Imatinib Analogues Research Articles

Bcr-Abl Inhibitory Activities of Imatinib Derivatives

Background: Imatinib, a frontline targeted-therapeutic agent for patients with chronic myelogenous leukemia (CML), was a synthetic tyrosine kinase inhibitor approved by the US Food and Drug Administration. Objective: To expand the structural diversity of Bcr-Abl inhibitors, we synthesized nine novel imatinib analogues (1a-1i) and evaluated their cytostatic effects against human cancer cell lines in vitro. Method: Imatinib and its analogues were successfully synthesized by an improved method in six main steps. Inhibitory activities of all compounds were evaluated on K562, HL-60, MCF-7, A549 and PBMC in vitro. Then, the effect of the most active compound was studied using flow cytometer, real-time qPCR and western blot experiments to determine its mechanism action. Finally, the molecular docking of the most active compound were determined. Results: The IC50 of one imatinib analogue (compound 1h) for K562 and HL-60 was lower than imatinib itself. Further studies indicate that the pro-apoptotic effect of compound 1h on K562 cells was stronger than imatinib over a range of concentrations. Importantly, the real-time qPCR and western blot experiments showed that compound 1h was superior to imatinib in inhibiting Bcr-Abl expression. The structure-activity relationship was analyzed by determining the inhibitory rate of each imatinib analogue. Introducing benzene (A ring) and piperidine (E ring) rings instead of pyridine (A ring) and piperazine (E ring) in imatinib significantly enhanced the potency of imatinib against K562 and HL-60 cell lines, which is consistent with the docking results. Conclusion: Imatinib analogue 1h showed a better inhibitory effect on leukemia cell lines than other cell lines, which was consistent with the imatinib-like structure, moreover, had little effect on PBMC. Overall, we conclude that compound 1h has the potential to treat chronic myeloid leukemia.

Expressing Enhanced Inhibitory Effects toward Arachidonic Acid Induced Platelet Activation: Design, Synthesis, DFT Calculations and in vitro Evaluation of Imatinib Analogues

AbstractEncouraged by the excellent antiplatelet properties of novel imatinib and nilotinib analogues in our previous study and based on a fact that slight structural changes, such as the incorporation of different substituents at the final phenyl ring of imatinib and nilotinib, have a strong impact on their antiplatelet potency, two pairs of constitutional isomers of the imatinib analogues 1, 2 and 3, 4, have been designed, synthesized and evaluated for their antiplatelet characteristics. The structure geometry of the imatinib analogues 1–4 and NBO (Natural Bond Orbital) charges of the lower energy conformation each of the analogues were explored by DFT. Molecular docking studies were also performed. All compounds were less efficient in inhibiting platelet aggregation induced by ADP or TRAP‐6 in comparison with arachidonic acid (AA). Similar results were obtained for the membrane expression of P‐selectin. The most active compound was also tested to inhibit c‐Src kinase. The present study demonstrates that appropriate modifications of the imatinib structure, may confer on this molecule potent antiplatelet characteristics.

In vitro and in silico analysis of imatinib analogues as anti-Trypanosoma cruzi drug candidates.

AbstractChagas disease (CD) is a neglected tropical disease caused by the intracellular protozoan Trypanosoma cruzi that remains a serious public health issue affecting more than 6 million people worldwide. The available treatment includes 2 nitro derivatives, benznidazole (BZ) and nifurtimox, that lack in efficacy in the later chronic phase and when administered against the several naturally resistant parasite strains and present several side-effects, demanding new therapeutic options. One strategy is based on repurposing by testing drugs already used for other illness that may share similar targets. In this context, our previous data on imatinib (IMB) and derivatives motivated the screening of 8 new IMB analogues. Our findings showed that all except 1 were active against bloodstream trypomastigotes reaching drug concentration capable of inducing a 50% of parasite lysis (EC50) values < 12 μm after 2 h while BZ was inactive. After 24 h, all derivatives were more potent than BZ, exhibiting EC50 values 1.5–5.5 times lower. Against intracellular forms, 7 out of 8 derivatives presented high activity, with EC50 values ≤ BZ. LS2/89 stood out as one of the most promising, reaching EC90 values of 1.68 and 4.9 μm on intracellular and trypomastigote forms, respectively, with the best selectivity index (>60) towards the proliferative forms. Physicochemical parameters as well as the absorption, distribution, metabolism, excretion and toxicity properties were predicted to be acceptable and with good chance of a favourable oral bioavailability. The promising results motivate further studies such as in vivo and combinatory assays aiming to contribute for a novel safer and effective therapy for CD.

Privileged fragment-based design, synthesis and in vitro antitumor activity of imatinib analogues.

Based on the privileged fragment-based drug design strategy, a series of imatinib analogues bearing the moiety of 3-(2-amino-2-oxoacetyl)-1H-indole were designed and synthesized, and the in vitro antitumor activity of these compounds was detected by MTT method using K562 (human myeloid leukemia) and K562R (imatinib-resistant chronic myeloid leukemia) cell lines. Molecular docking was used to preliminarily explain the possible binding modes. The most potent compound I2 exhibited better antitumor activity than those of imatinib against K562 and K562R cancer cells with IC50 values of 0.8 μM and 0.7 μM.

Synthesis, characterization, and pharmacological evaluation of new imatinib analogues as antiproliferative agents

Abstract Cancer is the second cause of death after the cardiovascular disease. There are many target receptors for a drug that acts as an anticancer. One of these targets is the tyrosine kinase which is considered one of the most platforms for cancer therapeutics in the recent years. For instance, imatinib is known as a prototype that acts by inhibiting tyrosine kinase receptors. Nevertheless, after one year of receiving imatinib, many patients developed resistance to treatment. Hence, there is an unmet necessity to develop new compounds in an attempt to tackle the resistance issues. In the current work, new imatinib analogues were synthesized with approved attributes. The structures were characterized and confirmed by spectral tools (FTIR,1HNMR, and 13CNMR). Furthermore, the physicochemical properties were acquired with variant reliable techniques (melting point by DSC, Retention factor by TLC, and material description alongside the physical appearance). Moreover, the cytotoxicity of the compound against human lung cancer cell line (A549) was investigated by viability test with an MTT reagent. As a result, compound IIX possesses IC50 =0.623 µM which is three-fold more potent than the reference drug, imatinib (IC50=2.479 µM).

Molecular modeling and assessment of cytotoxic and apoptotic potentials of imatinib analogues featuring (thio)urea motifs in human leukemia and lymphoma cells

Molecular modeling and assessment of cytotoxic and apoptotic potentials of imatinib analogues featuring (thio)urea motifs in human leukemia and lymphoma cells

Metabolic interactions between flumatinib and the CYP3A4 inhibitors erythromycin, cyclosporine, and voriconazole.

Flumatinib, indicated for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia, is a structural analog of imatinib and has shown higher potency than imatinib as a BCR-ABL inhibitor. In this paper, the metabolic profile of flumatinib was studied. It was found that CYP3A4 and CYP2C8 were the main cytochrome P450 enzyme substyles catalyzing the metabolism of flumatinib, and CYP3A4 has a stronger metabolic ability for flumatinib than CYP2C8. Erythromycin, cyclosporine, and voriconazole can inhibit the metabolism of flumatinib in vitro. Accordingly, co-administration of erythromycin and cyclosporine with flumatinib increased the plasma concentration and the systemic exposure of flumatinib in rats, which indicated that lower doses should be considered in clinical practice.

Structure-based analysis and biological characterization of imatinib derivatives reveal insights towards the inhibition of wild-type BCR-ABL and its mutants

To reveal insights into the inhibition of BCR-ABL and its mutants, structure-based computing methods, such as docking, molecular dynamics (MD) simulation, the molecular mechanics generalized born surface area (MMGBSA), and biological characterizations, were employed to analyze two main pharmacophore zones and two related regions of imatinib derivatives. The hydrophobic and halogen interactions formed by the trifluoromethyl, as well as T-shaped π-π interactions formed by the pyrimidine, were confirmed. For the imatinib derivatives, the impacts of the amide moiety (region A) and the pyridine (region B) on the formed interactions were explored. To reveal insights into the inhibition of BCR-ABL mutants, the bioactivities of imatinib, nilotinib and flumatinib against BCR-ABL mutants were evaluated, and a point mutant (Y253F) of BCR-ABL was simulated. The results of our structure-based analysis and biological characterization of imatinib derivatives towards the inhibition of wild-type BCR-ABL and its mutants may provide new ideas for the design of imatinib analogs with potent activity.

Modular Continuous Flow Synthesis of Imatinib and Analogues.

A modular continuous flow synthesis of imatinib and analogues is reported. Structurally diverse imatinib analogues are rapidly generated using three readily available building blocks via a flow hydration/chemoselective C-N coupling sequence. The newly developed continuous flow hydration and amidation modules each exhibit a broad scope with good to excellent yields. Overall, the method described does not require solvent switches, in-line purifications, or packed-bed apparatuses due to the judicious manipulation of flow setups and solvent mixtures.

Molecular Docking Studies for Design, Synthesis and Characterization of New Imatinib Analogues

Background: In silico drug design conducts a process for making conformations and directions of multiple ligands and chooses the best ones, then being selected. In silico studies are used to examine and model molecular interactions between target macromolecules and ligand. Tyrosine kinase is considered a potential target to design inhibitors. Tyrosine kinase inhibitor like imatinib this drug has succeeded to pass through clinical studies in an attempt to cure the cancer, which is considered as the second leading cause of deaths in the world. In this work, the GOLD program was employed to predict the bindings and thus the inhibitory activity toward the tyrosine kinase. Methodology: After the design and docking processes, the chemical synthesis of three imatinib analogues was achieved. Results: the percent of yield of the chemical synthesis was (81-85%). The synthesized compounds were well characterized using FTIR, NMR, DSC, and CHN elemental analyser. The present purity was within the globally accepted value of less than 0.4% with the employment of CHN combustion.

Design, synthesis and 3D QSAR based pharmacophore study of novel imatinib analogs as antitumor-apoptotic agents.

Imatinib possesses various mechanisms for combating cancer, making the development of imatinib analogs an attractive target for cancer research. Two series of analogs were designed and synthesized, maintaining the essential pharmacophoric features in imatinib structure. The synthesized compounds were subjected to cell-based antiproliferative assays against nonsmall lung (A549) and colon cancer cell lines. In addition, flow cytometry cell cycle and caspase-3 colorimetric assays were performed. Most compounds showed potent anticancer activity against both cell lines with IC50=0.14-5.07μM. Three compounds demonstrated ability to reinforce cell cycle arrest at G1 stage in a manner similar to imatinib. In addition, they induced apoptosis via activation of caspase-3.

Preparation and Properties of Protamine/Pectin-Ag Biopolymer Microcapsules Containing a 2-Arylaminopyrimidine Derivative

A synthetic 2-arylaminopyrimidine derivative (analog of imatinib mesylate) was incorporated into multilayer polyelectrolyte microcapsules prepared by alternating adsorption of protamine sulfate and pectin-Ag nanocomposite. The encapsulation effectiveness (EE) from an aqueous solution of the compound (4 mg/mL) was ~70% and reached 28 mass%. The release kinetics from the microcapsules depended significantly on the solution pH and ionic strength. Release of the imatinib analog was prolonged most in alkaline solutions. In vitro experiments on hemoblast suspension cultures showed that microencapsulation of the 2-arylaminopyrimidine derivative changed its antitumor activity and lowered the IC50 value by 1.4 – 2.2 times.

Получение и свойства биополимерных микрокапсул протамин/пектин-Ag, содержащих производное 2-ариламинопиримидина

Синтезированное производное 2-ариламинопиримидина (аналог иматиниба метансульфоната) включали в мультислойные полиэлектролитные микрокапсулы, полученные чередующейся адсорбцией протамина сульфата и нанокомпозита пектин-Ag. Установлено, что эффективность включения в микрокапсулы вещества из его водного раствора с концентрацией 4 мг/мл составляет ~ 70 % и достигает 28 масс. %. Кинетика высвобождения вещества из микрокапсул существенно зависит от рН и ионной силы среды, максимально пролонгированный выход аналога иматиниба наблюдается в щелочных растворах. В опытах in vitro на суспензионных культурах гемабластозов показано, что микрокапсулирование производного 2-ариламинопиримидина позволяет изменить его противоопухолевую активность, снизив показатель IC50 в 1,4 – 2,2 раза.

Imatinib binding to human c-Src is coupled to inter-domain allostery and suggests a novel kinase inhibition strategy.

Imatinib (Gleevec), a non-receptor tyrosine kinase inhibitor (nRTKI), is one of the most successful anti-neoplastic drugs in clinical use. However, imatinib-resistant mutations are increasingly prevalent in patient tissues and driving development of novel imatinib analogs. We present a detailed study of the conformational dynamics, in the presence and absence of bound imatinib, for full-length human c-Src using hydrogen-deuterium exchange and mass spectrometry. Our results demonstrate that imatinib binding to the kinase domain effects dynamics of proline-rich or phosphorylated peptide ligand binding sites in distal c-Src SH3 and SH2 domains. These dynamic changes in functional regulatory sites, distal to the imatinib binding pocket, show similarities to structural transitions involved in kinase activation. These data also identify imatinib-sensitive, and imatinib-resistant, mutation sites. Thus, the current study identifies novel c-Src allosteric sites associated with imatinib binding and kinase activation and provide a framework for follow-on development of TKI binding modulators.

Syntheses and biological evaluation of 1,2,3-triazole and 1,3,4-oxadiazole derivatives of imatinib.

Three novel series of 1,2,3-triazole and 1,3,4-oxadiazole derivatives of imatinib were prepared and evaluated in vitro for their cytostatic effects against a human chronic myeloid leukemia (K562), acute myeloid leukemia (HL60), and human leukemia stem-like cell line (KG1a). The structure-activity relationship was analyzed by determining the inhibitory rate of each imatinib analog. Benzene and piperazine rings were necessary groups in these compounds for maintaining inhibitory activities against the K562 and HL60 cell lines. Introducing a trifluoromethyl group significantly enhanced the potency of the compounds against these two cell lines. Surprisingly, some compounds showed significant inhibitory activities against KG1a cells without inhibiting common leukemia cell lines (K562 and HL60). These findings suggest that these compounds are able to inhibit leukemia stem-like cells.

An optimized approach in the synthesis of imatinib intermediates and analogues

We revisited the classical synthetic procedure for imatinib synthesis providing an improved and optimized approach in the preparation of a series of new imatinib analogues.

Synthesis and Biopharmaceutical Evaluation of Imatinib Analogues Featuring Unusual Structural Motifs.

A convenient synthesis of imatinib, a potent inhibitor of ABL1 kinase and widely prescribed drug for the treatment of a variety of leukemias, was devised and applied to the construction of a series of novel imatinib analogues featuring a number of non-aromatic structural motifs in place of the parent molecule's phenyl moiety. These analogues were subsequently evaluated for their biopharmaceutical properties (e.g., ABL1 kinase inhibitory activity, cytotoxicity). The bicyclo[1.1.1]pentane- and cubane-containing analogues were found to possess higher themodynamic solubility, whereas cubane- and cyclohexyl-containing analogues exhibited the highest inhibitory activity against ABL1 kinase and the most potent cytotoxicity values against cancer cell lines K562 and SUP-B15. Molecular modeling was employed to rationalize the weak activity of the compounds against ABL1 kinase, and it is likely that the observed cytotoxicity of these agents arises through off-target effects.

Enantioselective Synthesis of α‐Secondary and α‐Tertiary Piperazin‐2‐ones and Piperazines by Catalytic Asymmetric Allylic Alkylation

AbstractThe asymmetric palladium‐catalyzed decarboxylative allylic alkylation of differentially N‐protected piperazin‐2‐ones allows the synthesis of a variety of highly enantioenriched tertiary piperazine‐2‐ones. Deprotection and reduction affords the corresponding tertiary piperazines, which can be employed for the synthesis of medicinally important analogues. The introduction of these chiral tertiary piperazines resulted in imatinib analogues which exhibited comparable antiproliferative activity to that of their corresponding imatinib counterparts.

Enantioselective synthesis of α-secondary and α-tertiary piperazin-2-ones and piperazines by catalytic asymmetric allylic alkylation.

The asymmetric palladium-catalyzed decarboxylative allylic alkylation of differentially N-protected piperazin-2-ones allows the synthesis of a variety of highly enantioenriched tertiary piperazine-2-ones. Deprotection and reduction affords the corresponding tertiary piperazines, which can be employed for the synthesis of medicinally important analogues. The introduction of these chiral tertiary piperazines resulted in imatinib analogues which exhibited comparable antiproliferative activity to that of their corresponding imatinib counterparts.

Synthesis, Antiproliferative and Anti-inflammatory Activities of Novel Simplified Imatinib Analogues

We described the synthesis of carboxamide derivatives designed as novel simplified imatinib analogues and their antiproliferative and anti-inflammatory activities. Compound 2c showed a unique conformation determined by X-ray diffraction and by NMR 1H and displayed antiproliferative potency in the same magnitude order than the standard imatinib. Compounds 6-10 were prepared by structural modification in carboxamide 2c, and with exception of derivative 10, they were inactive as antiproliferative agent. However, these compounds showed same anti-inflammatory potency than imatinib, standing out carboxamide 9 that was six time more potent as TNF-α inhibitor production.