Voss Lab

Outline of chemistry strategy for FMRT proposal (Aim 1)

Fig 3

Similar to what we have determined with the SLF compound, other small molecules have been shown to block Aβ oligomer growth and/or fibril formation 1; 2. While the structures of these compounds (e.g. Congo Red, curcumin) are unrelated, they share the general features of an aromatic core for (suggesting they bind at a hydrophobic pocket) with hydroxyls amino groups for H-bonding. As shown in Fig 3, we propose three compounds with added hydrogen donors (A-C) and five compounds with added hydrogen acceptors (D-H). In addition, the fluorene compounds (E-H) are expected to provide increased metabolic stability. The synthetic route is shown in Scheme 1. Starting material 1 can be prepared according to approaches reported in the literatures3; 4; 5; 6; 7. Compound 3 will be generated by bromination of 1 followed by nitro reduction. N-alkylation of 3 with commercially available 3-bromomethyl-2,5-dihydro-2,2,5,5-tetramethyl-1H-pyrrol-1-yloxy (RBr) in presence of base triethylamine (TEA). Compound D can be easily synthesized from commercially available 5 using similar N-alkylation condition. Compound C will be synthesized from 5 by first reduction of keto to alcohol followed by N-alkylation.

 

Citations:

  1. Hard, T. & Lendel, C. (2012). Inhibition of amyloid formation. J Mol Biol 421, 441-65.
  2. Stevens, C. B., Hanna, J. M., Jr. & Lammi, R. K. (2013). Synthesis of tetrahydroxybiphenyls and tetrahydroxyterphenyls and their evaluation as amyloid-beta aggregation inhibitors. Bioorg Med Chem Lett 23, 1703-6.
  3. Fletcher, T. L., Namkung, M. J., Wetzel, W. H. & Pan, H.-L. (1960). Derivatives of fluorene. X. Fluorofluorenes. 3. J Org Chem 25, 1342-1348.
  4. Fletcher, T. L., Wetzel, W. H., Namkung, M. J. & Pan, H.-L. (1959). Derivatives of fluorene. VI. Fluorofluorenes 1. J Am Chem Soc 81, 1092-1094.
  5. Grantham, P. H., Weisburger, E. K. & Weisnurger, J. H. (1961). Ionization constants of derivatives of fluorene and other polycyclic compounds. J Organic Chem 26, 1008-1017.
  6. Suzuki, K., Weisburger, E. K. & Weisnurger, J. H. (1959). Nitration of 1- and 3-fluorofluorene. J Organic Chem 24, 1511-1517.
  7. Suzuki, K., Weisburger, E. K. & Weisnurger, J. H. (1961). Derivatives of 3-fluorofluorene by the Pschorr synthesis. J Org Chem 26, 2239-2242.