Synthesis and molecular modelling studies of 8-arylpyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amines as multitarget Ser/Thr kinases inhibitors

Loidreau, Yvonnick; Deau, Emmanuel; Marchand, Pascal; Nourrisson, Marie-Renée; Logé, Cédric; Coadou, Gaël; Loaëc, Nadège; Meijer, Laurent; Besson, Thierry

doi:10.1016/j.ejmech.2014.12.038

Cited by 48 publications

(23 citation statements)

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“…Protein kinases are involved in several cellular functions, such as gene transcription, cell cycle progression, cytoskeletal rearrangement, proliferation, differentiation, migration, and cell death [38,39]. Deregulation of the signaling pathways of these proteins is associated with several diseases, including cancer [40,41]. Consequently, this class of enzymes represents important therapeutic targets for treatment of diseases [42].…”

Section: Molecular Modelingmentioning

confidence: 99%

Biological Evaluation of Arylsemicarbazone Derivatives as Potential Anticancer Agents

et al. 2019

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Fourteen arylsemicarbazone derivatives were synthesized and evaluated in order to find agents with potential anticancer activity. Cytotoxic screening was performed against K562, HL-60, MOLT-4, HEp-2, NCI-H292, HT-29 and MCF-7 tumor cell lines. Compounds 3c and 4a were active against the tested cancer cell lines, being more cytotoxic for the HL-60 cell line with IC50 values of 13.08 μM and 11.38 μM, respectively. Regarding the protein kinase inhibition assay, 3c inhibited seven different kinases and 4a strongly inhibited the CK1δ/ε kinase. The studied kinases are involved in several cellular functions such as proliferation, migration, cell death and cell cycle progression. Additional analysis by flow cytometry revealed that 3c and 4a caused depolarization of the mitochondrial membrane, suggesting apoptosis mediated by the intrinsic pathway. Compound 3c induced arrest in G1 phase of the cell cycle on HL-60 cells, and in the annexin V assay approximately 50% of cells were in apoptosis at the highest concentration tested (26 μM). Compound 4a inhibited cell cycle by accumulation of abnormal postmitotic cells at G1 phase and induced DNA fragmentation at the highest concentration (22 μM).

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Section: Molecular Modelingmentioning

confidence: 99%

Biological Evaluation of Arylsemicarbazone Derivatives as Potential Anticancer Agents

et al. 2019

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“…Loidreau et al . synthesized a number of 8‐arylpyrido[3′,2′:4,5]thieno[3,2‐ d ]pyrimidin‐4‐amines 100 in four steps starting with reaction of 5‐bromo‐2‐chloronicotinonitrile 96 with 2‐mercaptopropiononitrile in the presence of KOH in DMF, followed by addition of bromoacetonitrile gave the 3‐amino‐5‐bromothieno[2,3‐ b ]pyridine‐2‐carbonitrile 97 . Formylation of 97 with DMF‐DMA led to formation of ( E )‐ N ′‐(5‐bromo‐2‐cyanothieno[2,3‐ b ]pyridin‐3‐yl)‐ N , N ‐dimethylformimidamide 98 , which undergo palladium‐catalyzed Suzuki–Miyaura cross‐coupling with a heteroaromatic boric acid to give cyanoamidine 99 .…”

Section: Protein Kinases Inhibitormentioning

confidence: 99%

“…Formylation of 97 with DMF‐DMA led to formation of ( E )‐ N ′‐(5‐bromo‐2‐cyanothieno[2,3‐ b ]pyridin‐3‐yl)‐ N , N ‐dimethylformimidamide 98 , which undergo palladium‐catalyzed Suzuki–Miyaura cross‐coupling with a heteroaromatic boric acid to give cyanoamidine 99 . Cyclization of the cyanoamidine intermediate 99 , gave the corresponding 8‐arylpyrido[3′,2′:4,5]thieno[3,2‐ d ]pyrimidin‐4‐amines 100 (Scheme ) . Furthermore, compound 105 was prepared following the same procedure outlined in Scheme starting with acetyl indole and the appropriate aldehydes (Scheme ) .…”

Section: Protein Kinases Inhibitormentioning

confidence: 99%

“…Cyclization of the cyanoamidine intermediate 99 , gave the corresponding 8‐arylpyrido[3′,2′:4,5]thieno[3,2‐ d ]pyrimidin‐4‐amines 100 (Scheme ) . Furthermore, compound 105 was prepared following the same procedure outlined in Scheme starting with acetyl indole and the appropriate aldehydes (Scheme ) .…”

Section: Protein Kinases Inhibitormentioning

confidence: 99%

“…The inhibitory potency of the 8‐arylpyrido[3′,2′:4,5]thieno[3,2‐ d ]pyrimidin‐4‐amines 100 was evaluated against five protein kinases (CDK5/p25, CK1δ/ε, GSK3α/β, DYRK1A, and CLK1) and revealed that 8‐(2,4‐dichlorophenyl)pyrido[3′,2′:4,5]thieno[3,2‐ d ] pyrimidin‐4‐amine 100g specifically inhibits CK1δ/ε and CLK1 (220 and 88 nM, respectively), while its 7‐(2,4‐dichlorophenyl)pyrido[3′,2′:4,5]thieno[3,2‐ d ]pyrimidin‐4‐amine isomer 105 showed no activity on the panel of tested kinases. Molecular modeling of 105 and 100g in the ATP binding sites of CK1d/e and CLK1 showed that functionalization at position 7 of pyrido[3′,2′:4,5]thieno[3,2‐ d ]pyrimidin‐4‐amines is likely to induce asteric clash on the CK1δ/ε P‐loop and thus a complete loss of inhibitory activity CK1δ/ε .…”

Section: Protein Kinases Inhibitormentioning

confidence: 99%

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A Review: Synthesis and Medicinal Importance of Nicotinonitriles and Their Analogous

Gouda

Hussein

Helal

et al. 2018

Journal of Heterocyclic Chem

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In silico Design, Synthesis and Biological Evaluation of Novel Thieno[3,2‐d]pyrimidine Derivatives for Cancer Therapy – A Preliminary Study on the Inhibitory Potential towards ATR Kinase Domain and PIKK Family

Sirakanyan,

Dilip,

Geronikaki

et al. 2024

Chemistry & Biodiversity

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Continuing our studies in the field of new heterocyclic compounds with biological interest, herein we report the synthesis and anticancer activity of new N‐ and S‐substituted derivatives of tetracyclic pyrido[3',2':4,5]thieno[3,2‐d]pyrimidines. In this regard, starting from the thieno[2,3‐b]pyridine‐2‐carboxylates, the corresponding 8(9)‐aminopyrido[3',2':4,5]thieno[3,2‐d]pyrimidin‐7(8)‐ones, as well as chloro derivatives were obtained. Based on the latter, amino, hydrazino and S‐alkyl derivatives of pyrido[3',2':4,5]thieno[3,2‐d]pyrimidines were synthesized subsequently. The current study focuses on identifying the potential of thieno[3,2‐d]pyrimidine derivatives primarily towards ATR kinase inhibition, through computational predictions, followed by synthesis and cancer cell viability studies, along with an aim to develop the core as PIKK inhibitors for cancer therapy.

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Synthesis and molecular modelling studies of 8-arylpyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amines as multitarget Ser/Thr kinases inhibitors

Cited by 48 publications

References 48 publications

Biological Evaluation of Arylsemicarbazone Derivatives as Potential Anticancer Agents

Biological Evaluation of Arylsemicarbazone Derivatives as Potential Anticancer Agents

A Review: Synthesis and Medicinal Importance of Nicotinonitriles and Their Analogous

In silico Design, Synthesis and Biological Evaluation of Novel Thieno[3,2‐d]pyrimidine Derivatives for Cancer Therapy – A Preliminary Study on the Inhibitory Potential towards ATR Kinase Domain and PIKK Family

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