Design and SAR of thienopyrimidine and thienopyridine inhibitors of VEGFR-2 kinase activity

doi:10.1016/j.bmcl.2003.10.030

Bioorganic & Medicinal Chemistry Letters

Volume 14, Issue 1, 5 January 2004, Pages 21-24

https://doi.org/10.1016/j.bmcl.2003.10.030 Get rights and content

Abstract

Novel classes of thienopyrimidines and thienopyridines have been identified as potent inhibitors of VEGFR-2 kinase. The synthesis and SAR of these compounds is presented, along with successful efforts to diminish EGFR activity present in the lead series.

Novel thienopyrimidines and thienopyridines have been identified as potent inhibitors of VEGFR-2 kinase activity. The synthesis and SAR of these compounds is presented, highlighting our successful effort to diminish the EGFR kinase activity in the lead series.

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In this study, we designed and synthesized several novel fused [1,2,3]triazolo [4′,5′:3,4]pyrrolo[1,2‐a]thieno[2,3‐d]pyrimidine derivatives using in a single [3 + 2] reaction cycloaddition reaction of 3‐(3‐iodoprop‐2‐yn‐1‐yl)thieno[2,3‐d]pyrimidin‐4(3H)‐one (4) followed by C‐C bond coupling with various aryl azides in a PEG‐400 medium. All of the newly synthesized compounds were evaluated in vitro for EGFR kinase inhibitory action as well as anti‐breast cancer activity against MDA‐MB‐231 and MCF‐7 breast cancer cell lines. When compared to the reference molecule, erlotinib, the majority of the compounds demonstrated adequate efficacy. The most promising compounds, 5g and 5i, demonstrated excellent anticancer activity against both cancer cell lines, with IC₅₀ values ranging from 04.17 ± 0.55 to 8.65 ± 0.89 μM, respectively, as well as excellent kinase inhibitory activities (EGFR: IC₅₀ = 0.467 ± 0.063 and 0.412 ± 0.081 μM). The in silico studies of five potent compounds 5f, 5g, 5h, 5i, and 5k were also carried out to identify the interactions against the EGFR receptor and found that the energy calculations were covenant with the obtained IC₅₀ values.
New poly heterocyclic compounds based on pyrimidine-2-thiones: synthesis, evaluation of putative antiviral agents, DFT calculation, and molecular modeling
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Owing to the enormous increase in viral infections in recent years, novel antiviral candidates are both eagerly awaited and unquestionably essential for the treatment of a variety of deadly and incapacitating viral disorders. As a part of our program in this area, a new series of thiazolopyrimidine, pyrimidothiazine, [1,2,4]triazolopyrimidine and N-substituted pyrimidinethione 6–17 have been synthesized in good yields (82–91%) through a facile method using new pyrimidinethione 4 as a building block and several reagents as halo acids/ketones or hydrazonyl halids in one framework. By using several spectroscopic methods, including IR, ¹H NMR, ¹³C NMR, elemental analysis, and DFT calculations, the chemical structures of the novel derivatives were confirmed. The synthetic compounds' cytotoxicity and in vitro antiviral efficacy were examined against HSV-1. Results demonstrated that compounds 6, 7b, 14b,c, and 17 have been found to have significant antiviral activity against HSV-1. Additionally, after examining compounds (6 and 7b)' mechanisms of action, we discovered that compound 6 had a virucidal effect and a mild effect on replication at higher concentrations, whereas compound 7b had activity in all three modes of action, with the virucidal effect being the most potent, followed by the replication effect, and then adsorption. In order to comprehend these results, we investigated the thermal and electrical stability of the generated compounds, where their chemical and thermal properties, dipole moment, subtraction of the highest occupied molecular orbital from the lowest unoccupied molecular orbital (HOMO-LUMO gap), and molecular electrostatic potential were computed. We also, examined the binding mechanism, binding affinity, and non-bonding contacts of the generated derivatives using molecular docking against the Herpes simplex virus type-1 thymidine kinase (PDB ID: 2KI5). A hypothetical pharmacophore model was made using the Molecular Operating Environment (MOE) tool and 10 compounds with structural resemblances to those synthesized with known antiviral activity. The current work recommends compounds 6 and 7b as potential lead structures for future research and development of novel anti-HSV-1 medicines.
Dual target inhibitors based on EGFR: Promising anticancer agents for the treatment of cancers (2017-)
2022, European Journal of Medicinal Chemistry
Citation Excerpt :
In addition, it also could suppress A549 cells migration through the Wnt/β-catenin signaling pathway in a dose-dependent manner. It was reported that 6-aryl-substituted thieno[3, 2-d]pyrimidine derivate 17 was identified as a VEGFR-2 and EGFR dual inhibitor, and N-methyl-4-methoxyanilino)thieno[3, 2-d]pyrimidine derivate 18 was discovered as a potent apoptosis inducer through inhibition of tubulin assembly, with IC50 < 1.0 μM in the tubulin polymerization assay [92,93]. Based on hybridization principles and bioisosteric replacement, three novel series of thieno[3, 2-d]pyrimidine derivates (I, II and III) were designed, synthesized and evaluated for their biological activities by Romagnoli's group (Fig. 13) [94].
The EGFR family play a significant role in cell signal transduction and their overexpression is implicated in the pathogenesis of numerous human solid cancers. Inhibition of the EGFR-mediated signaling pathways by EGFR inhibitors is a widely used strategy for the treatment of cancers. In most cases, the EGFR inhibitors used in clinic were only effective when the cancer cells harbored specific activating EGFR mutations which appeared to preserve the ligand–dependency of receptor activation but altered the pattern of downstream signaling pathways. Moreover, cancer is a kind of multifactorial disease, and therefore manipulating a single target may result in treatment failure. Although drug combinations for the treatment of cancers proved to be successful, the use of two or more drugs concurrently still was a challenge in clinical therapy owing to various dose-limiting toxicities and drug-drug interactions caused by pharmacokinetic profiles changed. Therefore, a single drug targeting two or multiple targets could serve as an effective strategy for the treatment of cancers. In recent, drugs with diverse pharmacological effects have been shown to be more advantageous than combination therapies due to their lower incidences of side effects and more resilient therapies. Accordingly, dual target-single-agent strategy has become a popular field for cancer treatment, and researchers became more and more interest in the development of novel dual-target drugs in recent years. In this review, we briefly introduce the EGFR family proteins and synergisms between EGFR and other anticancer targets, and summarizes the development of potential dual target inhibitors based on wild-type and/or mutant EGFR for the treatment of solid cancers in the past five years. Additionally, the rational design and SARs of these dual target agents are also presented in detailed, which will lay a significant foundation for the further development of novel EGFR-based dual inhibitors with excellent druggability.
New thieno[3,2-d]pyrimidine-based derivatives: Design, synthesis and biological evaluation as antiproliferative agents, EGFR and ARO inhibitors inducing apoptosis in breast cancer cells
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An array of newly synthesized thieno[3,2-d]pyrimidine-based derivatives and thienotriazolopyrimidines hybridized with some pharmacophoric anticancer fragments were designed, synthesized and assessed for their in vitro antiproliferative activity against MCF-7 and MDA-MB-231 breast cancer cell lines using erlotinib and pictilisib as reference standards in the MTT assay. In general, many compounds were endowed with considerable antiproliferative activity (IC₅₀ = 0.43–1.31 µM). Some of the tested compounds, namely 3c, 5b, 5c, 9d, 10, 11b and 13 displayed remarkable antiproliferative activity against both cell lines. Meanwhile, compounds 2c-e, 3b, 4a, 5a, 9c and 15b showed noticeable selectivity against MCF-7 cells while compounds 2b, 3a, 4b, 6a-c, 7, 8, 9b and 12 exhibited considerable selectivity against MDA-MB-231 cells. Further mechanistic evidences for their anticancer activities were provided by screening the most potent compounds against MCF-7 and/or MDA-MB-231 cells for EGFR and ARO inhibitory activities using erlotinib and letrozole as reference standards respectively. Results proved that, in general, tested compounds were better EGFRIs than ARIs. In addition, significant overexpression in caspase-9 level in treated MCF-7 breast cell line samples was observed for all tested compounds with the 4-fluorophenylhydrazone derivative 2d exhibiting the highest activation. In treated MDA-MB-231 breast cell line samples, 11b was found to highly induce caspase-9 level thereby inducing apoptosis. Cell cycle analysis and Annexin V-FITC/PI assay were also assessed for active compounds where results indicated that all tested compounds induced preG1 apoptosis and cell cycle arrest at G2/M phase. Compound 9d, as an inhibitor of ARO, was observed to downregulate the downstream signaling proteins HSP27 and p-ERK in MCF-7 cells. Furthermore, compound 11b downregulated EGFR expression as well as the downstream signaling protein p-AKT. Docking experiments on EGFR and ARO enzymes supported their in vitro results. Thus, the thienotriazolopyrimidines 11b and 12 showing good EGFR inhibition and the thieno[3,2-d]-pyrimidine derivatives 3b and 9d, eliciting the best ARO inhibition activity, can be considered as new candidates as anti-breast cancer agents that necessitate further development.
Discovery of thieno[2,3-d]pyrimidine-based derivatives as potent VEGFR-2 kinase inhibitors and anti-cancer agents
2021, Bioorganic Chemistry
Vascular endothelial growth factor-2 (VEGFR-2) is considered one of the most important factors in tumor angiogenesis, and consequently a number of anticancer therapeutics have been developed to inhibit VEGFR-2 signaling. Accordingly, eighteen derivatives of thieno[2,3-d]pyrimidines having structural characteristics similar to VEGFR-2 inhibitors were designed and synthesized. Anticancer activities of the new derivatives were assessed against three human cancer cell lines (HCT-116, HepG2, and MCF-7) using MTT. Sorafenib was used as positive control. Compounds 17c-i, and 20b showed excellent anticancer activities against HCT-116 and HepG2 cell lines, while compounds 17i and 17g was found to be active against MCF-7 cell line. Compound 17f exhibited the highest cytotoxic activities against the examined cell lines, HCT-116 and HepG2, with IC₅₀ values of 2.80 ± 0.16 and 4.10 ± 0.45 µM, respectively. Aiming at exploring the mechanism of action of these compounds, the most active cytotoxic derivatives were in vitro tested for their VEGFR-2 inhibitory activity. Compound 17f showed high activity against VEGFR-2 with an IC₅₀ value of 0.23 ± 0.03 µM, that is equal to that of reference, sorafenib (IC₅₀ = 0.23 ± 0.04 µM). Molecular docking studies also were performed to investigate the possible binding interactions of the target compounds with the active sites of VEGFR-2. The synthesized compounds were analyzed for their ADMET and toxicity properties. Results showed that most of the compounds have low to very low BBB penetration levels and they have non-inhibitory effect against CYP2D6. All compounds were predicted to be non-toxic against developmental toxicity potential model except compounds 17b and 20b.
Design, synthesis and biological evaluation of novel N-sulfonylamidine-based derivatives as c-Met inhibitors via Cu-catalyzed three-component reaction
2020, European Journal of Medicinal Chemistry
In our continuing efforts to develop novel c-Met inhibitors as potential anticancer candidates, a series of new N-sulfonylamidine derivatives were designed, synthesized via Cu-catalyzed multicomponent reaction (MCR) as the key step, and evaluated for their in vitro biological activities against c-Met kinase and four cancer cell lines (A549, HT-29, MKN-45 and MDA-MB-231). Most of the target compounds showed moderate to significant potency at both the enzyme-based and cell-based assay and possessed selectivity for A549 and HT-29 cancer cell lines. The preliminary SAR studies demonstrated that compound 26af (c-Met IC₅₀ = 2.89 nM) was the most promising compound compared with the positive foretinib, which exhibited the remarkable antiproliferative activities, with IC₅₀ values ranging from 0.28 to 0.72 μM. Mechanistic studies of 26af showed the anticancer activity was closely related to the blocking phosphorylation of c-Met, leading to cell cycle arresting at G2/M phase and apoptosis of A549 cells by a concentration-dependent manner. The promising compound 26af was further identified as a relatively selective inhibitor of c-Met kinase, which also possessed an acceptable safety profile and favorable pharmacokinetic properties in BALB/c mouse. The favorable drug-likeness of 26af suggested that N-sulfonylamidines may be used as a promising scaffold for antitumor drug development. Additionally, the docking study and molecular dynamics simulations of 26af revealed a common mode of interaction with the binding site of c-Met. These positive results indicated that compound 26af is a potential anti-cancer candidate for clinical trials, and deserves further development as a selective c-Met inhibitor.

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Design and SAR of thienopyrimidine and thienopyridine inhibitors of VEGFR-2 kinase activity

Abstract

Trends Pharmacol. Sci.

Nature Medicine

Cancer Res.