Diverted total synthesis

Diverted total synthesis in chemistry is a strategy in drug discovery aiming at organic synthesis of natural product analogues rather than the natural product itself.[1][2][3] The target can be the modification of a natural product or the modification of an intermediate. In this sense it differs from other strategies such as total synthesis and semisynthesis. The purpose can be gaining a scientific understanding of the biological activity of the original natural product or the discovery of new drugs with the same biological activity but simpler to produce. The concept was introduced by Samuel J. Danishefsky in 2006.[4] Notable examples of this strategy are the potential drug ixabepilone which is an analogue of the natural product epothilone B and carfilzomib which is derived from epoxomicin and eravacycline derived from tetracycline.[1] Cabergoline is derived from a number of ergot alkaloids one of which is lysergic acid and Simvastatin is based on Lovastatin.[4]

IxabepiloneEpothilone B R=CH3
CarfilzomibEpoxomicin
EravacyclineTetracycline
CabergolineLysergic acid
SimvastatinLovastatin

Diverted total synthesis is a topic in academic research.[5][6][7][8][9][10][11][12]

References

  1. 1 2 Design and synthesis of analogues of natural products Martin E. Maiera Org. Biomol. Chem., 2015,13, 5302-5343 doi:10.1039/C5OB00169B
  2. ↑ Fürstner, A. (2011), From Total Synthesis to Diverted Total Synthesis: Case Studies in the Amphidinolide Series. Isr. J. Chem., 51: 329–345. doi:10.1002/ijch.201100006
  3. ↑ Counting on natural products for drug design Tiago Rodrigues, Daniel Reker, Petra Schneider & Gisbert Schneider Nature Chemistry 8, 531–541 (2016) doi:10.1038/nchem.2479
  4. 1 2 Small Molecule Natural Products in the Discovery of Therapeutic Agents:  The Synthesis Connection Rebecca M. Wilson‡ and Samuel J. Danishefsky*,‡,§ The Journal of Organic Chemistry 2006 71 (22), 8329-8351 doi:10.1021/jo0610053
  5. ↑ Diverted total synthesis: Preparation of a focused library of latrunculin analogues and evaluation of their actin-binding properties Alois Fürstner, Douglas Kirk, Michaël D. B. Fenster, Christophe Aïssa, Dominic De Souza, and Oliver Müller PNAS vol. 102 no. 23 8103–8108 2005, doi:10.1073/pnas.0501441102
  6. ↑ Lei, X. and Danishefsky, Samuel J. (2008), Efficient Synthesis of a Novel Resorcyclide as Anticancer Agent Based on Hsp90 Inhibition. Adv. Synth. Catal., 350: 1677–1681. doi:10.1002/adsc.200800187
  7. ↑ Diverted Total Synthesis Leads to the Generation of Promising Cell-Migration Inhibitors for Treatment of Tumor Metastasis: In vivo and Mechanistic Studies on the Migrastatin Core Ether Analog Thordur Oskarsson, Pavel Nagorny, Isaac J. Krauss, Lucy Perez, Mihirbaran Mandal, Guangli Yang, Ouathek Ouerfelli, Danhua Xiao, Malcolm A. S. Moore, Joan Massagué, and Samuel J. Danishefsky Journal of the American Chemical Society 2010 132 (9), 3224-3228 doi:10.1021/ja9101503
  8. ↑ Synthetic studies toward (+)-cortistatin A Zhang Wang, Mingji Dai, Peter K. Park Samuel J. Danishefsky Tetrahedron Volume 67, Issue 52, 30 December 2011, Pages 10249–10260 doi:10.1016/j.tet.2011.10.026
  9. ↑ Design, synthesis, and evaluation of potent bryostatin analogs that modulate PKC translocation selectivity Paul A. Wender, Jeremy L. Baryza, Stacey E. Brenner, Brian A. DeChristopher, Brian A. Loy, Adam J. Schrier, and Vishal A. Verma Proc Natl Acad Sci U S A. 2011 Apr 26; 108(17): 6721–6726. doi:10.1073/pnas.1015270108
  10. ↑ Emergence of potent inhibitors of metastasis in lung cancer via syntheses based on migrastatin Nicolas Lecomte, Jon T. Njardarson, Pavel Nagorny, Guangli Yang, Robert Downey, Ouathek Ouerfelli, Malcolm A. S. Moore, and Samuel J. Danishefsky Proc Natl Acad Sci U S A. 2011 Sep 13; 108(37): 15074-15078 doi:10.1073/pnas.1015247108
  11. ↑ Nickel-catalyzed regiodivergent approach to macrolide motifs Abdur-Rafay Shareef, David H. Sherman and John Montgomery Chem. Sci., 2012,3, 892-895 doi:10.1039/C2SC00866A
  12. ↑ Nitroso Diels-Alder (NDA) Reaction as an Efficient Tool for the Functionalization of Diene-Containing Natural Products Serena Carosso and Marvin J. Miller Org Biomol Chem. 2014 Oct 14; 12(38): 7445–7468 doi:10.1039/c4ob01033g
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