Efficient synthesis of novel disubstituted pyrido[3,4-b]pyrazines for the design of protein kinase inhibitors

Antoine, Maud; Schuster, Tilmann; Seipelt, Irene; Aicher, Babette; Teifel, Michael; Günther, E; Gerlach, Matthias; Marchand, Pascal

doi:10.1039/c5md00424a

Cited by 5 publications

(4 citation statements)

References 34 publications

(11 reference statements)

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“…Although research on the biological activity of cercosporamide has increased in the last decade, few efforts have been carried out in the design of kinase inhibitor deriva-tives. The interest of the collaborators in this field of research [17][18][19][20][21][22] and the results of the literature highlighting cercosporamide as a kinase inhibitor and targeting human PKCα/β [4], Mnk1/2, Jak3, GSK3β, ALK4, and Pim-1 [7,8], from nanomolar to low micromolar ranges, prompted us to develop a new series of heterocyclic compounds inspired from cercosporamide (Figure 1).…”

Section: Synthesismentioning

confidence: 99%

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Dibenzofuran Derivatives Inspired from Cercosporamide as Dual Inhibitors of Pim and CLK1 Kinases

et al. 2021

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Pim kinases (proviral integration site for Moloney murine leukemia virus kinases) are overexpressed in various types of hematological malignancies and solid carcinomas, and promote cell proliferation and survival. Thus, Pim kinases are validated as targets for antitumor therapy. In this context, our combined efforts in natural product-inspired library generation and screening furnished very promising dibenzo[b,d]furan derivatives derived from cercosporamide. Among them, lead compound 44 was highlighted as a potent Pim-1/2 kinases inhibitor with an additional nanomolar IC50 value against CLK1 (cdc2-like kinases 1) and displayed a low micromolar anticancer potency towards the MV4-11 (AML) cell line, expressing high endogenous levels of Pim-1/2 kinases. The design, synthesis, structure–activity relationship, and docking studies are reported herein and supported by enzyme, cellular assays, and Galleria mellonella larvae testing for acute toxicity.

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Section: Synthesismentioning

confidence: 99%

“…for C 13 H 11 N 2 O 4 [M + H] + 259.071333, found: 259.07147. 1,3-Dihydroxydibenzo[b,d]furan-4-carboxamide(17)…”

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confidence: 99%

Dibenzofuran Derivatives Inspired from Cercosporamide as Dual Inhibitors of Pim and CLK1 Kinases

et al. 2021

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“…Quinoxalines and pyridopyrazines are aromatic heterocycles that can be easily synthesized and have diverse applications as organic semiconductors, dyes, electroluminescent materials, or bioactive materials in medical treatments of several illnesses. , These heterocyclic molecules can also form hydrogen-bonded complexes with polar solvents, such as alcohols or water, expanding their potential applications. The presence of multiple nitrogen atoms in quinoxalines and pyridopyrazines provides an opportunity to investigate the formation of multiple hydrogenated products by the homolytic abstraction of hydrogen from methanol or water.…”

Section: Introductionmentioning

confidence: 99%

Harnessing Proton-Coupled Electron Transfer for Hydrogenation of Aza-Arenes: Photochemistry of Quinoxaline Derivatives in Methanol

Morawski,

Gawryś,

Sobolewski

2023

J. Phys. Chem. A

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Three quinoxaline derivatives are investigated both experimentally and theoretically to assess their ability for the methanol oxidation and harvesting of hydrogen. In inert solvents, the nonplanar compounds exhibit very weak fluorescence from the lowest excited singlet state, whereas the planar and rigid chromophore emits non-Kasha fluorescence from the S2(ππ*) state despite the proximity of the S1(nπ*) state. In methanol, hydrogen-bonded complexes with solvent molecules are formed, and in all chromophores, the lowest singlet state is populated after excitation of the S2(ππ*) state. The switch from non-Kasha emission of the planar compound in inert solvents to regular emission in methanol is related to reduced symmetry of the hydrogen-bonded complex with methanol which results in effective mixing of ππ* and nπ* states and fast internal conversion to the lowest excited singlet state. The S1(nπ*) state of the hydrogen-bonded complex has charge-transfer character, and for all compounds in methanol, hydrogen transfer to the chromophore is observed. The chromophores retain the transferred hydrogen atoms, serving both as photocatalysts and as hydrogen storage materials. Undesired dark side reactions that occur are also discussed.

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“…Some derivatives are bioactive and are used as antimicrobial, anti-inflammatory, antimalarial, anticancer and antidepressant compounds [1,2]. Others are for example employed as organic dyes [3], electroluminescent materials [4], and organic semiconductors [5].…”

Section: Introductionmentioning

confidence: 99%

From Quinoxaline, Pyrido[2,3-b]pyrazine and Pyrido[3,4-b]pyrazine to Pyrazino-Fused Carbazoles and Carbolines

et al. 2018

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2,3-Diphenylated quinoxaline, pyrido[2,3-b]pyrazine and 8-bromopyrido[3,4-b]pyrazine were halogenated in deprotometalation-trapping reactions using mixed 2,2,6,6-tetramethyl piperidino-based lithium-zinc combinations in tetrahydrofuran. The 2,3-diphenylated 5-iodo- quinoxaline, 8-iodopyrido[2,3-b]pyrazine and 8-bromo-7-iodopyrido[3,4-b]pyrazine thus obtained were subjected to palladium-catalyzed couplings with arylboronic acids or anilines, and possible subsequent cyclizations to afford the corresponding pyrazino[2,3-a]carbazole, pyrazino[2′,3′:5,6] pyrido[4,3-b]indole and pyrazino[2′,3′:4,5]pyrido[2,3-d]indole, respectively. 8-Iodopyrido[2,3-b] pyrazine was subjected either to a copper-catalyzed C-N bond formation with azoles, or to direct substitution to introduce alkylamino, benzylamino, hydrazine and aryloxy groups at the 8 position. The 8-hydrazino product was converted into aryl hydrazones. Most of the compounds were evaluated for their biological properties (antiproliferative activity in A2058 melanoma cells and disease-relevant kinase inhibition).

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Efficient synthesis of novel disubstituted pyrido[3,4-b]pyrazines for the design of protein kinase inhibitors

Abstract: Urea and aniline derivatives were active at low micromomolar IC50 values against a panel of seven cancer-related protein kinases.

Cited by 5 publications

References 34 publications

Dibenzofuran Derivatives Inspired from Cercosporamide as Dual Inhibitors of Pim and CLK1 Kinases

Dibenzofuran Derivatives Inspired from Cercosporamide as Dual Inhibitors of Pim and CLK1 Kinases

Harnessing Proton-Coupled Electron Transfer for Hydrogenation of Aza-Arenes: Photochemistry of Quinoxaline Derivatives in Methanol

From Quinoxaline, Pyrido[2,3-b]pyrazine and Pyrido[3,4-b]pyrazine to Pyrazino-Fused Carbazoles and Carbolines

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