Concise Total Synthesis of the Potent Translation and Cell Migration Inhibitor Lactimidomycin

An efficient total synthesis of the antiproliferative macrolide and cell migration inhibitor lactimidomycin (3) is reported, which relies on the performance of ring closing alkyne metathesis (RCAM). The strained 12-membered 1,3-enyne 21 as the key intermediate was forged with the aid of [(Ph3SiO)3Mo≡CPh]·OEt2 (27) as the most effective member of a new generation of powerful alkyne metathesis catalysts. 21 was elaborated to the target by a ruthenium catalyzed trans-hydrosilylation/proto-desilylation sequence and a highly diastereoselective Mukaiyama aldol reaction controlled by oxazaborolidinone 29 as strategic operations

Total Syntheses and Biological Reassessment of Lactimidomycin, Isomigrastatin and Congener Glutarimide Antibiotics

Lactimidomycin (1) was described in the literature as an exquisitely potent cell migration inhibitor. Encouraged by this claim, we developed a concise and scalable synthesis of this bipartite glutarimide-macrolide antibiotic, which relies on the power of ring-closing alkyne metathesis (RCAM) for the formation of the unusually strained 12-membered head group. Subsequent deliberate digression from the successful path to 1 also brought the sister compound isomigrastatin (2) as well as a series of non-natural analogues of these macrolides into reach. A careful biological re-evaluation of this compound collection showed 1 and progeny to be potently cytotoxic against a panel of cancer cell lines, even after one day of compound exposure; therefore any potentially specific effects on tumor cell migration were indistinguishable from the acute effect of cell death. No significant cell migration inhibition was observed at sub-toxic doses. Although these findings cannot be reconciled with some reports in the literature, they are in accord with the notion that lactimidomycin is primarily a ribosome-binder able to effectively halt protein biosynthesis at the translation stage

Hybrides organiques de polyoxométallates (synthèses, structure et chiralité)

Ce manuscrit porte sur la fonctionnalisation de polyoxométallates (POMs) par des molécules organiques. Dans une première partie, nous avons mis au point de nouvelles méthodes efficaces de dérivatisation de polyoxotungstates : la click chemistry a permis de greffer aussi bien des molécules organosolubles qu hydrosolubles aux polyoxométallates, et l activation électrophile d oxygènes de POMs a permis la synthèse de structures inédites (lactones inorganiques et POMs doublement fonctionnalisés). Il devient ainsi possible de concevoir des hybrides organique inorganique toujours plus diversifiés, ce qui apporte de nombreuses perspectives d applications. Dans un second temps, nous avons étudié, à travers des hybrides POMs-peptides, les interactions de type liaisons hydrogène qui existent entre la chaîne organique et la structure inorganique. La compréhension des facteurs qui gouvernent ces interactions est importante au niveau fondamental. Mais elle nous a surtout permis de réaliser la première séparation des énantiomères de POMs à structure Dawson 1, rendant possible l utilisation de polyoxométallates chiraux énantiopurs en catalyse ou biologie.PARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Exploring the utility of organo-polyoxometalate hybrids to inhibit SOX transcription factors

© 2014 Narasimhan et al.; licensee BioMed Central Ltd. Background: SOX transcription factors constitute an attractive target class for intervention with small molecules as they play a prominent role in the field of regenerative biomedicine and cancer biology. However, rationally engineering specific inhibitors that interfere with transcription factor DNA interfaces continues to be a monumental challenge in the field of transcription factor chemical biology. Polyoxometalates (POMs) are inorganic compounds that were previously shown to target the high-mobility group (HMG) of SOX proteins at nanomolar concentrations. In continuation of this work, we carried out an assessment of the selectivity of a panel of newly synthesized organo-polyoxometalate hybrids in targeting different transcription factor families to enable the usage of polyoxometalates as specific SOX transcription factor drugs.Results: The residual DNA-binding activities of 15 different transcription factors were measured after treatment with a panel of diverse polyoxometalates. Polyoxometalates belonging to the Dawson structural class were found to be more potent inhibitors than the Keggin class. Further, organically modified Dawson polyoxometalates were found to be the most potent in inhibiting transcription factor DNA binding activity. The size of the polyoxometalates and its derivitization were found to be the key determinants of their potency.Conclusion: Polyoxometalates are highly potent, nanomolar range inhibitors of the DNA binding activity of the Sox-HMG family. However, binding assays involving a limited subset of structurally diverse polyoxometalates revealed a low selectivity profile against different transcription factor families. Further progress in achieving selectivity and deciphering structure-activity relationship of POMs require the identification of POM binding sites on transcription factors using elaborate approaches like X-ray crystallography and multidimensional NMR. In summary, our report reaffirms that transcription factors are challenging molecular architectures and that future polyoxometalate chemistry must consider further modification strategies, to address the substantial challenges involved in achieving target selectivity.Link_to_subscribed_fulltex

Exploring the utility of organo-polyoxometalate hybrids to inhibit SOX transcription factors

Abstract Background SOX transcription factors constitute an attractive target class for intervention with small molecules as they play a prominent role in the field of regenerative biomedicine and cancer biology. However, rationally engineering specific inhibitors that interfere with transcription factor DNA interfaces continues to be a monumental challenge in the field of transcription factor chemical biology. Polyoxometalates (POMs) are inorganic compounds that were previously shown to target the high-mobility group (HMG) of SOX proteins at nanomolar concentrations. In continuation of this work, we carried out an assessment of the selectivity of a panel of newly synthesized organo-polyoxometalate hybrids in targeting different transcription factor families to enable the usage of polyoxometalates as specific SOX transcription factor drugs. Results The residual DNA-binding activities of 15 different transcription factors were measured after treatment with a panel of diverse polyoxometalates. Polyoxometalates belonging to the Dawson structural class were found to be more potent inhibitors than the Keggin class. Further, organically modified Dawson polyoxometalates were found to be the most potent in inhibiting transcription factor DNA binding activity. The size of the polyoxometalates and its derivitization were found to be the key determinants of their potency. Conclusion Polyoxometalates are highly potent, nanomolar range inhibitors of the DNA binding activity of the Sox-HMG family. However, binding assays involving a limited subset of structurally diverse polyoxometalates revealed a low selectivity profile against different transcription factor families. Further progress in achieving selectivity and deciphering structure-activity relationship of POMs require the identification of POM binding sites on transcription factors using elaborate approaches like X-ray crystallography and multidimensional NMR. In summary, our report reaffirms that transcription factors are challenging molecular architectures and that future polyoxometalate chemistry must consider further modification strategies, to address the substantial challenges involved in achieving target selectivity

Regioselective Activation of Oxo Ligands in Functionalized Dawson Polyoxotungstates

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