Enriching the biologically relevant space sampled by natural products through biotransformations: speeding up the natural-product based drug discovery process

Natural products have been evolutionary selected to occupy the part of the chemical space that is of biological relevance [1]. Unfortunately, their inherent scaffold complexity has limited their fruitful integration in the drug discovery pipeline. We have exploited and established novel chemoenzymatic tools to manipulate in a very rapid and biologically targeted way the natural product core [2 – 5]. We will illustrate that rapid product screening, transformation efficacy and regioselectivity can be readily monitored in situ and in real time as also that evaluation of binding with putative drug targets can be conducted in a cost and time effective way [2 – 5]. The functionalized natural products have been then accessed for their bioactivity in traditionally thought “undruggable” targets [5 – 7]. Different examples from our research on natural product based molecular hybridization [4,6] as also natural product scaffold sculpting and associated biological evaluation in in vitro cancer cell lines and other therapeutic directions will be presented [6 – 10]. Acknowledgement: This project has been co-financed by the European Union (European Regional Development Fund- ERDF) and Greek national funds through the Operational Program “THESSALY-MAINLAND GREECE AND EPIRUS-2007 – 2013” of the National Strategic Reference Framework (NSRF 2007 – 2013). References: [1] Janga SC, Tzakos A., Mol Biosyst 2009, 5, 1536 – 48 [2] Geromichalou E et al., Eur J Med Chem. 2015 96: 47 – 57. [3] Primikyri A et al, Tetrahedron 2012, 68, 6887 – 6891. [4] Kyriakou E et al., Org Biomol Chem 2012, 10, 1739 – 42. [5] Nagulapalli M et al., Structure 2012 20, 522 – 33. [6] Papdopoulou A et al., Bioresour Technol. 2013 [7] Primikyri A, ACS Chem Biol. 2014 9 :2737 – 41. [8] Kellici TF, Mol Pharm. 2015 12 954 – 65. [9] Vujicic M, Nikolic I, Br J Nutr. 2015 113 770 – 82 [10] Ferlemi AV, Chem Biol Interact. 2015 in press