Indoles and Indole Isosteres

By: Dr. Mark Redlich, Chemfiles Volume 10 Article 2

          Dr. Mark Redlich

Dr. Mark Redlich
Product Manager
Email: mark.redlich@sial.com

The indole subunit is a near-ubiquitous component of biologically active natural products, and its study has been a major focus of research for generations. Substituted indoles have frequently been referred to as privileged structures since they are capable of binding to multiple receptors with high affinity, and thus have applications across a wide range of therapeutic areas.1 Due to this activity, it is not surprising that the indole ring system has become an important structural motif in many pharmaceutical agents.

The azaindole and indazole moieties differ only by the presence of an extra ring nitrogen, and thus exhibit excellent potential as bioisosteres of the indole ring system. Although considerably more rare in nature, they still constitute essential subunits in many pharmaceutically important compounds, and have been very valuable to synthetic and medicinal chemists.2,3 7-Azaindoles are of particular interest because of their ability to mimic purines in its role as a hydrogen-bonding partner. Various indazoles have been reported to display significant activity as antifungals, antiinflammatory agents, antiarrhythmic agents, analgesics, and nitric oxide synthase inhibitors.3a

Similarly, 7-deazapurines are an important class of compounds found in a wide variety of biological niches. For example, several naturally occurring 7-deazapurine ribonucleosides exhibit a broad spectrum of biological activity, such as tubercidin and toyocamycin.4 Also, 6-heteroaryl-7-deazapurine and 7-fluoro- 7-deazapurine ribonucleosides have been found to possess cytostatic effects at low nanomolar concentrations with the potency comparable to clofarabine.5

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Materials

     

References

  1. Horton, D. A. et al. Chem. Rev. 2003, 103, 893 and references there-in.
  2. Recent reviews of azaindoles: (a) Popowycz, F. et al. Tetrahedron 2007, 63, 1031. (b) Popowycz, F. et al. Tetrahedron 2007, 63, 8689. (c) Song, J. J. et al. Chem. Soc. Rev. 2007, 36, 1120.
  3. Recent reviews of indazoles: (a) Schmidt, A. et al. Eur. J. Org. Chem. 2008, 4073. (b) Cerecetto, H. et al. Mini-Rev. Med. Chem. 2005, 5, 869. (c) Stadlbauer, W.; Camp, N. In Science of Synthesis: Houben-Weyl Methods of Molecular Transformations; Bellus, D., Ley, S. V., Noyori, R., Regitz, M., Schaumann, E., Shinkai, E., Thomas, E. J., Trost, B. M., Reider, P. J., Eds.; Thieme: Stuttgart, Germany, 2002; Vol. 12, p 227.
  4. (a) Suhadolnik, R. J. Pyrrolopyrimidine Nucleosides in Nucleoside Antibiotics; Wiley-Interscience: New York, 1970; 298 and references therein. (b) Kasai, H. et al. Biochemistry 1975, 14, 4198.
  5. Nauš, P. et al. J. Med. Chem. 2010, 53, 460.

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