Synthesis of Isoquinolones by Sequential Suzuki Coupling of 2-Halobenzonitriles with Vinyl Boronate Followed by Cyclization

Jaime‐Figueroa, Saul; Bond, Michael J.; Vergara, José; Swartzel, Jake C; Crews, Craig M.

doi:10.1021/acs.joc.1c00472

“…The three putative EGFR‐sparing core scaffolds, SJF‐4601, DHC‐7657 and DC‐6142, were synthesized as shown in Scheme 1a–c. Concise synthesis of the isoquinoline scaffold of DHC‐7657 was enabled by the methodology recently reported by our lab [23] …”

Section: Resultsmentioning

confidence: 99%

Development of a Small Molecule Downmodulator for the Transcription Factor Brachyury

Chase,

Bebenek,

Nie

et al. 2024

Angew Chem Int Ed

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Brachyury is an oncogenic transcription factor whose overexpression drives chordoma growth. The downmodulation of brachyury in chordoma cells has demonstrated therapeutic potential, however, as a transcription factor it is classically deemed “undruggable”. Given that direct pharmacological intervention against brachyury has proven difficult, attempts at intervention have instead targeted upstream kinases. Recently, afatinib, an FDA‐approved kinase inhibitor, has been shown to modulate brachyury levels in multiple chordoma cell lines. Herein, we use afatinib as a lead to undertake a structure‐based drug design approach, aided by mass‐spectrometry and x‐ray crystallography, to develop DHC‐156, a small molecule that more selectively binds brachyury and downmodulates it as potently as afatinib. We eliminated kinase‐inhibition from this novel scaffold while demonstrating that DHC‐156 induces the post‐translational downmodulation of brachyury that results in an irreversible impairment of chordoma tumor cell growth. In doing so, we demonstrate the feasibility of direct brachyury modulation, which may further be developed into more potent tool compounds and therapies.

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“…Concise synthesis of the isoquinoline scaffold of DHC-7657 was enabled by the methodology recently reported by our lab. [23] We first sought to validate that our new scaffolds retained their ability to bind brachyury using LCMS (Figure 2d). Compounds were incubated with brachyury DBD for 5 hours.…”

Section: Design and Synthesis Of Egfr-sparing Scaffolds That Retain B...mentioning

confidence: 99%

Development of a Small Molecule Downmodulator for the Transcription Factor Brachyury

Chase,

Bebenek,

Nie

et al. 2024

Angewandte Chemie

Self Cite

0

View full text Add to dashboard Cite

Brachyury is an oncogenic transcription factor whose overexpression drives chordoma growth. The downmodulation of brachyury in chordoma cells has demonstrated therapeutic potential, however, as a transcription factor it is classically deemed “undruggable”. Given that direct pharmacological intervention against brachyury has proven difficult, attempts at intervention have instead targeted upstream kinases. Recently, afatinib, an FDA‐approved kinase inhibitor, has been shown to modulate brachyury levels in multiple chordoma cell lines. Herein, we use afatinib as a lead to undertake a structure‐based drug design approach, aided by mass‐spectrometry and x‐ray crystallography, to develop DHC‐156, a small molecule that more selectively binds brachyury and downmodulates it as potently as afatinib. We eliminated kinase‐inhibition from this novel scaffold while demonstrating that DHC‐156 induces the post‐translational downmodulation of brachyury that results in an irreversible impairment of chordoma tumor cell growth. In doing so, we demonstrate the feasibility of direct brachyury modulation, which may further be developed into more potent tool compounds and therapies.

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“…Figueroa et al reported a simple and efficient two-step synthesis of isoquinolinone 13 (Scheme 1). 42 Suzuki coupling between vinyl boronate ester 10 and 2-halobenzonitriles 9 leads to a vinyl ether adduct 11 that generates an amide–aldehyde intermediate 12 on hydrolysis. Compound 12 then switches to cascade cyclization followed by dehydration affording isoquinolone 13 .…”

Section: Transition Metal-mediated Cascade Reactionsmentioning

confidence: 99%

Diversely functionalized isoquinolines and their core-embedded heterocyclic frameworks: a privileged scaffold for medicinal chemistry

Vijayakumar,

Manod,

Krishna

et al. 2023

RSC Med. Chem.

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Synthesis of Isoquinolones by Sequential Suzuki Coupling of 2-Halobenzonitriles with Vinyl Boronate Followed by Cyclization

Abstract: A novel, facile, and expeditious two-step synthesis of 3,4-unsubstituted isoquinolin-1(2H)-ones from a Suzuki cross-coupling between 2-halobenzonitriles and commercially available vinyl boronates followed by platinum-catalyzed nitrile hydrolysis and cyclization is described.

Cited by 6 publications

References 34 publications

Development of a Small Molecule Downmodulator for the Transcription Factor Brachyury

Development of a Small Molecule Downmodulator for the Transcription Factor Brachyury

Development of a Small Molecule Downmodulator for the Transcription Factor Brachyury

Diversely functionalized isoquinolines and their core-embedded heterocyclic frameworks: a privileged scaffold for medicinal chemistry

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Synthesis of Isoquinolones by Sequential Suzuki Coupling of 2-Halobenzonitriles with Vinyl Boronate Followed by Cyclization

Abstract: A novel, facile, and expeditious two-step synthesis of 3,4-unsubstituted isoquinolin-1­(2H)-ones from a Suzuki cross-coupling between 2-halobenzonitriles and commercially available vinyl boronates followed by platinum-catalyzed nitrile hydrolysis and cyclization is described.

Cited by 6 publications

References 34 publications

Development of a Small Molecule Downmodulator for the Transcription Factor Brachyury

Development of a Small Molecule Downmodulator for the Transcription Factor Brachyury

Development of a Small Molecule Downmodulator for the Transcription Factor Brachyury

Diversely functionalized isoquinolines and their core-embedded heterocyclic frameworks: a privileged scaffold for medicinal chemistry

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Product

Resources

About

Abstract: A novel, facile, and expeditious two-step synthesis of 3,4-unsubstituted isoquinolin-1(2H)-ones from a Suzuki cross-coupling between 2-halobenzonitriles and commercially available vinyl boronates followed by platinum-catalyzed nitrile hydrolysis and cyclization is described.