Synthesis of amide and sulfonamide substituted N-aryl 6-aminoquinoxalines as PFKFB3 inhibitors with improved physicochemical properties

Boutard, Nicolas; Białas, Arkadiusz; Sabiniarz, Aleksandra; Guzik, Paweł; Banaszak, K.; Biela, Artur; Bień, Marcin; Buda, Anna; Bugaj, Barbara; Cieluch, Ewelina; Cierpich, Anna; Dudek, Łukasz; Eggenweiler, Hans-Michael; Fogt, Joanna; Gaik, Monika; Gondela, Andrzej; Jakubiec, K.; Jurzak, Mirek; Kitlińska, Agata; Kowalczyk, Piotr; Kujawa, Maciej; Kwiecinska, K.; Leś, Marcin; Lindemann, Ralph K.; Maciuszek, Monika; Mikulski, Maciej; Niedziejko, Paulina; Obara, Alicja; Pawlik, Henryk; Rzymski, Tomasz; Sieprawska-Lupa, Magdalena; Sowińska, Marta; Szeremeta-Spisak, Joanna; Stachowicz, Agata; Tomczyk, Mateusz Michał; Wiklik, Katarzyna; Włoszczak, Łukasz; Ziemianska, S.; Zarębski, Adrian; Brzózka, Krzysztof; Nowak, Mateusz; Fabritius, Charles-Henry

doi:10.1016/j.bmcl.2018.12.034

Cited by 21 publications

(11 citation statements)

References 19 publications

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“…The mass spectra were obtained on an Agilent 6125 LC/MSD system. As a positive control, compound 4 was synthesized with an identical procedure from published literature, which was also modified for the synthesis of compound 5 ( Boutard et al, 2019 ). All the synthesis procedures and characterization data can be found in the Supplementary Materials .…”

Section: Methodsmentioning

confidence: 99%

“…The PFKFB3 enzymatic activity assay followed an identical procedure used in previously published literature, along with the same regents and materials ( Boutard et al, 2019 ).…”

Section: Methodsmentioning

confidence: 99%

“…In addition, PFKFB3 showed the most potent activity compared with the other 3 isozymes, making it a driving force of cancer oxygen-independent glycolysis ( Chesney et al, 1999 ; Fukasawa et al, 2004 ). Therefore, PFKFB3 has attracted much attention and is regarded as a promising target for cancer therapy, and many novel compounds have been reported with potent PFKFB3 inhibitory activities ( Figure 1 ) ( Boyd et al, 2015 ; Boutard et al, 2019 ; Wang et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

“…With highly potent and selective activity against PFKFB3, the scaffold of aminoquinoxaline derivatives (compound 4) attracted our attention ( Boutard et al, 2019 ). With the goal to develop novel PFKFB3 PET tracers for tumor diagnosis, we performed the structural modification to the aminoquinoxaline scaffold and radiolabeled with 68 Ga for in vitro and in vivo evaluations.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis, radiolabeling, and evaluation of 68Ga-labeled aminoquinoxaline derivative as a potent PFKFB3-targeted PET tracer

Chen

et al. 2023

Front. Chem.

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Glycolysis, as a multi-step oxidation process, plays important roles in the energy supply for living cells, including malignant tumor cells. Recent studies have revealed that 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (named PFKFB3), a bifunctional enzyme in glycolysis, is upregulated in a variety of malignant solid tumors and has been regarded as a potential biomarker for the diagnosis and treatment of tumor patients. Based on the structure of selective PFKFB3 inhibitors, we designed and synthesized a radio-metal radiolabeled small molecule, 68Ga-5, which also showed potent selectivity in enzymatic and biochemical tests (with an IC50 value of 12.5 nM). According to further in vitro and in vivo evaluations, 68Ga-5 showed promising properties as a PET ligand, and selective accumulation in PFKFB3-positive tumors was observed in PET images (with max SUV values of 0.60). Our results indicated that radio-metal radiolabeled aminoquinoxaline derivative, as represented by 68Ga-5, held the potential to be developed as selective PFKFB3-targeted PET tracers, and further investigation and optimization would also be required for this scaffold.

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Section: Methodsmentioning

confidence: 99%

“…The PFKFB3 enzymatic activity assay followed an identical procedure used in previously published literature, along with the same regents and materials ( Boutard et al, 2019 ).…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Synthesis, radiolabeling, and evaluation of 68Ga-labeled aminoquinoxaline derivative as a potent PFKFB3-targeted PET tracer

Chen

et al. 2023

Front. Chem.

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“…Moreover, the unreactive hydroxyl group could then be promoted in a second BH reaction to afford aza-pyrrolidines also used for pharmaceutical purposes. [45][46][47] Our aims at the outset were twofold: (i) to first investigate the direct synthesis of hydroxy aza-heterocycles using a large scope of amines (ii) to take advantage of the remaining hydroxyl group for further functionalization to form novel CN bonds. Depending of the length of the triol, 3-substituted pyrrolidines along with 4-substituted piperidines could be targeted (Scheme 2b).…”

Section: Scheme 2 Previous Work and Our Strategy For The Sequential S...mentioning

confidence: 99%

Direct synthesis of functionalized 3-pyrrolidines and 4-piperidines using the borrowing hydrogen methodology

Larduinat

François

Jacolot

et al. 2023

Preprint

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Copper‐Catalyzed Cross‐Coupling Reactions of Organoboron Compounds

Nekvinda

Santos

2020

Copper Catalysis in Organic Synthesis

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Synthesis of amide and sulfonamide substituted N-aryl 6-aminoquinoxalines as PFKFB3 inhibitors with improved physicochemical properties

Cited by 21 publications

References 19 publications

Synthesis, radiolabeling, and evaluation of 68Ga-labeled aminoquinoxaline derivative as a potent PFKFB3-targeted PET tracer

Synthesis, radiolabeling, and evaluation of 68Ga-labeled aminoquinoxaline derivative as a potent PFKFB3-targeted PET tracer

Direct synthesis of functionalized 3-pyrrolidines and 4-piperidines using the borrowing hydrogen methodology

Copper‐Catalyzed Cross‐Coupling Reactions of Organoboron Compounds

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