Advancing biological understanding and therapeutics discovery with small-molecule probes

Small-molecule probes can illuminate biological processes and aid in the assessment of emerging therapeutic targets by perturbing biological systems in a manner distinct from other experimental approaches. Despite the tremendous promise of chemical tools for investigating biology and disease, small-molecule probes were unavailable for most targets and pathways as recently as a decade ago. In 2005, the NIH launched the decade-long Molecular Libraries Program with the intent of innovating in and broadening access to small-molecule science. This Perspective describes how novel small-molecule probes identified through the program are enabling the exploration of biological pathways and therapeutic hypotheses not otherwise testable. These experiences illustrate how small-molecule probes can help bridge the chasm between biological research and the development of medicines but also highlight the need to innovate the science of therapeutic discovery

Concerning The Application Of The1h Nmr Abx Analysis For Assignment Of Stereochemistry To Aldols Deriving From Aldehydes Lacking β-branches

Attempts to apply the 1H NMR ABX method for assignment of stereochemistry of β-hydroxy ketones to aldols 4-10 deriving from α-methyl aldehydes lacking β-branches reveals that the presence of a β-branch in the aldehyde reaction partner is necessary so that the average chemical environment of Ha and Hb is different for the Felkin and anti-Felkin aldols (see conformational pairs A/B and C/D, respectively). When the chiral α-methyl aldehyde lacks a β-branch, as in the case of the aldehyde precursors to 4-10, the conformational energies of E and F (for the Felkin β-hydroxy ketone derivatives), and conformers G and H for the anti-Felkin aldols, are too close in energy (within each pair), such that the average chemical and magnetic environments of Ha and Hb in the two diastereomers cannot be easily distinguished. This analysis provides a rational basis for application of the 1H NMR ABX pattern analysis to other β-hydroxy ketone derivatives. © 2005 American Chemical Society.70251046110465Dias, L.C., Baú, R.Z., De Sousa, M.A., Zuckerman-Schpector, J., (2002) Org. Lett., 4, p. 4325Liu, C.M., Smith III, W.J., Gustin, D.J., Roush, W.R., (2005) J. Am. Chem. Soc., 127, p. 5770Cowden, C.J., Paterson, I., (1997) Org. React., 51, p. 1Franklin, A.S., Paterson, I., (1994) Contemp. Org. Synth., 1, p. 317Heathcock, C.H., (1991) Comprehensive Organic Synthesis, 2, p. 181. , Heathcock, C. H., Ed.Pergamon Press: New YorkKim, E.M., Williams, S.F., Masamune, S., (1991) Comprehensive Organic Synthesis, 2, p. 239. , Heathcock, C. H., Ed.Pergamon Press: New YorkPaterson, I., (1991) Comprehensive Organic Synthesis, 2, p. 301. , Heathcock, C. H., Ed.Pergamon Press: New YorkBraun, M., (1987) Angew. Chem., Int. Ed. Engl., 26, p. 24Heathcock, C.H., (1984) Asymmetric Synth., 3, p. 111Evans, D.A., Nelson, J.V., Taber, T.R., (1982) Top. Stereochem., 13, p. 1Paterson, I., Goodman, J.M., (1989) Tetrahedron Lett., 30, p. 997Paterson, I., Florence, G.J., (2000) Tetrahedron Lett., 41, p. 6935Evans, D.A., Coleman, P.J., Côté, B., (1997) J. Org. Chem., 62, p. 788Evans, D.A., Trotter, B.W., Coleman, P.J., Côté, B., Dias, L.C., Rajapakse, H.A., Tyler, A.N., (1999) Tetrahedron, 29, p. 8671Paterson, I., Collett, L.A., (2001) Tetrahedron Lett., 42, p. 1187Paterson, I., Gibson, K.R., Oballa, R.M., (1996) Tetrahedron Lett., 37, p. 8585Tanimoto, N., Gerritz, S.W., Sawabe, A., Noda, T., Filla, S.A., Masamune, S., (1994) Angew Chem., Int. Ed. Engl., 33, p. 673Roush, W.R., Bannister, T.D., Wendt, M.D., Jablonowski, J.A., Scheidt, K.A., (2002) J. Org. Chem., 67, p. 4275Arefolov, A., Panek, J.S., (2002) Org. Lett., 4, p. 2397Roush, W.R., Bannister, T.D., Wendt, M.D., Vannieuwenhze, M.S., Gustin, D.J., Dilley, G.J., Lane, G.C., Smith III, W.J., (2002) J. Org. Chem., 67, p. 4284Oikawa, Y., Yoshioka, T., Yonemitsu, O., (1982) Tetrahedron Lett., 23, p. 889noteHeathcock, C.H., Pirrung, M., Sohn, J.E., (1979) J. Org. Chem., 44, p. 4294not