Synthesis of the polyketide section of seragamide A and related cyclodepsipeptides via Negishi cross coupling

Lang, Jan; Lindel, Thomas

doi:10.3762/bjoc.15.53

Cited by 8 publications

(4 citation statements)

References 48 publications

(37 reference statements)

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“…The Negishi cross‐coupling [45] was selected for its broad substrate acceptance, good tolerance of different functional groups and mild reaction conditions. l ‐Tyrosine was iodinated in aqueous ammonia with slow addition of I 2 under cooling to avoid the formation of the explosive NI 3 [46] . No diiodination of tyrosine was observed.…”

Section: Resultsmentioning

confidence: 99%

“…l-Tyrosine was iodinated in aqueous ammonia with slow addition of I 2 under cooling to avoid the formation of the explosive NI 3 . [46] No diiodination of tyrosine was observed. Subsequently, compound 8 was protected as methyl ester using thionyl chloride in methanol and the aminogroup was Boc protected without intermediary purification (Scheme 2).…”

Section: Synthesis Of Conjugable Rgd Mimeticsmentioning

confidence: 96%

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RGD Peptidomimetic MMAE‐Conjugate Addressing Integrin αVβ3‐Expressing Cells with High Targeting Index**

Paulus

Nachtigall

Meyer

et al. 2023

Chemistry A European J

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Small molecule‐drug conjugates (SMDCs) mimicking the RGD sequence (‐Arg‐Gly‐Asp‐) with a non‐peptide moiety require a pharmacophore‐independent attachment site. A library of 36 sulfonamide‐modified RGD mimetics with nM to pM affinity for integrin αVβ3 was synthesized and analysed via DAD mapping. The best structure of the conjugable RGD mimetic was used and a linker was attached to an aromatic ring by Negishi cross‐coupling. The product retained high affinity and selectivity for integrin αVβ3. The conjugable RGD mimetic was then attached to an enzymatically cleavable GKGEVA linker equipped with a self‐immolative PABC and the antimitotic drug monomethyl auristatin E (MMAE). The resulting SMDC preferred binding to integrin αVβ3 over α5β1 in a ratio of 1 : 4519 (ELISA) and showed selectivity for αVβ3‐positive WM115 cells over αVβ3‐negative M21‐L cells in the in vitro cell adhesion assay as well as in cell viability assays with a targeting index of 134 (M21‐L/WM115).

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Section: Resultsmentioning

confidence: 99%

Section: Synthesis Of Conjugable Rgd Mimeticsmentioning

confidence: 96%

RGD Peptidomimetic MMAE‐Conjugate Addressing Integrin αVβ3‐Expressing Cells with High Targeting Index**

Paulus

Nachtigall

Meyer

et al. 2023

Chemistry A European J

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“…Problems arise from the low nucleophilicity of the alcohol and the moderate reactivity of the activated carboxylic acid, which can undergo unwanted side reactions upon activation. Furthermore, the size of the activating reagent often additionally impairs reaction outcome [40,41] …”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, the size of the activating reagent often additionally impairs reaction outcome. [ 40 , 41 ]…”

Section: Resultsmentioning

confidence: 99%

Total Synthesis and Bioactivity Mapping of Geodiamolide H

Nasufović

Küllmer

Bößneck

et al. 2021

Chemistry A European J

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The first total synthesis of the actin‐stabilizing marine natural product geodiamolide H was achieved. Solid‐phase based peptide assembly paired with scalable stereoselective syntheses of polyketide building blocks and an optimized esterification set the stage for investigating the key ring‐closing metathesis. Geodiamolide H and synthetic analogues were characterized for their toxicity and for antiproliferative effects in cellulo, by characterising actin polymerization induction in vitro, and by docking on the F‐actin target and property computation in silico, for a better understanding of structure‐activity relationships (SAR). A non‐natural analogue of geodiamolide H was discovered to be most potent in the series, suggesting significant potential for tool compound design.

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Collective and Diverted Total Synthesis of the Strasseriolides: A Family of Macrolides Endowed with Potent Antiplasmodial and Antitrypanosomal Activity

Isak,

Schwartz,

Schulthoff

et al. 2024

Angewandte Chemie

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The strasseriolide macrolides show promising in vitro and in vivo activities against P. falciparum and T. cruzi, the parasites causing malaria and Chagas disease, respectively. However, the as yet poor understanding of structure/activity relationships and the fact that one family member proved systemically toxic for unknown reasons render a more detailed assessment of these potential lead compounds difficult. To help overcome these issues, a collective total synthesis was devised. The key steps consisted of a ring closing alkyne metathesis (RCAM) reaction to forge a common macrocyclic intermediate followed by a hydroxy‐directed ruthenium catalyzed trans‐hydrostannation of the propargyl alcohol site thus formed. The resulting alkenyltin derivative served as the central node of the synthesis blueprint, which could be elaborated into the natural products themselves as well as into a set of non‐natural analogues according to the concept of diverted total synthesis. The recorded biological data confirmed the potency of the compounds and showed the lack of noticeable cytotoxicity. The “northern” allylic alcohol subunit was recognized as an integral part of the pharmacophore, yet it provides opportunities for chemical modification.

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Synthesis of the polyketide section of seragamide A and related cyclodepsipeptides via Negishi cross coupling

Cited by 8 publications

References 48 publications

RGD Peptidomimetic MMAE‐Conjugate Addressing Integrin αVβ3‐Expressing Cells with High Targeting Index**

RGD Peptidomimetic MMAE‐Conjugate Addressing Integrin αVβ3‐Expressing Cells with High Targeting Index**

Total Synthesis and Bioactivity Mapping of Geodiamolide H

Collective and Diverted Total Synthesis of the Strasseriolides: A Family of Macrolides Endowed with Potent Antiplasmodial and Antitrypanosomal Activity

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