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We previously highlighted the interest in 6,5,6-fused tricyclic analogues of 4-aminoquinazolines as kinase inhibitors in the micromolar to the nanomolar range of IC50 values. For the generation of chemical libraries, the formamide-mediated cyclization of the cyanoamidine precursors was carried out under microwave irradiation in an eco-friendly appr...
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Context 1
... inhibitory potency of the synthesized pyrimido[4,5-b]indol-4-amines and pyrimido [5,4- b]indol-4-amines towards CDK5/p25, CK1δ/ε, DYRK1A, and GSK-3α/β was investigated according preceding procedures [11][12][13][14]. Data are listed in Table 3 including results obtained with harmine (11a) and its congeners (11b-d). ...Context 2
... N-methyl, Nethyl, and N-benzyl derivatives (11b, 11c, and 11d) were totally inactive against the three kinases CDK5/p25, CK1δ/ε, and GSK3α/β. Their affinity was focused on DYRK1A with interesting IC50 values, quite close to the nanomolar range IC50 obtained for the lead harmine (11a) (see Table 3), confirming recently-published results [29]. ...Context 3
... inhibitory potency of the synthesized pyrimido[4,5-b]indol-4-amines and pyrimido [5,4- b]indol-4-amines towards CDK5/p25, CK1δ/ε, DYRK1A, and GSK-3α/β was investigated according preceding procedures [11][12][13][14]. Data are listed in Table 3 including results obtained with harmine (11a) and its congeners (11b-d). ...Context 4
... N-methyl, Nethyl, and N-benzyl derivatives (11b, 11c, and 11d) were totally inactive against the three kinases CDK5/p25, CK1δ/ε, and GSK3α/β. Their affinity was focused on DYRK1A with interesting IC50 values, quite close to the nanomolar range IC50 obtained for the lead harmine (11a) (see Table 3), confirming recently-published results [29]. ...Citations
... Recently, a benzo[e]pyrimidine emerged as a good candidate for phase I and phase II clinical trials in patients with metastatic melanoma and glioblastoma multiforme [25]. Pyrimidines have also shown activity as antitubercular, [26,27] antioxidant, [28,29] anti-inflammatory, [30,31] anticonvulsant, [32,33] antimicrobial, [34,35] antibacterial [36][37][38] and antitumor agents [39][40][41][42][43][44]. ...
... Interestingly, harmine 1 was described as partially kinase-selective (Table 1). [49][50][51][52][53][54][55][56][57]64,65 Especially, when considering Alzheimer's disease-related kinases, it was found active against DYRK1A and CLK1 (IC 50 = 22−350 nM and 26−220 nM respectively), but not against CDK5 and CK1/2 (IC 50 > 1.5 μM). Its activity against GSK-3β, on the other hand, was discordant from study to [8,7-b]indole-1,3(2H,8H)-diones, derived from the natural alkaloid granulatimide, was tested against these same five kinases. ...
The natural β-carboline alkaloids display similarities with neurotransmitters that can be favorably exploited to design bioactive and bioavailable drugs for Alzheimer's disease (AD) therapy. Several AD targets are currently and intensively being investigated, divided in different hypotheses: mainly the cholinergic, the amyloid β (Aβ), and the Tau hypotheses. To date, only symptomatic treatments are available involving acetylcholinesterase and NMDA inhibitors. On the basis of plethoric single-target structure-activity relationship studies, the β-carboline scaffold was identified as a powerful tool for fostering activity and molecular interactions with a wide range of AD-related targets. This knowledge can undoubtedly be used to design multitarget-directed ligands, a highly relevant strategy preferred in the context of multifactorial pathology with intricate etiology such as AD. In this review, we first individually discuss the AD targets of the β-carbolines, and then we focus on the multitarget strategies dedicated to the deliberate design of new efficient scaffolds.
... All details concerning the synthesis of cyanoenamines (1a-d) are described in preceding work [26][27][28]. MPC-6827 was synthesized according to our previous methods [20]. ...
Efficient microwave-assisted chemical processes were applied to the synthesis of an array of novel N-(4-methoxyphenylamino)-2-methyl benzo-, pyrido- or pyrazino-thieno[3,2-d]pyrimidin-4-amine derivatives. These heteroaromatic systems were envisioned as potent bioisosteric analogues of MPC-6827, an anticancer agent previously developed until phase II clinical studies. A brief evaluation and comparison of their antiproliferative activity on HT-29 and Caco-2, two human colorectal cancer cell lines, were also reported. At the tested concentrations (5 and 10 µM), thieno[3,2-d]pyrimidin-4-amines 4a and 4c exhibited an inhibitory effect similar to MPC-6827 on human colorectal cancer cell proliferation.
Despite the fact that the small atypical serine/threonine cyclin-dependent kinase 5 (Cdk5) is expressed in a number of tissues, its activity is restricted to the central nervous system due to the neuron-only localization of its activators p35 and p39. Although its importance for the proper development and function of the brain and its role as a switch between neuronal survival and death are unmistakable and unquestionable, Cdk5 is nevertheless increasingly emerging, as supported by a large number of publications on the subject, as a therapeutic target of choice in the fight against Alzheimer's disease. Thus, its aberrant over activation via the calpain-dependent conversion of p35 into p25 is observed during the pathogenesis of the disease where it leads to the hyperphosphorylation of the β-amyloid precursor protein and tau. The present review highlights the pivotal roles of the hyperactive Cdk5-p25 complex activity in contributing to the development of Alzheimer's disease pathogenesis, with a particular emphasis on the linking function between Aβ and tau that this kinase fulfils and on the fact that Cdk5-p25 is part of a deleterious feed forward loop giving rise to a molecular machinery runaway leading to AD pathogenesis. Additionally, we discuss the advances and challenges related to the possible strategies aimed at specifically inhibiting Cdk5-p25 activity and which could lead to promising anti-AD therapeutics.
Alzheimer’s Disease (AD) is one of the significant diseases of the aging population and affects Central Nervous System dominantly. Blood-brain-barrier permeation is a substantial complication in developing CNS drugs, and it is considered challenging with minimal success rates. Although Glycogen synthase kinase-3β (GSK-3β) is an attractive disease-modifying target for AD, there is no single GSK-3β inhibitor in clinical trials for AD. Here we performed structure-based virtual screening on the Chembridge CNS-Set library compounds. 10 hits were identified based on interaction, binding energy, dock score, and a potential ADME profile. These 10 chosen compounds were then investigated for in vitro kinase inhibitory activity against GSK-3β and other AD-related kinases. Among these, the molecule 7114202 showed 48% GSK-3β inhibition while showing selectivity over other AD-related kinases. Molecular dynamic simulations of apoenzyme, co-crystallized molecule, and 7114202 validated the Lys85, Val135, Leu188, Asp200 located in the active site of enzyme play a significant role in GSK-3β complex formation with inhibitors, and they are responsible for activity and selectivity. The in vitro studies also revealed a potent and selective Casein Kinase 1ε (CK1ε) inhibitor 7774767 with IC50 5.10 µM.
Graphical abstract
Casein kinase 1 (CK1) belongs to the serine-threonine kinase family and is expressed in all eukaryotic organisms. At least six human isoforms of CK1 (termed α, γ1-3, δ and ε) have been cloned and characterized. CK1 isoform modulates several physiological processes, including DNA damage repair, circadian rhythm, cellular proliferation and apoptosis. Therefore, CK1 dysfunction may trigger diverse pathologies, such as cancer, inflammation and central nervous system disorders. Overexpression and aberrant activity of CK1 has been connected to hyperphosphorylation of key proteins implicated in the development of neurodegenerative disorders, such as Parkinson’s and Alzheimer’s diseases and Amyotrophic Lateral Sclerosis. Thus, CK1 inhibitors have attracted attention as potential drugs for these pathologies and several compounds have been synthesized or isolated from natural sources to be evaluated for their CK1 inhibitory activity. Here we report a comprehensive review on the development of CK1 inhibitors, with a particular emphasis on structure-activity relationships and computational studies which provide useful insight for the design of novel inhibitors.
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.
