Synthesis of <i>N</i>-Glyoxyl Prolyl and Pipecolyl Amides and Thioesters and Evaluation of Their In Vitro and In Vivo Nerve Regenerative Effects

Hamilton, Gregory S.; Wu, Yong; Limburg, David C.; Wilkinson, Douglas E.; Vaal, Mark J.; Li, Jia He; Thomas, Christine K.; Huang, Wei; Sauer, H.; Ross, Douglas T.; Soni, Raj; Chen, Yi; Guo, Hongshi; Howorth, P. J. N.; Valentine, Heather; Shi, Liang; Spicer, Dawn; Fuller, Mike; Steiner, Joseph P.

doi:10.1021/jm010556c

Cited by 46 publications

(18 citation statements)

References 17 publications

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“…We decided to employ proline-derived, as opposed to pipecolinic acid-based site 1 fragments for further investigation, as these have been shown previously to exhibit increased binding affinity to FKBP. [38][39][40] Other studies have shown the activities of proline-and pipecolinic acid-derived ligands to be similar. [32,[41][42][43] The synthesis of site 1 ligands equipped with suitable functionalities was started by coupling a-ketoacid 15 with commercially available tBu-protected proline 17 to yield compound 18 (Scheme 2, 80 %).…”

Section: Chemistrymentioning

confidence: 97%

Fragment‐Based Synthesis and SAR of Modified FKBP Ligands: Influence of Different Linking on Binding Affinity

et al. 2007

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The viability of the fragment-based approach for lead discovery depends on reliable fragment-screening methods combined with straightforward fragment-linking- or fragment-growing-chemistry. In the present study we sought a flexible synthetic approach that would allow efficient synthesis of a variety of linkers that can subsequently be tested for biological activity. We applied this approach to fragments known to bind to FKBP12 (FK506 binding protein), a peptidyl-prolyl isomerase involved in immunosuppression and neural functioning. In our set of linked FKBP ligands, ester and thioester linkages resulted in high-affinity ligands, whereas an amide linkage decreased affinity remarkably; oxime and triazole linkages were not tolerated by the target protein's binding pocket, rendering these ligands ineffective. By investigating corresponding derivatized non-linked fragments and docking studies of linked fragments, we were able to evaluate the effect of the linker region on ligand binding affinity.

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Section: Chemistrymentioning

confidence: 97%

Fragment‐Based Synthesis and SAR of Modified FKBP Ligands: Influence of Different Linking on Binding Affinity

et al. 2007

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“…Pipecolic acid (2‐piperidine carboxylic acid, a homolog of proline) is an attractive synthetic target because it is a key constituent of many synthetic and natural bioactive molecules (e.g., anesthetic bupivacaine or anticancer agent VX 710, Table ) and a building block in preparation of peptides and peptide mimetics …”

Section: Synthesis Of Pipecolic Acidmentioning

confidence: 99%

Significance of the Natural Occurrence of L‐ Versus D‐Pipecolic Acid: A Review

et al. 2013

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Pipecolic acid naturally occurs in microorganisms, plants, and animals, where it plays many roles, including the interactions between these organisms, and is a key constituent of many natural and synthetic bioactive molecules. This article provides a review of current knowledge on the natural occurrence of pipecolic acid and the known and potential significance of its L- and D-enantiomers in different scientific disciplines. Knowledge gaps with perspectives for future research identified within this article include the roles of the L- versus the D-enantiomer of pipecolic acid in plant resistance, nutrient acquisition, and decontamination of polluted soils, as well as rhizosphere ecology and medical issues.

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“…The discovery that small molecule ligands for peptidyl‐prolyl isomerase (PPIase) possess powerful neuroprotective and neuroregenerative properties in vitro and in vivo suggests therapeutic utility for such compounds in neurodegenerative disease 67 . The neurotrophic effects of these compounds are independent of the immunosuppressive pathways by which drugs such as FK506 and rapamycin operate 68 …”

Section: Enhancing Neuroprotection By Combining Hypothermia With Addimentioning

confidence: 99%

Combinatorial techniques for enhancing neuroprotection

Kuffler

2010

Annals of the New York Academy of Sciences

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Brain and spinal cord (CNS) trauma typically kill a number of neurons, but even more neurons are killed by secondary causes triggered by the initial trauma. Thus, a minor insult may rapidly cause the death of a vastly larger number of neurons and complete paralysis. The best mechanism for reducing the extent of neurological deficits is to minimize the number of neurons killed by post-trauma sequelae. Neuroprotection techniques take many diverse forms with a breadth too great for a short review. Therefore, this review focuses on the neuroprotection provided by hypothermia and a number of other neuroprotective techniques, when administered singly or in combination, because it is generally found that combinations of applications lead to significantly better neuroprotection than is achieved by any one alone. The combinatorial approach to neuroprotection holds great promise for enhancing the degree of neuroprotection following trauma, leading to maximum maintenance of neurological function.

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Synthesis of N-Glyoxyl Prolyl and Pipecolyl Amides and Thioesters and Evaluation of Their In Vitro and In Vivo Nerve Regenerative Effects

Cited by 46 publications

References 17 publications

Fragment‐Based Synthesis and SAR of Modified FKBP Ligands: Influence of Different Linking on Binding Affinity

Fragment‐Based Synthesis and SAR of Modified FKBP Ligands: Influence of Different Linking on Binding Affinity

Significance of the Natural Occurrence of L‐ Versus D‐Pipecolic Acid: A Review

Combinatorial techniques for enhancing neuroprotection

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