Discovery of novel substituted benzo-anellated 4-benzylamino pyrrolopyrimidines as dual EGFR and VEGFR2 inhibitors

Fischer, Tim; Krüger, Thomas; Najjar, Abdulkarim; Totzke, Frank; Schächtele, Christoph; Sippl, Wolfgang; Hilgeroth, Andreas

doi:10.1016/j.bmcl.2017.04.053

Cited by 21 publications

(10 citation statements)

References 22 publications

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“…Other compounds in this series all yield weaker cellular activities (>100 nM) against the NCI-H1975 cancer cell line. Taken together, the allenamide-containing analogues (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) have high kinase inhibition activities for both double mutant and wild type EGFR kinases. However, the selectivity varies between double mutant and wild type EGFR kinasecontaining cancer cell lines.…”

Section: Resultsmentioning

confidence: 99%

“…[10][11][12] The clinical success of 1-3 and other TCIs has spurred a passion to search for other α,β-unsaturated carbonyls as bioisosteres of the acrylamide moiety in drug discovery. 2,3,5,9,13,14 For example, a but-2-ynamide moiety has been used as the warhead of 4 (acalabrutinib), which covalently bonds to the Cys-481 residue of BTK and was recently approved by the FDA for treating mantle cell lymphoma. 11,15 Another earlier example, 5 (ethacrynic acid), has also been approved for the treatment of high blood pressure and swelling for more than 30 years, and it is currently being investigated in clinics for the treatment of bladder cancer.…”

Section: Introductionmentioning

confidence: 99%

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Allenamide as a bioisostere of acrylamide in the design and synthesis of targeted covalent inhibitors

et al. 2018

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The success of acrylamide-containing drugs in treating cancers has spurred a passion to search for acrylamide bioisosteres. In our endeavour, we have identified that an allenamide group can be a reactive bioisostere of the acrylamide group. In our development of allenamide-containing compounds, we found that the most potent compound, , inhibited the kinase activities of both T790M/L858R double mutant and wild type EGFR in a low nM range. also inhibited the growth of NCI-H1975 lung cancer cells at IC = 33 nM, which is comparable to that of acrylamide-containing osimertinib. The western blot analysis showed that the phosphorylation of EGFR, AKT, and ERK1/2 was simultaneously inhibited in a dose-dependent manner when NCI-H1975 cells were treated with . By measuring the conjugate addition product formed by and GSH, we obtained a reaction rate constant of 302.5 × 10 min, which is about 30-fold higher than that of osimertinib. Taken together, our data suggest that the allenamide-containing compounds inhibited EGFR kinases through covalent modifications. Our study indicates that the allenamide group could serve as an alternative electrophilic warhead in the design of targeted covalent inhibitors, and this bioisostere replacement may have broad applications in medicinal chemistry.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Allenamide as a bioisostere of acrylamide in the design and synthesis of targeted covalent inhibitors

et al. 2018

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“…Of the different synthesized compounds identified (cpd 49) exhibited very good kinase inhibitory activity for both targets (EGFR Ki 1.87 uM, VEGFR Ki 0.85 uM). These compounds can be used as lead compounds for further drug development studies [11].…”

Section: Cpd 49mentioning

confidence: 99%

“…Pyrrolopyrimidines have aroused recent attention from chemical and biological view points since they have useful properties as ant-inflammatory [2], antimicrobial [3,4], antiviral anti-diabetic [5] and anti-cancer [6][7][8][9][10][11][12][13]. They have useful properties as antimetabolites in purine biochemical reactions.…”

Section: Introductionmentioning

confidence: 99%

Pyrrolopyrimidine, A Multifaceted Scaffold in Cancer Targeted Therapy

et al. 2018

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Pyrrolopyrimidine derivatives represent a class of biologically active heterocyclic compounds which can serve as promising scaffolds that display remarkable biological activities, such as anti-inflammatory, antimicrobial, antiviral and anticancer. In the last few years, several pyrrolopyrimidine derivatives have been approved by the US FDA and in other countries for the treatment of different diseases or are currently in phase I/II clinical trials. Due to their inimitable antioxidant and anti-tumor properties, researchers were inspired to develop novel derivatives for the treatment of different types of cancer. The present review summarizes recent literature up to 2017 on the most recent development in the medicinal chemistry of pyrrolopyrimidine derivatives and their potential as anticancer therapeutics, especially compounds acting as kinase inhibitors.

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“…Also modified 7‐deazapurine nucleosides display variety of biological activitites, in particular antiviral and cytostatic effects which were recently reviewed . Benzo‐fused deazapurine analogues (pyrimido[4, 5‐ b ]indoles, Figure ) have been studied especially as a new tools to combat cancer and were reported as inhibitors of tyrosine kinase and thymidylate synthase, inhibitors of EGFR and VEGFR2,, and BET (bromodomain and extra‐terminal) inhibitors for treatment of several types of cancer . Pyrimido[4, 5‐ b ]indoles are also known for their microtubule depolymerazing and stabilizing effects,, as a broad‐spectrum antimicrobial agents targeting DNA gyrase and topoisomerase IV, and as inhibitors of Toxoplasma gondii thymidylate synthase, a target to treat T. gondii infection ,…”

Section: Introductionmentioning

confidence: 99%

Thienopyrrolo[2, 3‐d]pyrimidines, New Tricyclic Nucleobase Analogues: Synthesis and Biological Activities

et al. 2018

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Three isomeric series of 4‐substituted thieno‐fused 7‐deazapurine nucleobases were synthesized by palladium catalyzed couplings or nucleophilic substitutions from protected key‐intermediate 4‐chlorothienopyrrolopyrimidines. Most final nucleobases exerted micromolar activity against hepatitis C virus and respiratory syncytial virus, as well as some in vitro cytostatic activities against several cancer and leukemia cell lines. Three new nucleosides derived from 8H‐thieno[3′, 4′:4,5]pyrrolo[2, 3‐d]pyrimidine were also synthesized and were significantly more cytostatic than corresponding nucleobases, with activities in submicromolar range and low toxicity to normal cycling fibroblasts.

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Discovery of novel substituted benzo-anellated 4-benzylamino pyrrolopyrimidines as dual EGFR and VEGFR2 inhibitors

Cited by 21 publications

References 22 publications

Allenamide as a bioisostere of acrylamide in the design and synthesis of targeted covalent inhibitors

Allenamide as a bioisostere of acrylamide in the design and synthesis of targeted covalent inhibitors

Pyrrolopyrimidine, A Multifaceted Scaffold in Cancer Targeted Therapy

Thienopyrrolo[2, 3‐d]pyrimidines, New Tricyclic Nucleobase Analogues: Synthesis and Biological Activities

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