Synthesis of N-protected nortopsentins B and D

As part of an ongoing study to elucidate the SAR of bisindole alkaloid inhibitors against the evolutionary conserved MRSA pyruvate kinase (PK), we present here the synthesis and biological activity of six dihalogenated analogues of the naturally occurring sponge metabolite deoxytopsentin, including the naturally occurring dibromodeoxytopsentin. The most active compounds displayed potent low nanomolar inhibitory activity against MRSA PK with concomitant significant selectivity for MRSA PK over human PK orthologues. Computational studies suggest that these potent MRSA PK inhibitors occupy a region of the small interface of the enzyme tetramer where amino acid sequence divergence from common human PK orthologues may contribute to the observed selectivity.

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“…For spectroscopic data of compounds 25 , 26 , and 28 – 31 see the Supporting Information. Compounds 25 and 29 have been reported previously.…”

Section: Methodsmentioning

confidence: 87%

Synthetic Analogues of the Marine Bisindole Deoxytopsentin: Potent Selective Inhibitors of MRSA Pyruvate Kinase

Veale

Zoraghi²,

Young

et al. 2014

J. Nat. Prod.

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“…4 In addition to the use of a nonbenign solvent, yields of the reaction varied from poor to moderate, and column chromatography was often needed for product isolation. Use of other solvents such as alcohols, 5 DMF, 6 and acetonitrile 7 have also been reported for this reaction, but yields are also frequently poor.…”

Section: Introductionmentioning

confidence: 99%

An Optimized Process for Formation of 2,4-Disubstituted Imidazoles from Condensation of Amidines and α-Haloketones

Chiu

Hank

et al. 2002

Org. Process Res. Dev.

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“…With dione 3 in hand, the amidine intermediate 4 was prepared following a similar pathway as previously described in the synthesis of nortopsentin B and synthetic analogue D (Scheme ). The synthesis began with 6-bromoindole ( 7 ), a common building block available in multigram quantities. Di- tert -butyl dicarbonate was used to protect the indole’s nitrogen, affording 13 in 96% yield.…”

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confidence: 99%

Total Synthesis of Nortopsentin D via a Late-Stage Pinacol-like Rearrangement

Keel

Tepe

2021

Org. Lett.

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Nortopsentin D is part of a class of bis(indole) alkaloids known for their biological activity, including inhibitory activity in tumoral cells and antifungal activity. Herein we describe the first total synthesis of nortopsentin D, in which amidine and dione undergo a pivotal condensation and subsequent cyclization via a pinacol-like rearrangement. This synthesis represents a unique strategy for the formation of 5,5-disubstituted (4H)imidazol-4-one containing natural products, many of which have yet to succumb to total synthesis.

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Synthesis of N-protected nortopsentins B and D

Abstract: Indole-3-carboxamidines 13 and 14, prepared from the corresponding amides 7 and 8 via the thioamides 9 and 10, were reacted with 3-bromoacetylindole 15 to give the 2,4-diindolylimidazoles 20 and 21, N-protected nortopsentins δ and B.

Cited by 16 publications

References 9 publications

Synthetic Analogues of the Marine Bisindole Deoxytopsentin: Potent Selective Inhibitors of MRSA Pyruvate Kinase

Synthetic Analogues of the Marine Bisindole Deoxytopsentin: Potent Selective Inhibitors of MRSA Pyruvate Kinase

An Optimized Process for Formation of 2,4-Disubstituted Imidazoles from Condensation of Amidines and α-Haloketones

Total Synthesis of Nortopsentin D via a Late-Stage Pinacol-like Rearrangement

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