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Review
. 2009 Dec 18;74(24):9245-64.
doi: 10.1021/jo901767e.

Organic chemistry and biology: chemical biology through the eyes of collaboration

Victor J Hruby  1
Affiliations
Review

Organic chemistry and biology: chemical biology through the eyes of collaboration

Victor J Hruby. J Org Chem. .

Abstract

From a scientific perspective, efforts to understand biology including what constitutes health and disease has become a chemical problem. However, chemists and biologists "see" the problems of understanding biology from different perspectives, and this has retarded progress in solving the problems especially as they relate to health and disease. This suggests that close collaboration between chemists and biologists is not only necessary but essential for progress in both the biology and chemistry that will provide solutions to the global questions of biology. This perspective has directed my scientific efforts for the past 45 years, and in this overview I provide my perspective of how the applications of synthetic chemistry, structural design, and numerous other chemical principles have intersected in my collaborations with biologists to provide new tools, new science, and new insights that were only made possible and fruitful by these collaborations.

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Figures

Figure 1
Figure 1
Evolution of a peptide hormone and neurotransmitter from a flexible linear peptide with short half-life to cyclic conformationally constrained receptor-selective analogues that cross the blood–brain barrier.
Figure 2
Figure 2
Development of ligands for pain.
Figure 3
Figure 3
Conversion of somatostatin to a potent highly μ opioid receptor selective ligand.
Figure 4
Figure 4
φ, ψ, ω, and χ torsional angles.
Figure 5
Figure 5
χ-1 vs χ-2 plot of tyrosine.
Figure 6
Figure 6
General structure of some χ-constrained aromatic amino acids.
Figure 7
Figure 7
χ-1/χ-2 plot of l- and d-Tyr and for the four isomers of 2′,6′-dimethyl-β-methyltyrosine (TMT).
Figure 8
Figure 8
Asymmetric synthesis of (2S,3R)-2′,6′-dimethyl-β-methyltyrosine.
Figure 9
Figure 9
Methods for the asymmetric synthesis of pyroglutamic acids analogues.
Figure 10
Figure 10
Asymmetric synthesis of β-functionalized γ,δ-unsaturated amino acids.
Figure 11
Figure 11
Measurement of the prolonged biological activity of the four isomers of [β-MeTrp9]-MT-II in the frog skin bioassay.
Figure 12
Figure 12
Design of a multivalent ligand for pain (Bzl = benzyl).
Figure 13
Figure 13
Synthetic scheme for the synthesis of a heterobivalent ligand.
See this image and copyright information in PMC

References

    1. Hruby VJ, Yamashiro D, du Vigneaud V. J Am Chem Soc. 1968;90:7106–7110. - PubMed

    1. For those who might be interested in what an organic chemist could do at the interface of chemistry and biology at that time I list a few of our chemical accomplishments below and in ref 3 our contributions to biology. Barstow LE, Hruby VJ. J Org Chem. 1971;36:1305–1306.Hruby VJ, Groginsky CM. J Chromatogr. 1971;63:423–428.Hruby VJ, Barstow LE. Macromol Synth. 1972;4:91–94.Hruby VJ, Brewster AI, Glasel JA. Proc Natl Acad Sci U S A. 1971;68:450–453.Glasel JA, Hruby VJ, McKelvy JF, Spatola AF. J Mol Biol. 1973;79:555–575.Bower A, Sr, Hadley ME, Hruby VJ. Science. 1974;184:70–72.Hruby VJ. In: Chemistry and Biochemistry of Amino Acids, Peptides and Proteins. Weinstein B, editor. Vol. 3. Marcel Dekker; New York: 1974. pp. 1–188.Hruby VJ, Upson DA, Agarwal NS. J Org Chem. 1977;42:3552–3557..

    1. Early biological work: Bower A, Sr, Hadley ME, Hruby VJ. Biochem Biophys Res Commun. 1971;45:1185–1191.Hruby VJ, Smith CW, Bower A, Sr, Hadley ME. Science. 1972;176:1331–1332.Walter R, Kirchberger ML, Hruby VJ. Experientia. 1972;28:959–960.Hruby VJ, Muscio FA, Groginsky CM, Gitu PM, Saba D, Chan WY. J Med Chem. 1973;16:624–629.Hadley ME, Bower A, Sr, Hruby VJ. Yale J Biol Med. 1973;46:602–616.Bower A, Sr, Hadley ME, Hruby VJ. Science. 1974;184:70–72.Hadley ME, Hruby VJ, Bower A., Sr Gen Comp Endrocrinol. 1975;26:24–35..

    1. The instrument we designed later served as a prototype for commercial instruments produced by Vega Biotechnologies and was the first to have monitoring devices to assess synthetic progress. Hruby VJ, Barstow LE, Linhart T. Anal Chem. 1972;44:343–350..

    1. Hruby VJ. Acc Chem Res. 2001;34:389–397. - PubMed

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