Synthesis of new dipeptide analogs containing novel ketovinyl and hydroxyethylidene isosteres via Grignard addition to chiral .alpha.-amino aldehydes

Hanson, Gunnar J.; Lindberg, Thomas

doi:10.1021/jo00225a085

Cited by 52 publications

(15 citation statements)

References 3 publications

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“…Therefore, a new lead discovery in the rational design of peptide-based drugs is paramount [152]. Ketovinyl and hydroxyethylidene dipeptide metaphors, as well as heterocyclic and unnatural amino acids, are shown to be replacements for the peptide bond [153]. The peptide bond isosteres (Figure 46) provide the platform, for studying the mechanism-based enzyme inhibitors and proteolytic reactions, on the stability of the unnatural peptide linkage.…”

Section: Peptidomimeticsmentioning

confidence: 99%

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Squaryl Molecular Metaphors – Application to Rational Drug Design and Imaging Agents

Kitson¹

2017

J Diagn Imaging Ther

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Molecular Metaphors is the application of squaryl building blocks towards creative functional group chemistry to produce lead compounds and imaging agents. This strategy is applied to rational drug design and to various imaging agents that would normally contain conventional functional group chemistry. These, include carboxylic acids, α-amino acids, peptide bonds and phosphonates. Moreover, the squaryl metaphor is a precursor to complex organic molecules involving functional group interchange (FGI) and rearrangements. This article discusses the application of these metaphors in the area of neurochemistry, especially NMDA receptors. An important area of drug design is the inhibition of angiotensin II enzyme by the use of losartan. This commercial drug contains a tetrazole moiety that can be modified using the squaryl group to give a semisquarate derivative. These concepts can extend to the semisquarate of ibuprofen. Moreover, a discussion on peptidomimetics regarding the substitution of the peptide bond for squaramide allows for a change in the biological properties due to modification at the peptide bond. Furthermore, the topic on how squaryl metaphors can be exploited primarily by the central 1,3-hydroxyamide sequence to the generation of a novel class of HIV protease inhibitors. Also, squaryl metaphors can be used to develop potential inhibitors of glutathione and novel anti-migraine drugs. The discussion continues on the design of anticancer drugs: in particular, a novel class of metalloproteases, including phosphonates for semisquaramides, leading to squaryl nucleosides. This review concludes with the application of squaryl metaphors in the design of positron emission tomography (PET) and magnetic resonance imaging (MRI) agents towards theranostics. describe the ability of individual functional chemical groups to mimic other moieties [2,3]. KeywordsErlenmeyer rationalised these concepts and categorised isosteres into atoms, ions and molecules based on the valence level of electrons [4]. A further understanding by Friedman led to the term bioisosterism to include all atoms and molecules that fit the broadest definition of isosteres [5]. This approach was independent of whether the drug was an agonist or an antagonist towards biological activity.Moreover, Thornber applied the term bioisosterism to include subunits, groups or molecules that possess physicochemical properties of similar biological effects [6]. Finally, in 1991 Burger widened the definition of bioisosteres to include compounds or groups that possess similar molecular shapes and volumes independent of agonists or antagonists [7]. REVIEW ARTICLE Squaryl KitsonThese bioisosteres would require approximately the same distribution of electrons and give a high probability of generating comparable physical properties such as hydrophobicity [8]. Currently, bioisosterism is one of the most useful tools to the medicinal chemist in rational drug design and in particular regarding the carboxylic acid bioisosteres [9]. The carboxylic acid functional ...

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Section: Peptidomimeticsmentioning

confidence: 99%

“…Both ketomethylene and hydroxyethylene isosteres have the potential for directing alkylating agents (indicated by the arrows in Figure 46) such as cysteine thiol [153]. The hydroxyethylidene template can provide a tool for drug design, utilising the conformational restriction about the C-2 and C-3 bond.…”

Section: Peptidomimeticsmentioning

confidence: 99%

Squaryl Molecular Metaphors – Application to Rational Drug Design and Imaging Agents

Kitson¹

2017

J Diagn Imaging Ther

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“…The amino aldehyde 49 was generated in situ from the reduction of amino ester 48 , which was found to be crucial to the diastereoselectivity of the reaction, because the vinyl Grignard addition to purified N ‐Boc‐phenylalaninal was previously found to be unselective 59. This suggests that aluminum is integral to the selectivity of the reaction.…”

Section: Nucleophilic Additions To α‐Amino Aldehydesmentioning

confidence: 99%

Synthesis of Chiral Amines Using α‐Amino Aldehydes

2008

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O2 can do: Innocuous molecular oxygen O2 is the only reagent needed to perform highly chemoselective biocatalytic single‐step alkene‐cleavage reactions (see scheme). The products are analogous to those of (reductive) ozonization and related metal‐based methods. In contrast neither special equipment nor an additional reducing agent is required. The biocatalytic reaction can be performed at ambient temperature. Depending on the substrate, aldehydes or ketones are obtained.

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“…To a stirred suspension of NaH (1.58 g, 66.0 mmol) in dry THF (40 cm 3 ) was added dropwise a solution of the known allyl alcohol 6a 19 (4.58 g, 16.5 mmol) in dry THF (60 cm 3 ) at 0 ЊC under argon, and the mixture was heated under reflux for 15 min. (Boc) 2 O (7.20 g, 33.0 mmol) was added to the mixture at 0 ЊC, and the mixture was stirred for 1.5 h with warming to room temperature.…”

Section: (4s5s)-4-benzyl-n-(tert-butoxycarbonyl)-5-ethenyl-13-oxazoli...mentioning

confidence: 99%

Regio- and stereoselective ring-opening of chiral 1,3-oxazolidin-2-one derivatives by organocopper reagents provides novel access to di-, tri- and tetra-substituted alkene dipeptide isosteresElectronic supplementary information (ESI) available: synthetic procedures and characterization for 4a,b, 5a,b, 7b, 8a,b, 9a,b, 10b, 11a,b, 12b,c, 13b, 14a,b, 15, 16a,b, 17a,b, 18, 19b, 20b. See http://www.rsc.org/suppdata/p1/b2/b203482d/

Oishi

Niida

Kamano

et al. 2002

J. Chem. Soc., Perkin Trans. 1

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Synthesis of new dipeptide analogs containing novel ketovinyl and hydroxyethylidene isosteres via Grignard addition to chiral .alpha.-amino aldehydes

Cited by 52 publications

References 3 publications

Squaryl Molecular Metaphors – Application to Rational Drug Design and Imaging Agents

Squaryl Molecular Metaphors – Application to Rational Drug Design and Imaging Agents

Synthesis of Chiral Amines Using α‐Amino Aldehydes

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