Synthesis of a simplified triazole analogue of pateamine A

Cumming, Hemi; Brown, Sarah L.; Xu, Tao; Cuyamendous, Claire; Field, Jessica J.; Miller, John H.; Harvey, Joanne E.; Teesdale‐Spittle, Paul

doi:10.1039/c6ob00086j

Cited by 10 publications

(39 citation statements)

References 34 publications

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“…2 In 2013, Hemi Cumming, a former PhD student at Victoria University of Wellington (VUW), synthesised a simplified triazole-containing pateamine analogue. 15 These syntheses are described in detail below. Fragments 2 and 3 were coupled together through Mitsunobu esterification, followed by βlactam-opening macrolactonisation to provide the 19-membered bis-lactone core.…”

Section: Pateamine and Analogue Synthesismentioning

confidence: 99%

“…In 2013 a triazole-containing pateamine analogue 96 (Figure 1.11) was synthesised at VUW by former PhD student Hemi Cumming. 15 The thiazole of pateamine was replaced with a triazole in order to determine whether the thiazole ring is a necessary functional group in pateamine. 15 Figure 1.11 Simplified triazole analogue synthesised by Cumming.…”

Section: Simplified Triazole-containing Analogue Prepared By Cummingmentioning

confidence: 99%

“…15 The thiazole of pateamine was replaced with a triazole in order to determine whether the thiazole ring is a necessary functional group in pateamine. 15 Figure 1.11 Simplified triazole analogue synthesised by Cumming. 15 This analogue also contained a number of structural simplifications, such as the removal of the amino and methyl functional groups at carbon 3 and 5, respectively, inspired by the DMDA analogue 68.…”

Section: Simplified Triazole-containing Analogue Prepared By Cummingmentioning

confidence: 99%

“…A solution of 1,3-propanediol (106) was heated in a Dean-Stark apparatus with paraanisaldehyde to afford cyclic acetal 107 (Scheme 1.14). 15 The para-methoxybenzyl (PMB) ether protecting group was used for this fragment due to the benefit of being able to mono-protect the diol 106 via a cyclic acetal, as well as the added benefit of containing a chromophore to facilitate ultra-violet (UV) visualisation on thin layer chromatography (TLC).…”

Section: Synthesis Of Lactone 98mentioning

confidence: 99%

“…Scheme 1.14 Synthesis of fragment 98. 15 Reductive cleavage of 107 followed by a Swern oxidation provided the aldehyde 109. The one pot synthesis of 110 was achieved by a Grignard reaction with allylmagnesium bromide, followed by acryloylation of the resultant alcohol.…”

Section: Synthesis Of Lactone 98mentioning

confidence: 99%

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Design and Synthesis of a Highly Simplified Pateamine Analogue

Brown¹

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<p>Pateamine (1) is a natural product from the marine sponge Mycale hentscheli that exhibits potent anticancer properties, and has potential as an antiviral agent, and in preventing the muscle wasting disorder cachexia. This biological activity of pateamine is due to its ability to inhibit the eukaryotic initiation factor eIF4A, which leads to the formation of stress granules, the inhibition of protein synthesis, and ultimately cell death. Unfortunately, pateamine is obtained in very small amounts from Mycale hentscheli; thus, it is necessary to synthesise pateamine and novel structural analogues in the laboratory. Previously a separate binding and scaffolding domain of pateamine was proposed, which led to the synthesis of a simplified des-methyl des- amino analogue that reduced the number of synthetic steps compared to pateamine while retaining its biological activity. This was followed by the synthesis of a simplified triazole- containing analogue 9 6 ; unfortunately, this exhibited substantially reduced bioactivity compared to pateamine, and it is therefore necessary to determine if the reduction in bioactivity was due to the replacement of the thiazole ring with a triazole ring, or due to the removal of key methyl groups of pateamine. Thus, the thiazole-containing analogue of 96 is deemed to be an important synthetic target. In this Master’s project a highly simplified side chain-free analogue 130 was synthesised, which laid the groundwork for future synthesis of a thiazole-containing analogue of 96. The synthesis of 130 was achieved through a convergent synthesis with one commercially available and two prepared fragments. Particular attention was paid to the development of an efficient thiazole formation methodology, as well as optimising fragment synthesis and coupling reactions. Determination of the binding of analogue 130 with eIF4A using a competitive bioactivity assay in the presence of pateamine was then undertaken, which showed that either 130 does not bind to eIF4A or that it binds non-covalently and is then displaced by pateamine.</p>

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Section: Pateamine and Analogue Synthesismentioning

confidence: 99%

Section: Simplified Triazole-containing Analogue Prepared By Cummingmentioning

confidence: 99%

Section: Simplified Triazole-containing Analogue Prepared By Cummingmentioning

confidence: 99%

Section: Synthesis Of Lactone 98mentioning

confidence: 99%

Section: Synthesis Of Lactone 98mentioning

confidence: 99%

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Design and Synthesis of a Highly Simplified Pateamine Analogue

Brown¹

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A Structure‐Activity Investigation of the Fungal Metabolite (−)‐TAN‐2483B: Inhibition of Bruton's Tyrosine Kinase

McCone,

Teesdale‐Spittle,

Flanagan

et al. 2024

Chemistry A European J

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The natural product (‐)‐TAN‐2483B is a fungal secondary metabolite which displays promising anti‐cancer and immunomodulatory activity. Our previous syntheses of (‐)‐TAN‐2483B and sidechain analogues uncovered inhibitory activity against Bruton’s tyrosine kinase (Btk), an established drug target for various leukaemia and immunological diseases. A structure‐based computational study using ensemble docking and molecular dynamics was performed to determine plausible binding modes for (‐)‐TAN‐2483B and analogues in the Btk binding site. These hypotheses guided the design of new analogues which were synthesised and their inhibitory activities determined, providing insights into the structural determinants of the furopyranone scaffold that confer both activity and selectivity for Btk. These findings offer new perspectives for generating optimised (‐)‐TAN‐2483B‐based kinase inhibitors for the treatment of leukaemia and immunological diseases.

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Recent Applications and Trends in the Julia‐Kocienski Olefination

Rinu¹,

Radhika²,

Anilkumar³

2022

ChemistrySelect

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The Julia-Kocienski (J-K) olefination is a modified version of Julia-Lythgoe olefination. In this reaction, an aldehyde or ketone is coupled with heterocycle-bearing sulfone in the presence of a strong base to yield alkene. It has shown wide application in the synthesis of olefinic fragments in natural product synthesis. The Julia-Kocienski olefination is one of the most efficient protocols for the synthesis of E-alkenes. Nowa-days, a variety of natural products were synthesised by using the Julia-Kocienski olefination as the key step, and several developments and modifications were witnessed in this area. This review comprehends the recent developments and achievements in Julia-Kocienski olefination along with its application in natural product synthesis covering literature from 2016 to 2021.

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Synthesis of a simplified triazole analogue of pateamine A

Cited by 10 publications

References 34 publications

Design and Synthesis of a Highly Simplified Pateamine Analogue

Design and Synthesis of a Highly Simplified Pateamine Analogue

A Structure‐Activity Investigation of the Fungal Metabolite (−)‐TAN‐2483B: Inhibition of Bruton's Tyrosine Kinase

Recent Applications and Trends in the Julia‐Kocienski Olefination

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