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Thiazoles and Imidazoles

By: Mark Redlich, Aldrich ChemFiles 2010, 10.3, 14.

Thiazoles and imidazoles have been frequently discovered as a vital component of novel and structurally diverse natural products that exhibit a wide variety of biological activities. The exceptional range of antitumor, antiviral, and antibiotic activities, as well as their presence in peptides, or ability to bind to proteins, DNA, and RNA, has directed numerous synthetic studies and new applications of these azole heterocycles.

The thiazole ring has been identified as a central feature of myriad natural products, perhaps the best known being the epothilones (Figure 1). These are antitumor agents that display improved potency against Taxol-resistant tumor cell lines, and variants of epothilone B in particular have been pursued by several major pharmaceutical companies.1


Figure 1. Structure of Epothilones A-F

Figure 1. Structure of Epothilones A-F

Additionally, thiazoles are frequently cropping up in peptide research. For example, the pseudopeptide dolastatin 10 (Figure 2) is an exceptionally potent antineoplastic agent,2 and other thiazole-containing marine cyclic peptides have demonstrated significant cytotoxicity.3 A recent report demonstrates the use of ethyl 2-methylthiazole-4-carboxaldehyde (716308) as a starting material to the pyridine-thiazole structure 1 (Scheme 1), a protected form of the core cluster of thiopeptide antibiotics micrococcin P1-P2, thiocillin I, and YM266183.4


Figure 2. Structure of Dolastatin 10

Figure 2. Structure of Dolastatin 10


Scheme 1. Ethyl 2-methylthiazole-4-carboxaldehyde as a starter for pyridinethiazole structure 1

Scheme 1. Ethyl 2-methylthiazole-4-carboxaldehyde as a starter for pyridinethiazole structure 1 (716308)

Thiazoles can also serve as a protected formyl group that can be liberated in the late stages of a complex natural product synthesis.5

While thiazoles are prevalent in a wide range of bioactive natural products, the imidazole ring occurs largely in the context of the natural amino acid histidine. In addition, the imidazole ring has appeared as a component of unnatural cyclic peptides,6 and used as an ester isostere in peptidomimetic studies.7However, the applications of imidazole are not limited to the realm of peptides and peptidomimetics. They are present in the large family of bromopyrrole-imidazole alkaloids isolated from marine sponges based on the common metabolite oroidin (Figure 3) that feature significant biological activities.1 The imidazole ring is also present in the pilocarpine alkaloids, as well as potential therapuetic agents for thrombosis, cancer, and inflammatory diseases.8


Figure 3. Structure of Oroidin

Figure 3. Structure of Oroidin

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Materials

     

References

  1. Jin, Z. Nat. Prod. Rep., 2005, 22, 196.
  2. Pettit, G. R. et al. J. Am. Chem. Soc. 1987, 109, 6883.
  3. (a) Davidson, B. S. Chem. Rev. 1993, 93, 1771. (b) Fusetani, N.; Matsunaga, S. Chem. Rev. 1993, 93, 1793. (c) Wipf, P. Chem. Rev. 1995, 95, 2115.
  4. Aulakh, V. S.; Ciufolini, M. A. J. Org. Chem. 2009, 74, 5750.
  5. Dondoni, A.; Marra, A. Chem. Rev. 2004, 104, 2557.
  6. Haberhauer, G.; Rominger, F. Eur. J. Org. Chem. 2003, 3209.
  7. Dhanak, D. et al. Bioorg. Med. Chem. Lett. 2001, 11, 1445
  8. (a) Appleby, I. et al. Org. Lett 2005, 7, 1931. (b) Allerton, C. M. N. et al. W.O. Pat. Appl. 2002014285, 2002; Chem. Abstr. 2002, 136, 184120.

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