Synthesis and Biological Evaluation of Migrastatin Macrotriazoles

Gabba, Adele; Robakiewicz, Stefania; Taciak, Bartłomiej; Ulewicz, Katarzyna; Broggini, Gianluigi; Rastelli, Giulio; Krol, Magadalena; Murphy, Paul V.; Passarella, Daniele

doi:10.1002/ejoc.201600988

Cited by 13 publications

(8 citation statements)

References 24 publications

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“…In line with our previous experience on triazole compounds,[ 37 , 38 , 39 ] the synthetic construction of inhibitors 4 a – 4 f was accomplished by a multistep procedure. The preparation of triazole 1 (Scheme 1 ) is based on Huisgen cycloaddition between azide C and ethyl 3‐(pyridin‐4‐yl)‐propiolate and subsequent base induced ester hydrolysis.…”

Section: Resultsmentioning

confidence: 99%

Design and Synthesis of Hsp90 Inhibitors with B‐Raf and PDHK1 Multi‐Target Activity

et al. 2021

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The design of multi‐target ligands has become an innovative approach for the identification of effective therapeutic treatments against complex diseases, such as cancer. Recent studies have demonstrated that the combined inhibition of Hsp90 and B‐Raf provides synergistic effects against several types of cancers. Moreover, it has been reported that PDHK1, which presents an ATP‐binding pocket similar to that of Hsp90, plays an important role in tumor initiation, maintenance and progression, participating also to the senescence process induced by B‐Raf oncogenic proteins. Based on these premises, the simultaneous inhibition of these targets may provide several benefits for the treatment of cancer. In this work, we set up a design strategy including the assembly and integration of molecular fragments known to be important for binding to the Hsp90, PDHK1 and B‐Raf targets, aided by molecular docking for the selection of a set of compounds potentially able to exert Hsp90‐B‐Raf‐PDHK1 multi‐target activities. The designed compounds were synthesized and experimentally validated in vitro . According to the in vitro assays, compounds 4 a , 4 d and 4 e potently inhibited Hsp90 and moderately inhibited the PDHK1 kinase. Finally, molecular dynamics simulations were performed to provide further insights into the structural basis of their multi‐target activity.

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Section: Resultsmentioning

confidence: 99%

Design and Synthesis of Hsp90 Inhibitors with B‐Raf and PDHK1 Multi‐Target Activity

et al. 2021

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“…In 2017, Gabba et al synthesized the migrastatin-triazole derivatives 201 and 204 and evaluated their biological activities (Scheme 20 ). 28 In order to prepare the target macrocycles, the synthons 194 and 198a – c were first synthesized. Activation of 5-hexen-1-ol 194 with methanesulfonyl chloride followed by treatment with sodium azide led to the formation of alkenylazide 195 .…”

Section: Anticancer Derivativesmentioning

confidence: 99%

Synthesis of Bioactive 1,2,3-Triazole-Fused Macrocycles via Azide-Alkyne Cycloaddition

Ansary,

Jahan,

Pal

2023

SynOpen

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A systematic highlight on the syntheses of 1,2,3-triazole fused macrocycles possessing biological activities like anticancer, antibacterial, antiviral, anti-inflammatory, antilarval and more has been presented in this review since 2006. The well-renowned Cu-catalyzed azide-alkyne cycloaddition reaction was noted to be one of the highly efficient and most common methods utilized by several scientists for the synthesis of 1,4-disubstituted triazole fused macrocycles while the Ru-catalyzed cycloaddition led to the 1,5-disubstituted bioactive triazoles. This review would thus be extremely beneficial for both synthetic organic and medicinal chemists.

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“…Migrastatin is a natural product isolated from Streptomyces platensis bacteria and is an inhibitor of fascin, a protein involved in cell motility. The triazole analogues of an active lactam derivative of migrastatin 38 ( Figure 17 ), synthesized using CuAAC, showed a significant effect in reducing the migration capacity of MDA-MB-361 cell lines [ 66 ].…”

Section: 123- Triazole Moiety and Peptide Structurementioning

confidence: 99%

1,2,3-Triazoles as Biomimetics in Peptide Science

2021

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Natural peptides are an important class of chemical mediators, essential for most vital processes. What limits the potential of the use of peptides as drugs is their low bioavailability and enzymatic degradation in vivo. To overcome this limitation, the development of new molecules mimicking peptides is of great importance for the development of new biologically active molecules. Therefore, replacing the amide bond in a peptide with a heterocyclic bioisostere, such as the 1,2,3-triazole ring, can be considered an effective solution for the synthesis of biologically relevant peptidomimetics. These 1,2,3-triazoles may have an interesting biological activity, because they behave as rigid link units, which can mimic the electronic properties of amide bonds and show bioisosteric effects. Additionally, triazole can be used as a linker moiety to link peptides to other functional groups.

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Synthesis and Biological Evaluation of Migrastatin Macrotriazoles

Cited by 13 publications

References 24 publications

Design and Synthesis of Hsp90 Inhibitors with B‐Raf and PDHK1 Multi‐Target Activity

Design and Synthesis of Hsp90 Inhibitors with B‐Raf and PDHK1 Multi‐Target Activity

Synthesis of Bioactive 1,2,3-Triazole-Fused Macrocycles via Azide-Alkyne Cycloaddition

1,2,3-Triazoles as Biomimetics in Peptide Science

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