Discovery of New Aminosubstituted Pyrrolopyrimidines with Antiproliferative Activity Against Breast Cancer Cells and Investigation of their Effect Towards the PI3Kα Enzyme

Daniilides, Konstantinos; Lougiakis, Nikolaos; Evangelidis, Thomas; Kostakis, Ioannis K.; Pouli, Nicole; Marakos, Panagiotis; Mikros, Emmanuel; Skaltsounis, Alexios‐Léandros; Bach, Stéphane; Baratte, Blandine; Ruchaud, Sandrine; Karamani, Valia; Papafotika, Alexandra; Christoforidis, Savvas; Argyros, Orestis; Kouvari, Eva; Tamvakopoulos, Constantin

doi:10.2174/1871520616666161207143450

Cited by 3 publications

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“…E0771 cells were a kind gift of Dr Fernando Rodriguez-Serrano (University of Granada) and were grown as described previously [ 46 ]. Cell toxicity was measured by the MTT assay [ 44 , 47 ].…”

Section: Methodsmentioning

confidence: 99%

Targeting of the breast cancer microenvironment with a potent and linkable oxindole based antiangiogenic small molecule

et al. 2017

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The clinical efficacy of antiangiogenic small molecules (e.g., sunitinib) in breast carcinoma has largely failed with substantial off-target toxicity. We rationally designed and evaluated preclinically a novel sunitinib analogue, SAP, with favourable pharmacological properties and the ability to be readily conjugated to a targeting peptide or antibody for active tumour targeting.SAP was evaluated in silico and in vitro in order to verify target engagement (e.g., VEGFR2). Pharmacokinetic and biodistribution parameters were determined in mice using LC-MS/MS. SAP efficacy was tested in two breast cancer xenograft and two syngeneic animal models and pharmacodynamic evaluation was accomplished using phosphokinase assays and immunohistochemistry. Cardiac and blood toxicity of SAP were also monitored.SAP retained the antiangiogenic and cytotoxic properties of the parental molecule with an increased blood exposure and tumor accumulation compared to sunitinib. SAP proved efficacious in all animal models. Tumors from SAP treated animals had significantly decreased Ki-67 and CD31 markers and reduced levels of phosphorylated AKT, ERK and S6 compared to vehicle treated animals. In mice dosed with SAP there was negligible hematotoxicity, while cardiac function measurements showed a reduction in the percentage left ventricular fractional shortening compared to vehicle treated animals.In conclusion, SAP is a novel rationally designed conjugatable small antiangiogenic molecule, efficacious in preclinical models of breast cancer.

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Section: Methodsmentioning

confidence: 99%

Targeting of the breast cancer microenvironment with a potent and linkable oxindole based antiangiogenic small molecule

et al. 2017

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“…This marker is of utmost importance, and there are currently clinical studies evaluating the activity of some inhibitors of this pathway ( 77 ). Recently, it was reported that a group of compounds derived from pyrrolo pyrimidines have activity on PI3K and could act particularly on BCSCs ( 78 ). Another study found that fisetin, a dietary flavonoid, alone or in combination with 5-FU, affects tumorigenesis in the mammalian intestine.…”

Section: Natural Products In the Control Of Bcsc And The Induction Ofmentioning

confidence: 99%

Phyto-Immunotherapy, a Complementary Therapeutic Option to Decrease Metastasis and Attack Breast Cancer Stem Cells

et al. 2020

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In this review, we report on the complexity of breast cancer stem cells as key cells in the emergence of a chemoresistant tumor phenotype, and as a result, the appearance of distant metastasis in breast cancer patients. The search for mechanisms that increase sensitivity to chemotherapy and also allow activation of the tumor-specific immune response is of high priority. As we observed throughout this review, natural products isolated or in standardized extracts, such as P2Et or others, could act synergistically, increasing tumor sensitivity to chemotherapy, recovering the tumor microenvironment, and participating in the induction of a specific immune response. This, in turn, would lead to the destruction of cancer stem cells and the decrease in metastasis. Source of Data: Relevant studies were found using the following keywords or medical subject headings (MeSH) in PubMed, and Google Scholar: "immune response" and "polyphenols" and "natural products" and "BCSC" and "therapy" and "metabolism" and "immunogenic cell death." The focus was primarily on the most recent scientific publication.

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Design and Synthesis of New Substituted Pyrazolopyridines with Potent Antiproliferative Activity

Giannouli

Lougiakis

Kostakis

et al. 2020

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Background: Purine isosteres are often endowed with interesting pharmacological properties, due to their involvement in cellular processes replacing the natural purines. Among these compounds, pyrazolopyridines are under active investigation for potential anticancer properties. Objective: Based on previously discovered substituted pyrazolopyridines with promising antiproliferative activity, we designed and synthesized new, suitably substituted analogues aiming to investigate their potential activity and contribute to SAR studies of this class of bioactive compounds. Methods: The new compounds were synthesized using suitably substituted 2-amino-4-picolines, which upon ring-closure provided substituted pyrazolo[3,4-c] pyridine-5-carbonitriles that served as key intermediates for the preparation of the target 3,5,7 trisubstituted derivatives. The antiproliferative activity of 31 new target derivatives was evaluated against three cancer cell lines (MIA PaCa-2, PC-3 and SCOV3), whereas cell-cycle perturbations of exponentially growing PC-3 cells, using three selected derivatives were also performed. Results: Eight compounds displayed IC50 values in the low μM range, allowing the extraction of interesting SAR’s. Two of the most potent compounds against all cell lines share a common pattern, by accumulating cells at the G0/G1 phase. From this project, a new carboxamidine-substituted hit has emerged. Conclusion: Among the new compounds, those possessing the 3-phenylpyrazolo[3,4-c]pyridine scaffold, proved to be worth investigating and the majority of them showed strong cytotoxic activity against all cell lines, with IC50 values ranging from 0.87-4.3 µM. A carboxamidine analogue that resulted from the synthetic procedure, proved to be highly active against the cancer cells and could be considered as a useful lead for further optimization.

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Discovery of New Aminosubstituted Pyrrolopyrimidines with Antiproliferative Activity Against Breast Cancer Cells and Investigation of their Effect Towards the PI3Kα Enzyme

Cited by 3 publications

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Targeting of the breast cancer microenvironment with a potent and linkable oxindole based antiangiogenic small molecule

Targeting of the breast cancer microenvironment with a potent and linkable oxindole based antiangiogenic small molecule

Phyto-Immunotherapy, a Complementary Therapeutic Option to Decrease Metastasis and Attack Breast Cancer Stem Cells

Design and Synthesis of New Substituted Pyrazolopyridines with Potent Antiproliferative Activity

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