-basierten Ring-Systemen
Research Concept
Organic synthesis is a leading as well as enabling discipline when it comes to creating novel bioactive molecules and their applications in medicinal and chemical biology research respectively. The developments in compound screening abilities in the last decade call for parallel advances in the synthesis of three dimensionally complex small molecules to identify selective modulators of diverse biological functions. Despite its rich and long history, organic synthesis has not been able to reach out to a broader chemical space and synthetic chemists have been creating very similar kind of small molecules. A recent analysis of small molecules created by organic synthesis community revealed that a major part of it (>75%) represent only 5% of the scaffolds that are known in the literature and the situation is even worse for the screening libraries.[1] In short, a vast, novel and unique chemical space remains to be explored and exploited for drug and probe discovery research. Our research explores the potential of novel chemical transformations as well as new synthesis concepts that could provide solutions and address the challenge of building novel scaffolds based on biologically relevant structural motifs [2].
Current Research
The chemistry challenges are so addressed that they also pave the ways to build a diverse and structurally rich compound collection which on exposure to biological screenings delivers novel small molecule modulators of different biological functions (Figure 1) [2-7, (Garcia-Castro M. et al. 2015)].
Two different synthesis designs are followed to build structurally diverse and complex small molecules. In the first case, novel annulation or cycloaddition reactions have been developed utilizing substrates that could afford privileged scaffold based novel ring-systems (Figure 2i). For instance, a number of annulation reactions have been developed affording complex and polycyclic benzopyrones and indole based frameworks.[8-15, (Wang et al. 2014), (Sankar et al. 2016), (Danda et al. 2016)]. In particular, various annulation reactions between electronically similar substrates has been developed.[7-12, (Sankar et al. 2016), (Danda et al. 2016)]. For instance, electron-poor chromones were successfully used with electron-poor acetylenes, allenes, diazacarboxylates etc. to afford tri- and tetracyclic benzopyrones in various diastereo- and enantioselective annulation reactions [8-9, (Sankar et al. 2016) , (Danda et al. 2016)]. The substrate design is often so envisioned that could afford adducts supporting different functional groups amenable to further easy transformations yielding novel scaffolds (Figure 2i) [8-9]. Gold and transition metal catalyzed reactions were developed for cyclization of electron-rich substrates like enynes and leading to interesting and novel molecular frameworks.[16-20, (Dakas et al. 2013) ].
In the second approach, reaction planning stems with the aim to create a range of different scaffolds in a quick and efficient manner and takes the inspiration from nature´s biosynthetic strategies. Branching cascades for instance utilize well designed substrates with many reactive sites and that can be transformed into a number of distinct structures by varying the reagents that trigger different cascade reactions (Figure 2ii)[21-22] The strategy can be planned to build collections based on either biologically relevant scaffolds or completely novel chemical entities. The biological screenings of the structurally rich compound collection that results from above synthesis efforts provide initial hits and starting points for either medicinal chemistry programs or ideas for further chemical biology research [6, (Garcia-Castro M. et al. 2015)]. In both the cases, an iterative synthesis cycle is often followed up to reach a good structure activity relationship.
Literature
1. Lipkus, A. H., Yuan, Q., Lucas, K. A., Funk, S. A., Bartelt III, W. F., Schenck, R. J., Trippe, A. J. (2008). Structural Diversity of Organic Chemistry. A Scaffold Analysis of the CAS Registry. J. Org. Chem. 73, 4443–4451.
2. Garcia-Castro, M., Zimmerman, S., Sankar, M.. G., Kumar, K. (2016). Scaffold diversity synthesis and its application in probe and drug discovery. Angewandte Chemie Int. Ed. (DOI: 10.1002/anie.- 201508818).
3. Kumar, K., Waldmann, H. (2009). Synthesis of Natural Product Inspired Compound Collections. Angewandte Chemie Int. Ed. 48, 3224 – 3242.
4. Schröder, P., Förster, T., Kleine, S., Becker, C., Richters, A., Ziegler, S., Rauh, D. Kumar, K., Waldmann, H. (2015).
Neuritogenic Militarinone-Inspired 4-Hydroxypyridones Target the Stress Pathway Kinase MAP4K4. Angewandte Chemie Int. Ed. 54, 12398-12403.
5. Svenda, J., Shermet, M., Kremer, L., Maier, L., Bauer, J. O., Strohmann, C., Ziegler, S. Kumar, K., Waldmann, H. (2015). Biology-Oriented Synthesis of a Withanolide-Inspired Compound Collection Reveals Novel Modulators of Hedgehog Signaling. Angewandte Chemie Int. Ed. 54, 5596-5602.
6. Garcia-Castro, M., Kremer, L., Reinkemeier, C. D., Bauer, J. O., Strohmann, C., Ziegler, S., Ostermann, C., Kumar, K. (2015). De Novo Branching Cascades for Structural and Functional Diversity in Small Molecules. Nature Commun., 6, 6516 doi:10.1038/ncomms7516.
7. Eschenbrenner-Lux, V., Küchler, P., Ziegler, S., Kumar, K., Waldmann, H. (2014). An Enantioselective Inverse-Electron-Demand Imino-Diels-Alder Reaction. Angewandte Chemie Int. Ed. 53, 2134 –2137.
8. Sankar, M. G., Garcia-Castro, M., Golz, C., Strohman, C., Kumar (2016). Engaging Allene Derived Zwitterions in an Unprecedented Mode of Asymmetric [3+2]-Annulation Reaction, Angewandte Chemie Int. Ed. (DOI: 10.1002/anie.201603936.
9. Danda, A., Kesava-Reddy, N., Golz, C., Strohmann, C., Kumar, K. (2016). Asymmetric Roadmap to Diverse Polycyclic Benzopyrans via Phosphine-Catalyzed Enantio-selective [4+2]-Annulation Reaction. Org. Letters. Doi: 10.1021/acs.orglett.6b01030.
10. Sankar, M. G., Garcia-Castro, M., Wang, Y., Kumar, K. (2013). A Facile Dipolar Entry to Diverse Dihydro-1H-1,2,4-Triazoles. Asian Journal of Organic Chemistry 2, 646 – 649.
11. Baskar, B., Dakas, P.-Y., Kumar, K. (2011). Natural Product Biosynthesis Inspired Concise and Stereoselective Synthesis of Benzopyrones and Related Scaffolds. Org. Lett. 13, 1988-1991.
12. Baskar, B., Wittstein, K., Sankar, M. G., Khedkar, V., Schürmann, M., Kumar. K. (2012) Stereoselective Cascade Double-Annulations Provide Diversely Ring-Fused Tetracyclic Benzopyrones. Org. Lett. 14, 5924-5927.
13. Wang, Y., Bauer, J. O., Strohman, C., Kumar, K. (2014). A Bio-inspired Catalytic Oxygenase Cascade to Complex Oxindoles. Angewandte Chemie Int. Ed. 53, 7514-7518.
14. Eschenbrenner-Lux, V., Kumar, K. Waldmann, H. (2014). Asymmetric Hetero-Diels-Alder Reaction for the Synthesis of Bioactive Compounds. Angewandte Chemie Int. Ed. 53, 11146–11157.
15. Eschenbrenner-Lux, V., Dückert, H., Khedkar, V., Bruss, H., Waldmann, H., Kumar, K. (2013). Cascade Syntheses Routes to the Centrocountins. Chemistry- A Eur. J. 19, 2294-2304.
16. Dakas, P.-Y., Parga, J. A., Höing, S., Schöler, H. R., Sterneckert, J,. Kumar, K., Waldmann, H. (2013). Discovery of Novel Natural Product-Inspired Neuritogenic Compound Classes. Angewandte Chemie Int. Ed. 52, 9576 –9581.
17. Perez-Galan, P., Waldmann, H., Kumar, K. (2016). Building polycyclic indole scaffolds via gold(I)-catalyzed intra- and inter-molecular cyclization reactions of 1,6-enynes. Tetrahedron, doi.org/10.1016/- j.tet.2016.03.020.
18. Meiß, R., Kumar, K., Waldmann, H. (2015). Divergent Gold(I)-Catalyzed Skeletal Rearrangements of 1,7-Enynes. Chemistry – A Eur. J. 21, 13526 – 13530.
19. Danda, A., Kumar, K., Waldmann, H. (2015). A General Catalytic Reaction Sequence to Alkaloid-Inspired Indole Polycycles. Chem. Commun. 51, 7536-7539.
20. Kolundžić, F., Murali, A., Perez-Galan, P., Bauer, J. O., Strohmann, C., Kumar, K., Waldmann, H. (2014). A Novel Cyclization-Rearrangement Cascade Yields Structurally Complex Chiral Gold(I)-Aminocarbene Complexes. Angewandte Chemie Int. Ed. 53, 8122-8126.
21. Liu, W., Khedkar, V., Baskar, B., Sch�rmann, M., Kumar, K. (2011). Branching Cascades: A Concise Synthetic Strategy Targeting Diverse and Complex Molecular Frameworks. Angew. Chem. Int. Ed. 50, 6900–6905.
22. Murali, A., Medda, F., Winkler, M., Giordanetto, F., Kumar, K. (2015). Branching cascades provide access to two amino-oxazoline compound libraries. Bioorganic Med. Chem. 23, 2656-2665.