Design, Synthesis, and Pharmacological Activities of Dynorphin A Analogues Cyclized by Ring-Closing Metathesis

Fang, Wei-Jie; Cui, Yanjun; Murray, Thomas F.; Aldrich, Jane V.

doi:10.1021/jm900577k

Cited by 30 publications

(32 citation statements)

References 49 publications

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“…Analogues of Dyn A (1–11)-NH 2 were cyclized at positions 2 and 5 or 5 and 8 through an allyl glycine [79]. The positioning and stereochemistry of the cyclization impacted both KOR affinity and selectivity.…”

Section: Introductionmentioning

confidence: 99%

Cyclic Opioid Peptides

Remesic

Lee

Hruby³

2016

CMC

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For decades the opioid receptors have been an attractive therapeutic target for the treatment of pain. Since the first discovery of enkephalin, approximately a dozen endogenous opioid peptides have been known to produce opioid activity and analgesia, but their therapeutics have been limited mainly due to low blood brain barrier penetration and poor resistance to proteolytic degradation. One versatile approach to overcome these drawbacks is the cyclization of linear peptides to cyclic peptides with constrained topographical structure. Compared to their linear parents, cyclic analogues exhibit better metabolic stability, lower off-target toxicity, and improved bioavailability. Extensive structure-activity relationship studies have uncovered promising compounds for the treatment of pain as well as further elucidate structural elements required for selective opioid receptor activity. The benefits that come with employing cyclization can be further enhanced through the generation of polycyclic derivatives. Opioid ligands generally have a short peptide chain and thus the realm of polycyclic peptides has yet to be explored. In this review, a brief history of designing ligands for the opioid receptors, including classic linear and cyclic ligands, is discussed along with recent approaches and successes of cyclic peptide ligands for the receptors. Various scaffolds and approaches to improve bioavailability are elaborated on and concluded with a discourse towards polycyclic peptides.

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Section: Introductionmentioning

confidence: 99%

Cyclic Opioid Peptides

Remesic

Lee

Hruby³

2016

CMC

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“…The reaction conditions used for arodyn analogs containing allylglycine (40mol% and 3mM of catalyst at 60 o C for 2 days) [5] gave only 20% of the desired RCM product for the model dipeptide plus a number of desallyl side products (Figure 2), as determined by HPLC. Different reaction parameters and strategies to enhance the yield of the RCM product were then examined on the model dipeptide.…”

Section: Resultsmentioning

confidence: 99%

“…In contrast to high yields observed in RCM using allylglycine in Dyn A analogs [5], a mixture of side products (Figure 2) compromised the RCM product yield of arodyn analogs containing Tyr(All) [4]. Olefin isomerization due to degradation products of the Grubbs catalyst could lead to the observed side products [6].…”

Section: Introductionmentioning

confidence: 99%

Peptide Ring Closing Metathesis: Minimizing Side Reactions in Arodyn Analogs

Gisemba¹,

Aldrich²

2015

Peptides 2015, Proceedings of the 24th American Peptide Symposium

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“…In this case the Petasis olefination and a RCM reaction was utilized as key steps. A convenient sequential on-resin RCM approach has also be used for the synthesis of a carbocyclic lantibiotic peptide [35], the synthesis of a new peptidomimetic alkene-structure (a dipeptidosulfonamide isostere) described by Liskamp and co-authors [36] on solid phase via a olefin CM reaction, the RCM reaction for the synthesis of b3-peptides [37], synthesis of analogues to Dynorphin A-peptides [38], and preparation of histone deacetylase inhibitors [39], cyclic peptoids [40], cyclic pseudopeptides [41], cyclic 11-and 10-mer peptide derivatives [42], glycopeptoids [43], lipophilic tetrapeptides [44], and peptide thioureas and triazole-containing macrocycles [45]. The CM reaction has nevertheless also been used for the preparation of many simple organic molecules and heterocycles (Fig.…”

Section: Introductionmentioning

confidence: 99%

Metathesis Reactions on Solid-Phase: Towards New Synthesis Challenges

Franzén

2016

Top Catal

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Today there are many types of transition-metalcatalyzed carbon-carbon bond-forming reactions. Of these, the olefin metathesis has made possible a wide range of transformations with commercially available and easily handled catalysts. Olefin metathesis is widely considered as one of the most powerful synthetic tool in organic chemistry. During the last 20 years many new catalysts with excellent selectivity and efficiency have been developed, also to be used in solid phase organic chemistry protocols. The understanding of the mechanisms and interactions between the catalyst and substrate has resulted that an increasing number of research groups have employed these reactions in multistep procedures and in the synthesis of active pharmaceutical ingredients and natural products. Although the olefin metathesis reaction still proceeds better in homogeneous phase, some structural modifications of the catalyst and new approaches for immobilization have provided interesting possibilities towards more efficient use also in heterogeneous phase. To celebrate 10 years since the Nobel Prize in Chemistry given to Yves Chauvin, Richard Schrock and Robert Grubbs for the ''development of the metathesis method in organic synthesis'' and to summarize recent results obtained in the field of solid phase metathesis chemistry this short review was written.Keywords Olefin metathesis Á Heterogeneous catalysis Á Solid supported catalyst Á Carbon-carbon bonds BackgroundSolid phase ring-closing metathesis (RCM) was first time applied for the synthesis of seven membered cycloolefins in 1996 by van Maarseveen et al. [1]. This cyclization/cleavage approach proceeded in a moderate 54 % yield, due to intermolecular ''metathetical dimerizations'' at the resin according to the authors. As the catalyst, the well-known and utilized ruthenium carbene complex described by Grubbs and co-authors [2-4] was used. A few years later, this strategy was further utilized for the preparation of unsaturated a-estersubstituted N-heterocycles from solid phase-bound olefinic amino acid derivatives.[5] and for the preparation of b-turn mimetics [6] (Fig. 1). The methodology has more recently been used for the macrocyclization strategies to obtain peptide-peptoid hydrid-molecules [7] On the other hand, the ringopening cross metathesis (ROM) of bicyclic alkenes with terminal aryl alkenes on solid support described in 1997 by Cuny et al. [8] is a excellent example of a highly regioselective reaction, marking the start for the utilization of metathesis reactions on solid phase of this reaction-type. Robert Grubbs and co-authors [9-11] described the same year, that norbornyl monomers polymerize readily at ROM conditions. This gave the starting point also for ring-opening metathesis polymerization (ROMP) that found applications for example in the preparation of terpyridine-based silica supports [12], and norbornene-based resins for applications in organic synthesis and other different immobilized polymers [13,14] (Fig. 2). Towards More Complicated StructuresSeeberger and c...

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Design, Synthesis, and Pharmacological Activities of Dynorphin A Analogues Cyclized by Ring-Closing Metathesis

Cited by 30 publications

References 49 publications

Cyclic Opioid Peptides

Cyclic Opioid Peptides

Peptide Ring Closing Metathesis: Minimizing Side Reactions in Arodyn Analogs

Metathesis Reactions on Solid-Phase: Towards New Synthesis Challenges

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