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This study outlines the synthesis of pyrazine sulfonamides (3 a–3 i) along with halo‐phenyl derivatives (4 a–4 j and 5 a–5 e). The antiproliferative effects were tested against MCF‐7 breast cancer, and colon carcinoma HT‐29, HCT‐116 WT, and HCT‐116 p53 knock‐out mutant cell lines. Compounds 3 b and 3 c were notably active against HCT‐116 WT cells, while 3 e and 3 h were moderately effective against MCF‐7 cells. Among the halo‐phenyl sulfonamides, 4e and 4j were active against MCF‐7 cells, and 5 b was active against HCT‐116 WT cells. The most promising compounds were evaluated against non‐tumorigenic cells, demonstrating cancer selectivity. Compounds 3 b, 3 c, 3 e, 3 h, and 5 b showed dose‐dependent inhibition of colony formation. Compound 3 f exhibited free radical scavenging activity comparable to ascorbic acid. Molecular docking revealed strong binding to thymidylate synthase (3 b, 5 b), Akt‐3 protein kinase (3 e, 3 h, 4 e, 4 j), and tyrosinase (3 f, 3 h). The compounds also exhibited antiparasitic activity against Toxoplasma gondii and Leishmania major, with modifications enhancing selectivity for T. gondii. Substitutions in compounds 4 b and 4 d increased activity against T. gondii while reducing toxicity. Notably, compound 4 f emerged as a T. gondii‐selective lead drug. These findings suggest sulfonamides may help treat complex diseases like cancer and infections. [ABSTRACT FROM AUTHOR]

In order to investigate the stability of an experimental anticancer platinum(IV) prodrug in cell culture media, (OC‐6‐33)‐dichloridobis((4‐ethoxy)‐4‐oxobutanoato)bis(ethylamine)‐platinum(IV) was synthesized with 15N labeled equatorial and fully 13C labeled axial ligands. The title compound as well as its stability in cell culture media was investigated in depth by 1H, 13C, 15N, and 195Pt one‐ and two‐dimensional NMR spectroscopy as well as HPLC‐MS. Different platinum(IV) compounds as a result of hydrolysis were detected in cell culture media as main species. Besides hydrolysis of one or both equatorial chlorido ligands, also hydrolysis of the ester moiety in the axial ligands and release of ethanol could be observed. The different mono and dihydroxidoplatinum(IV) species were proven by 195Pt and 13C NMR spectroscopy as well as HPLC coupled to MS and HRMS. Reduction of the title compound to the corresponding platinum(II) analog or reaction of the complex with ingredients of the cell culture media were not observed. In cell culture medium supplemented with fetal calf serum (FCS), the formation of hydrolysis species was slowed down by a factor of two. [ABSTRACT FROM AUTHOR]

ABSTRACT Due to its intricate molecular and structural characteristics, vascular endothelial growth factor receptor 2 (VEGFR‐2) is essential for the development of new blood vessels in various pathological processes and conditions, especially in cancers. VEGFR‐2 inhibitors have demonstrated significant anticancer effects by blocking many signaling pathways linked to tumor growth, metastasis, and angiogenesis. Several small compounds, including the well‐tolerated sunitinib and sorafenib, have been approved as VEGFR‐2 inhibitors. However, the widespread side effects linked to these VEGFR‐2 inhibitors—hypertension, epistaxis, proteinuria, and upper respiratory infection—motivate researchers to search for new VEGFR‐2 inhibitors with better pharmacokinetic profiles. The key molecular interactions required for the interaction of the small molecules with the protein target to produce the desired pharmacological effects are identified using computer‐aided drug design (CADD) methods such as pharmacophore and QSAR modeling, structure‐based virtual screening, molecular docking, molecular dynamics (MD) simulation coupled with MM/PB(GB)SA, and other computational strategies. This review discusses the applications of these methods for VEGFR‐2 inhibitor design. Future VEGFR‐2 inhibitor designs may be influenced by this review, which focuses on the current trends of using multiple screening layers to design better inhibitors. [ABSTRACT FROM AUTHOR]

The genus Diospyros has gained significant attention in the scientific community owing to its diverse bioactivities ascribed to specific bioactive constituents present in different species of this plant. Phytochemicals like flavonoids, terpenoids, and xanthones have been reported to be present in other Diospyros species responsible for their pharmacological properties. These compounds are well known for their diverse potent therapeutic potentials, such as antimicrobial, antioxidant, anti‐inflammatory, and anticancer properties. This review enlightens the details of the Genus Diospyros, ranging from an overview of its species to an in‐depth analysis of phytochemistry, ethnopharmacology, and their potential as anticancer agents. Different species, including Diospyros lotus, Diospyros kaki, Diospyros maritima, Diospyros mespiliformis, and Diospyros tricolor, presented with an enormous range of anticancer activities against human cancer cell cultures. Moreover, this review highlights the results of various in vitro (antiproliferative, cytotoxic effects against), in vivo (inhibition of tumor, apoptosis), and in silico (GLU234, GLU278, and LYS158 protein residues) studies, elucidating its preclinical anticancer potential. The anticancer potential displays inhibition of cellular proliferation, induction of apoptosis, and mitigation of angiogenesis. Furthermore, this review may elaborate the use of traditional knowledge, modern research, and potential therapeutic applications in the field of anticancer ethnopharmacology. As the modern‐day research approaches novel alternatives to combat diseases like cancer, the Genus Diospyros may emerge as a promising avenue with the potential to yield innovative and effective therapeutic agents. [ABSTRACT FROM AUTHOR]

Poly(ADP-ribose) polymerases (PARPs) are crucial nuclear proteins that play important roles in various cellular processes, including DNA repair, gene transcription, and cell death. Among the 17 identified PARP family members, PARP1 is the most abundant enzyme, with approximately 1–2 million molecules per cell, acting primarily as a DNA damage sensor. It has become a promising biological target for anticancer drug studies. Enhanced PARP expression is present in several types of tumors, such as melanomas, lung cancers, and breast tumors, correlating with low survival outcomes and resistance to treatment. PARP inhibitors, especially newly developed third-generation inhibitors currently undergoing Phase II clinical trials, have shown efficacy as anticancer agents both as single drugs and as sensitizers for chemo- and radiotherapy. This review explores the properties, characteristics, and challenges of PARP inhibitors, discussing their development from first-generation to third-generation compounds, more sustainable synthesis methods for discovery of new anti-cancer agents, their mechanisms of therapeutic action, and their potential for targeting additional biological targets beyond the catalytic active site of PARP proteins. Perspectives on green chemistry methods in the synthesis of new anticancer agents are also discussed. [ABSTRACT FROM AUTHOR]

The virions of plant viruses and their structurally modified particles (SP) represent valuable platforms for recombinant vaccine epitopes and antitumor agents. The possibility of modifying their surface with biological compounds makes them a tool for developing medical biotechnology applications. Here, we applied a new type of SP derived from virions and virus-like particles (VLP) of Alternanthera mosaic virus (AltMV) and well-studied SP from Tobacco mosaic virus (TMV). We have tested the ability of SP from AltMV (AltMV SPV) and TMV virions also as AltMV VLP to bind to and penetrate Ewing sarcoma cells. The adsorption properties of AltMV SPV and TMV SP are greater than those of the SP from AltMV VLP. Compared to normal cells, AltMV SPV adsorbed more effectively on patient-derived sarcoma cells, whereas TMV SP were more effective on the established sarcoma cells. The AltMV SPV and TMV SP were captured by all sarcoma cell lines. In the established Ewing sarcoma cell line, the effectiveness of AltMV SPV penetration was greater than that of TMV SP. The usage of structurally modified plant virus particles as a platform for drugs and delivery systems has significant potential in the development of anticancer agents. [ABSTRACT FROM AUTHOR]

Application of the [1,2]-Wittig rearrangement and cyclisation approach to 3-arylphthalides has been evaluated for the synthesis of three bioactive natural products. While this is successful in the case of crycolide, providing the second synthesis of this compound, the more sterically demanding targets isopestacin and cryphonectric acid prove not to be amenable to this approach, with the 2,6-disubstituted aryl groups causing the failure of the rearrangement and alkylation steps, respectively. Direct oxidation of the substituted benzhydrols resulting from [1,2]-Wittig rearrangement using MnO2 provides a new route to 3-aryl-3-hydroxyisoindolinones, and this method has been used in the synthesis of two 3-aryl-3-benzyloxyisoindolinone anticancer agents. [ABSTRACT FROM AUTHOR]

The rise of antimicrobial resistance presents a critical challenge in modern healthcare, demanding the development of innovative therapeutic agents. Metal-based antibiotics, or metalloantibiotics, have gained attention due to their enhanced biological efficacy. Schiff base metal ion complexes, a subset of metalloantibiotics have demonstrated promising antibacterial, antifungal, antiviral, and anticancer properties. This study aims to synthesize and characterize novel Schiff base metal ion derivatives to contribute to the development of next-generation antimicrobial agents. Novel Schiff base metal ion derivatives were synthesized via the condensation of aldehydes and primary amines, followed by complexation with transition metal ions. The resulting metal complexes were characterized using Fourier-transform infrared (FTIR) spectroscopy, nuclear magnetic resonance (NMR) spectroscopy. FTIR was used to confirm the formation of the imine group (-CH=N) and metal-ligand coordination. NMR spectroscopy provided insights into the electronic environment of the protons and carbons within the complexes. FTIR spectra confirmed the successful formation of the Schiff base complexes, indicated by the presence of characteristic imine (-CH=N) peaks and metal-ligand interactions. NMR analysis revealed shifts in chemical signals consistent with metal coordination. Biological assays indicated that the synthesized metal ion derivatives exhibited enhanced antibacterial activity compared to the unmodified Schiff base ligands, with significant inhibition zones observed against common bacterial strains. In conclusion, this research provides valuable insights into the synthesis and characterization of Schiff base metal ion derivatives. The enhanced antimicrobial activity observed in the synthesized complexes supports their potential as next-generation agents to combat bacterial resistance, offering new possibilities for drug discovery and development in medicinal chemistry. [ABSTRACT FROM AUTHOR]

Despite breakthroughs in the development of cancer diagnosis and therapy, most current therapeutic approaches lack precise specificity and sensitivity, resulting in damage to healthy cells. Selective delivery of anti-cancer agents is thus an important goal of cancer therapy. Scorpion venom (SV) and/or body parts have been used since early civilizations for medicinal purposes, and in cultures, SV is still applied to the treatment of several diseases including cancer. SV contains numerous active micro and macromolecules with diverse pharmacological effects. These include potent anti-microbial, anti-viral, anti-inflammatory, and anti-cancer properties. This review focuses on the recent advances of SV-derived peptides as promising anti-cancer agents and their diagnostic and therapeutic potential applications in cancers such as glioma, breast cancer, prostate cancer, and colon cancer. Well-characterized SV-derived peptides are thus needed to serve as potent and selective adjuvant therapy for cancer, to significantly enhance the patients' survival and wellbeing. [ABSTRACT FROM AUTHOR]

AbstractIn this work, an efficient and sustainable procedure for the one-pot synthesis of thiopyrimidine derivatives starting 1,3-diketone cut off β-O-4 lignin precursors to create anticancer agents. Microwave-ultrasonic assisted lignin extract in accessing various heterocyclic precursors such as pyrimidine, pyridine, and thiophene moieties. The results designated the ultrasonic-assisted microwave significantly accelerated synthesis with reduced time. We have diversely prolonged to tight-binding approaches to the electron ionization mass spectrometry with quantum stimulation (DFT/EIMS) to examine electron ionization mass spectra correlated to the experiment. Moreover, DFT/EIMS provides into the mechanism of the reaction of mass spectra trials. It cabins on the fragmentation method to raise the challenging bond breaking and structural rearrangements. The quantum chemical process for effective precursors of a mass spectrum is exactness required and discussed. Foremost fragmentation designs are studied and related to experimental data of the pyrimidin-thione derivatives and their glycosides. [ABSTRACT FROM AUTHOR]

AbstractWe have synthesized and characterized five copper(II) complexes, [Cu(L1)(alanine)(NO3)]·2H2O (1), [Cu(L1)(methionine)(H2O)]NO3·4H2O (2), [Cu(L2)(glycine)] NO3·3H2O (3), [Cu(L2)(alanine)Cl]·2H2O (4) and [Cu(L3)(phenylalanine)Br] (5), (L1 = 3-(1H-imidazo[4,5-f][1, 10]phenanthrolin-2-yl)phenol; L2 = 2-(4-fluorophenyl)-1Himidazo[4,5-f][1, 10]phenanthroline; L3 = 4-(1H-imidazo[4,5-f][1, 10]phenanthrolin-2-yl)phenol). Antiproliferative activity was examined using MTT assay against seven human cancer cells. Complexes 1 and 3 induced apoptosis in MDA-MB-231 cells. We also have investigated the potential anti-stemness properties in which the proportion of breast cancer stem cells in MDA-MB-231 cells (CD44 + CD24– cell subpopulation) were significantly reduced by 1 and 3. Furthermore, they decrease the size and mammospheres formed, inhibit tumor cell migration, and reverse epithelial–mesenchymal transition progression, as well as induce a reduction in expression of stemness markers, Nanog, and Sox-2 proteins. The copper(II) complexes may possess potential in treating TNBC with stem cell-like properties. [ABSTRACT FROM AUTHOR]

Herein we have developed a heterogeneous catalyst for synthesizing various anticancer and antidiabetic polyhydroquinoline derivatives via heterocyclic synthesis under solvent-free conditions at mild temperatures. This approach eliminates the need for complex cleanup or column chromatography, thus minimizing waste production. Moreover, the catalyst can be recovered and reused up to multiple times without compromising product yields, demonstrating its sustainability and environmental friendliness. Additionally, we evaluated each synthetic derivative for anticancer and antidiabetic activities. Initial assays revealed that certain derivatives exhibit promising inhibition against human breast cancer cells, suggesting their potential as lead structures for future anticancer agents. Furthermore, the synthesized derivatives were assessed for antidiabetic activity, showing superior efficacy. Notably, derivatives containing –H, –CH3, and –OCH3 substituents demonstrated excellent anticancer activity, while derivatives containing –H and –Br substituents showed notable antidiabetic activities, highlighting their therapeutic potential. Thus, our study presents an effective and sustainable approach for synthesizing polyhydroquinoline derivatives, emphasizing the catalyst's dual benefits in organic synthesis and medicinal chemistry applications. [ABSTRACT FROM AUTHOR]

The natural lignan diphyllin has shown promising antitumor activity, although its clinical advancement has been impeded by challenges such as low solubility, poor metabolic stability, and limited potency. In response, we developed and synthesized two sets of diphyllin 4‐C derivatives, comprising six ester derivatives and eight 1, 2, 3‐triazole derivatives. Notably, among these derivatives, 1, 2, 3‐triazole derivatives 7c and 7e demonstrated the most potent cytotoxic effects, with IC50 values ranging from 0.003 to 0.01 μM. Treatment with 0.2 μM of 7c and 7e resulted in a reduction of V‐ATPase activity in HGC‐27 cells to 23% and 29%, respectively. [ABSTRACT FROM AUTHOR]

A sophisticated electrochemical sensor is presented employing a glassy carbon electrode (GCE) modified with a novel composite of synthesized graphitic carbon nitride (g-C3N4) and CoNiO2 bimetallic oxide nanoparticles (g-C3N4/CoNiO2). The sensor's electrocatalytic capabilities for Sunitinib (SUNI) oxidation were demonstrated exceptional performance with a calculated detection limit (LOD) of 52.0 nM. The successful synthesis and integrity of the composite were confirmed through meticulous characterization using various techniques. FT-IR analysis affirmed the successful synthesis of g-C3N4/CoNiO2 by providing insights into its molecular structure. XRD, FE-SEM, SEM–EDX, and BET analyses collectively validated the material's structural integrity, surface morphology, and electrocatalytic performance. Optimization of key analytical parameters, such as loading volume, concentration, electrolyte solution type, and pH, enhanced the electrocatalytic sensing capabilities of g-C3N4/CoNiO2. The synergistic interaction between g-C3N4 and CoNiO2 bimetallic oxide nanoparticles executed the sensor highly effective in the electrical oxidation of SUNI. Across a concentration range of 0.1–83.8 µM SUNI, the anodic peak current exhibited a linear increase with good precision. Application of the newly developed g-C3N4/CoNiO2 system to detect SUNI in a variety of samples, including urine, human serum, and capsule dosage forms, obtained satisfactory recoveries ranging from 97.1 to 103.0%. This methodology offers a novel approach to underscore the potential of the developed sensor for applications in biological and pharmaceutical monitoring. [ABSTRACT FROM AUTHOR]

A 3D structure-based pharmacophore model built for bromodomain-containing protein 4 (BRD4) is reported here, specifically developed for investigating and identifying the key structural features of the (+)-JQ1 known inhibitor within the BRD4 binding site. Using this pharmacophore model, 273 synthesized and purchased compounds previously considered for other targets but yielding poor results were screened in a drug repositioning campaign. Subsequently, only six compounds showed potential as BRD4 binders and were subjected to further biophysical and biochemical assays. Compounds 2, 5, and 6 showed high affinity for BRD4, with IC50 values of 0.60 ± 0.25 µM, 3.46 ± 1.22 µM, and 4.66 ± 0.52 µM, respectively. Additionally, these compounds were tested against two other bromodomains, BRD3 and BRD9, and two of them showed high selectivity for BRD4. The reported 3D structure-based pharmacophore model proves to be a straightforward and useful tool for selecting novel BRD4 ligands. [ABSTRACT FROM AUTHOR]

Despite recent advances in the management and therapeutic of cancer, the treatment of the disease is limited by its high cost and severe side effects. In this scenario, there is an unmet need to identify novel treatment alternatives for this dreaded disease. Recently there is growing evidence that parasites may cause anticancer effects because of a negative correlation between parasitic infections and tumour growth despite some parasites that are known to exhibit pro-carcinogenic effects. It has been observed that parasites exert an anticancer effect either by activating the host's immune response or by secreting certain molecules that exhibit anticancer potential. The activation of the immune response by these parasitic organisms results in the inhibition of some of the hallmarks of cancer such as tumour proliferation, angiogenesis, and metastasis. This review summarizes the current advances as well as the mechanisms underlying the possible implications of this diverse group of organisms as anticancer agents. [ABSTRACT FROM AUTHOR]

Abstract Despite breakthroughs in the development of cancer diagnosis and therapy, most current therapeutic approaches lack precise specificity and sensitivity, resulting in damage to healthy cells. Selective delivery of anti-cancer agents is thus an important goal of cancer therapy. Scorpion venom (SV) and/or body parts have been used since early civilizations for medicinal purposes, and in cultures, SV is still applied to the treatment of several diseases including cancer. SV contains numerous active micro and macromolecules with diverse pharmacological effects. These include potent anti-microbial, anti-viral, anti-inflammatory, and anti-cancer properties. This review focuses on the recent advances of SV-derived peptides as promising anti-cancer agents and their diagnostic and therapeutic potential applications in cancers such as glioma, breast cancer, prostate cancer, and colon cancer. Well-characterized SV-derived peptides are thus needed to serve as potent and selective adjuvant therapy for cancer, to significantly enhance the patients’ survival and wellbeing. Graphical abstract

The 4,6-substituted-1,3,5-triazin-2(1H)-ones are promising inhibitors of human DNA topoisomerase IIα. To further develop this chemical class targeting the enzyme´s ATP binding site, the triazin-2(1H)-one substitution position 6 was optimized. Inspired by binding of preclinical substituted 9H-purine derivative, bicyclic substituents were incorporated at position 6 and the utility of this modification was validated by a combination of molecular simulations, dynamic pharmacophores, and free energy calculations. Considering also predictions of Deepfrag, a software developed for structure-based lead optimization based on deep learning, compounds with both bicyclic and monocyclic substitutions were synthesized and investigated for their inhibitory activity. The SAR data showed that the bicyclic substituted compounds exhibited good inhibition of topo IIα, comparable to their mono-substituted counterparts. Further evaluation on a panel of human protein kinases showed selectivity for the inhibition of topo IIα. Mechanistic studies indicated that the compounds acted predominantly as catalytic inhibitors, with some exhibiting topo IIα poison effects at higher concentrations. Integration of STD NMR experiments and molecular simulations, provided insights into the binding model and highlighted the importance of the Asn120 interaction and hydrophobic interactions with substituents at positions 4 and 6. In addition, NCI-60 screening demonstrated cytotoxicity of the compounds with bicyclic substituents and identified sensitive human cancer cell lines, underlining the translational relevance of our findings for further preclinical development of this class of compounds. The study highlights the synergy between simulation and AI-based approaches in efficiently guiding molecular design for drug optimization, which has implications for further preclinical development of this class of compounds.

Abstract In an attempt to develop potent anti-cancer agents, a new 1,3,4-substituted-thiadiazole derivatives (8b-g), starting from 4-substituted-thiazol-2-chloroacetamides (4b-g), were synthesized and evaluated for their cytotoxic effects on multiple human cancer cell lines, including the hepatocellular carcinoma (HEPG-2), human lung carcinoma (A549), human breast carcinoma (MCF-7) and pseudo-normal human embryonic liver (L02) cancer cell lines by an MTT assay. Among all synthesized compounds, compound 8d showed the potent anti-cancer activities with GI50 values of 2.98, 2.85 and 2.53 μM against MCF-7, A549 and HepG-2 cell lines respectively as compared to standard drug Doxorubicin. Furthermore, molecular modelling studies have spotlighted the anchoring role of 1,3,4-substituted-thiadiazole moiety in bonding and hydrophobic interaction with the key amino acid residues. Therefore, these results can provide promising starting points for further development of best anti-cancer agents. Graphical Abstract

The clinical use of many potent anticancer agents is limited by their non‐selective toxicity to healthy tissue. One of these examples is vorinostat (SAHA), a pan histone deacetylase inhibitor, which shows high cytotoxicity with limited discrimination for cancerous over healthy cells. In an attempt to improve tumor selectivity, we exploited the properties of cobalt(III) as a redox‐active metal center through stabilization with cyclen and cyclam tetraazamacrocycles, masking the anticancer activity of SAHA and other hydroxamic acid derivatives to allow for the complex to reach the hypoxic microenvironment of the tumor. Biological assays demonstrated the desired low in vitro anticancer activity of the complexes, suggesting effective masking of the activity of SAHA. Once in the tumor, the bioactive moiety may be released through the reduction of the CoIII center. Investigations revealed long‐term stability of the complexes, with cyclic voltammetry and chemical reduction experiments supporting the design hypothesis of SAHA release through the reduction of the CoIII prodrug. The results highlight the potential for further developing this complex class as novel anticancer agents by masking the high cytotoxicity of a given drug, however, the cellular uptake needs to be improved. [ABSTRACT FROM AUTHOR]

Non‐steroidal anti‐inflammatory drugs (NSAIDs) are extensively prescribed pharmaceutical agents worldwide. Due to their analgesic, antipyretic, and anti‐inflammatory properties, they are used in clinical practice for the treatment of numerous inflammatory diseases. The mechanism of action primarily involves the inhibition of prostaglandin synthesis mediated by cyclooxygenases (COX), key enzymes of the inflammatory cascade. Indomethacin, a non‐selective derivative of indole‐3‐acetic acid exhibits diverse mechanisms to exert its anti‐tumor effects, including angiogenesis suppression, induction of apoptosis, and reduction of tumorigenesis through immune modulation. Numerous studies suggest that derivatives of indomethacin may inhibit cell proliferation and reduce levels of anti‐apoptotic proteins through COX‐independent mechanisms. Given the diverse potential mechanisms through which indomethacin impacts cancer progression, this review provides an overview of structural analogs that possess antitumor activity and outlines future directions in developing new candidates that may have substantial efficacy in cancer therapy. [ABSTRACT FROM AUTHOR]

Ruthenium polypyridyl complexes are promising anticancer candidates, while their cellular targets have rarely been identified, which limits their clinical application. Herein, we design a series of Ru(II) polypyridyl complexes containing bioactive β-carboline derivatives as ligands for anticancer evaluation, among which Ru5 shows suitable lipophilicity, high aqueous solubility, relatively high anticancer activity and cancer cell selectivity. The subsequent utilization of a photo-clickable probe, Ru5a , serves to validate the significance of ATP synthase as a crucial target for Ru5 through photoaffinity-based protein profiling. Ru5 accumulates in mitochondria, impairs mitochondrial functions and induces mitophagy and ferroptosis. Combined analysis of mitochondrial proteomics and RNA-sequencing shows that Ru5 significantly downregulates the expression of the chloride channel protein, and influences genes related to ferroptosis and epithelial-to-mesenchymal transition. Finally, we prove that Ru5 exhibits higher anticancer efficacy than cisplatin in vivo. We firstly identify the molecular targets of ruthenium polypyridyl complexes using a photo-click proteomic method coupled with a multiomics approach, which provides an innovative strategy to elucidate the anticancer mechanisms of metallo-anticancer candidates. [ABSTRACT FROM AUTHOR]

Chromone‐based compounds have established cytotoxic, antiproliferative, antimetastatic, and antiangiogenic effects on various cancer cell types via modulating different molecular targets. Herein, 17 novel chromone‐2‐carboxamide derivatives were synthesized and evaluated for their in vitro anticancer activity against 15 human cancer cell lines. Among the tested cell lines, MDA‐MB‐231, the triple‐negative breast cancer cell line, was found to be the most sensitive, where the N‐(2‐furylmethylene) (15) and the α‐methylated N‐benzyl (17) derivatives demonstrated the highest growth inhibition with GI50 values of 14.8 and 17.1 μM, respectively. In vitro mechanistic studies confirmed the significant roles of compounds 15 and 17 in the induction of apoptosis and suppression of EGFR, FGFR3, and VEGF protein levels in MDA‐MB‐231 cancer cells. Moreover, compound 15 exerted cell cycle arrest at both the G0‐G1 and G2‐M phases. The in vivo efficacy of compound 15 as an antitumor agent was further investigated in female mice bearing Solid Ehrlich Carcinoma. Notably, administration of compound 15 resulted in a marked decrease in both tumor weight and volume, accompanied by improvements in biochemical, hematological, histological, and immunohistochemical parameters that verified the repression of both angiogenesis and inflammation as additional Anticancer mechanisms. Moreover, the binding interactions of compounds 15 and 17 within the binding sites of all three target receptors (EGFR, FGFR3, and VEGF) were clearly illustrated using molecular docking. [ABSTRACT FROM AUTHOR]

Oxidative stress is a defense mechanism that occurs when there is an imbalance between the production of reactive metabolites and free radicals and the antioxidants’ ability to eliminate them. Reactive metabolites are free radicals referred to as oxidants or reactive oxygen species (ROS). Cells are harmed by this imbalance, which may influence the entire body. When the intra- and extracellular environmental circumstances in cells change, ROS is essential for stimulating the corresponding signaling pathways. All aspects of carcinogenesis, including prevention and treatment, are tightly associated with reactive species, particularly ROS. Numerous tumor suppressor genes and proto-oncogenes are deregulated by ROS, which also modify several cellular signaling pathways. However, most chemotherapy drugs and even radiation therapy dramatically raise the ROS concentrations in the tumor microenvironment. Antioxidants cause programmed cell death, which is used in cancer treatment; yet people receiving chemotherapy benefit from antioxidants. Nevertheless, the exact processes underlying this anticancer action remain unclear. Many studies carried out in laboratories and on animals revealed high concentrations of exogenic antioxidants, that inhibit the forms of free radical injury linked with the formation of cancer. There haven’t been many human clinical trials looking into the potential of dietary supplementation to reduce the risk of cancer development or death. Since there have been studies on the advantages and downsides of antioxidants in the treatment of cancer, several considerations need to be deemed before administering antioxidant supplements. In conclusion, little is known about the mechanism underlying antioxidant effect in cancer treatment. [ABSTRACT FROM AUTHOR]

AbstractFocal Adhesion Kinase (FAK) is a non-receptor protein tyrosine kinase that plays a crucial role in various oncogenic processes related to cell adhesion, migration, proliferation, and survival. The strategic targeting of FAK represents a burgeoning approach to address resistant tumours, such as pancreatic ductal adenocarcinoma (PDAC). Herein, we report a new series of twenty imidazo[2,1-b][1, 3, 4]thiadiazole derivatives assayed for their antiproliferative activity against the National Cancer Institute (NCI-60) panel and a wide panel of PDAC models. Lead compound 10l exhibited effective antiproliferative activity against immortalised (SUIT-2, CAPAN-1, PANC-1, PATU-T, BxPC-3), primary (PDAC-3) and gemcitabine-resistant clone (PANC-1-GR) PDAC cells, eliciting IC50 values in the low micromolar range (1.04–3.44 µM), associated with a significant reduction in cell-migration and spheroid shrinkage in vitro. High-throughput kinase arrays revealed a significant inhibition of the FAK signalling network, associated to induction of cell cycle arrest in G2/M phase, suppression of tumour cell invasion and apoptosis induction. The high selectivity index/toxicity prompted studies using PDAC mouse xenografts, demonstrating significant inhibition of tumour growth and safety. In conclusion, compound 10l displayed antitumor activity and safety in both in vitro and in vivo models, emerging as a highly promising lead for the development of FAK inhibitors in PDAC. [ABSTRACT FROM AUTHOR]

Src homology‐2 (SH2) domain‐containing phosphatase‐2 (SHP2), the first protooncogenic phosphatase is a key mediator in the development and progression of various cancers. Several allosteric sites have been identified in SHP2, inhibitors of which are being developed. In the current study, we have designed and synthesized a library of 21 thioacetamide‐tethered thiadiazole‐1,2,4‐triazole hybrids (compounds 16–36) and evaluated their in vitro SHP2 inhibitory potential. Compound 28 (N‐(5‐(benzo[d][1,3]dioxol‐5‐yl)‐1,3,4‐thiadiazol‐2‐yl)‐2‐((5‐(4‐methoxyphenyl)‐4H‐1,2,4‐triazol‐3‐yl)thio)acetamide) emerged as the most potent SHP2 inhibitor (IC50=0.318±0.001 μM) inhibiting the enzyme in a mixed to non‐competitive manner. In silico studies revealed that the lead inhibitor strongly binds to the tunnel allosteric site of SHP2. Further, cytotoxicity studies revealed that compound 28 caused death of SHP2‐driven MCF‐7 (GI50=37.02±0.25 μM) and U87MG cells (GI50=68.69±0.21 μM) in a dose‐dependent manner and inhibited MCF‐7 cell colony formation and migration. Flow cytometric analysis showed that it exerted its antiproliferative effect on U87MG cells by inducing early apoptosis (Q2 phase) and inhibiting cell cycle progression at the G1 and S phase. Compound 28 was shown to increase oxidative stress in the U87 cells by promoting ROS generation and loss of mitochondrial integrity. In summary, the present study produced a potent SHP2 inhibitor (compound 28) with a promising in vitro cytotoxicity profile, thus meriting further investigation. [ABSTRACT FROM AUTHOR]

Research on the energy metabolism of cancer cells is becoming a central element in oncology, and in recent decades, it has allowed us to better understand the mechanisms underlying the onset and chemoresistance of oncological pathologies. Mitochondrial bioenergetic processes, in particular, have proven to be fundamental for the survival of tumor stem cells (CSC), a subpopulation of tumor cells responsible for tumor recurrence, the onset of metastasis, and the failure of conventional anticancer therapies. Over the years, numerous natural products, in particular flavonoids, widely distributed in the plant kingdom, have been shown to interfere with tumor bioenergetics, demonstrating promising antitumor effects. Herein, the anticancer potential of Licoflavanone, a flavanone isolated from the leaves of G. glabra, was explored for the first time in breast cancer cells. The results obtained highlighted a marked antitumor activity that proved to be greater than that mediated by Glabranin or Pinocembrin, flavanones isolated from the same plant matrix. Furthermore, the investigation of Licoflavanone's effects on breast cancer energy metabolism highlighted the inhibitory activity of this natural product on tumor bioenergetics, a mechanism that could underlie its ability to reduce tumor proliferation, invasiveness, and stemness. [ABSTRACT FROM AUTHOR]

Because of synergism between tubulin and HDAC inhibitors, we used the pharmacophore fusion strategy to generate potential tubulin–HDAC dual inhibitors. Drug design was based on the introduction of a N-hydroxyacrylamide or a N-hydroxypropiolamide at the 5-position of the 2-aroylbenzo[b]furan skeleton, to produce compounds 6a–i and 11a–h, respectively. Among the synthesized compounds, derivatives 6a, 6c, 6e, 6g, 11a, and 11c showed excellent antiproliferative activity, with IC50 values at single- or double-digit nanomolar levels, against the A549, HT-29, and MCF-7 cells resistant towards the control compound combretastatin A-4 (CA-4). Compounds 11a and 6g were also 10-fold more active than CA-4 against the Hela cell line. When comparing the inhibition of tubulin polymerization versus the HDAC6 inhibitory activity, we found that 6a–g, 6i, 11a, 11c, and 11e, although very potent as inhibitors of tubulin assembly, did not have significant inhibitory activity against HDAC6. [ABSTRACT FROM AUTHOR]

Organometallic compounds are gaining prominence today as they are found to be potent anticancer agents due to their diverse chemical nature along with the metal with which they are chelated. In these organometallic compounds, many different hetero-organic compounds like Schiff bases, Indoles, Quinolines, Pyrroles are chelated with different metals. As these heterocyclic compounds are proven cytotoxic agents at a higher dose, their potency get enhanced by many fold by metal complexation. Schiff base derivatives are reportedly more powerful agents against tumours of different types, they are gaining prominence as antitumour agents. In this present study, different derivatives of Schiff bases are synthesized and chelated with Aluminium (Al) and characterised with IR, NMR, LCMS and also subjected to metal analysis by ICPMS. Later, these compounds were screened by in vitro analysis of their cytotoxic potentials against cancer cell lines by MCF method and are found to be potent cytotoxic agents. Among all, MC-2 and MC-3 are nearer to the cytotoxic range given by NIH. Hence, we anticipate that although all the synthesized organometal complexes are potential cytotoxic agents, however MC 1 and MC 5 are significantly good cytotoxic agents. However, further study is needed to justify this claim. [ABSTRACT FROM AUTHOR]

In the present work, synthesis of 4,5-dehydrospiulosine and its chain analogues (7-9) as potential Sphingosine Kinase I inhibitors has been achieved via the diastereoselective Grignard reaction and stereoselective cross-metathesis reaction followed by N-acylation with p-nitrophenyl butyrate to give the corresponding butyrate ceramides (10-12). All compounds were obtained in high yield and purity. Molecular docking simulation studies were performed for the synthesized compounds that indicated their varying binding affinities with the Sphingosine Kinase 1 (SPHK1) protein. Following, molecular dynamics simulations were performed for the SPHK1-compound (10) complex that indicated compound (10) to be structurally and energetically stable within the binding pocket of SPHK1. Further, the biological evaluation studies, as potential anti-prostate cancer agents and as anti-colon cancer agents by inhibiting the SPHK1 of all synthesized compounds (7-12) on PC-3 cell lines and HCT-116 cell lines by the SRB method were done. Compound N-((2S,3S,E)-3-hydroxyheptadec-4-en-2-yl) butyramide (10) exhibited remarkable cytotoxicity with an IC50 value of 0.018 μM against PC-3 cell lines and 0.076 μM against HCT-116 cell lines, whereas compound (11) showed best cytotoxicity with an IC50 value of 0.062 μM against HCT-116 cell lines. [ABSTRACT FROM AUTHOR]

Fourteen diphyllin 4-C-substituted alkylide derivatives were designed and synthesized using a Heck coupling and subsequent hydrogenation reaction. Olefins 3g and 3i exhibited the highest cytotoxicity on breast cancer cell lines MCF-7 with IC50 values of 0.08 and 0.07 µM, and they showed weaker V-ATPase inhibitory potency compared to diphyllin. [ABSTRACT FROM AUTHOR]

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The approved anthelmintic salicylanilide drug niclosamide has shown promising anticancer and antimicrobial activities. In this study, new niclosamide derivatives with trifluoromethyl, trifluoromethylsulfanyl, and pentafluorosulfanyl substituents replacing the nitro group of niclosamide were prepared (including the ethanolamine salts of two promising salicylanilides) and tested for their anticancer activities against esophageal adenocarcinoma (EAC) cells. In addition, antifungal activity against a panel of Madurella mycetomatis strains, the most abundant causative agent of the neglected tropical disease eumycetoma, was evaluated. The new compounds revealed higher activities against EAC and fungal cells than the parent compound niclosamide. The ethanolamine salt 3a was the most active compound against EAC cells (IC50 = 0.8–1.0 µM), and its anticancer effects were mediated by the downregulation of anti-apoptotic proteins (BCL2 and MCL1) and by decreasing levels of β-catenin and the phosphorylation of STAT3. The plausibility of binding to the latter factors was confirmed by molecular docking. The compounds 2a and 2b showed high in vitro antifungal activity against M. mycetomatis (IC50 = 0.2–0.3 µM) and were not toxic to Galleria mellonella larvae. Slight improvements in the survival rate of G. mellonella larvae infected with M. mycetomatis were observed. Thus, salicylanilides such as 2a and 3a can become new anticancer and antifungal drugs. [ABSTRACT FROM AUTHOR]

In an attempt to develop potent anti-cancer agents, a new 1,3,4-substituted-thiadiazole derivatives (8b-g), starting from 4-substituted-thiazol-2-chloroacetamides (4b-g), were synthesized and evaluated for their cytotoxic effects on multiple human cancer cell lines, including the hepatocellular carcinoma (HEPG-2), human lung carcinoma (A549), human breast carcinoma (MCF-7) and pseudo-normal human embryonic liver (L02) cancer cell lines by an MTT assay. Among all synthesized compounds, compound 8d showed the potent anti-cancer activities with GI50 values of 2.98, 2.85 and 2.53 μM against MCF-7, A549 and HepG-2 cell lines respectively as compared to standard drug Doxorubicin. Furthermore, molecular modelling studies have spotlighted the anchoring role of 1,3,4-substituted-thiadiazole moiety in bonding and hydrophobic interaction with the key amino acid residues. Therefore, these results can provide promising starting points for further development of best anti-cancer agents. [ABSTRACT FROM AUTHOR]

A family of bifunctional dihetarylmethanes and dibenzoxanthenes is assembled via a reaction of acetals containing a 2-chloroacetamide moiety with phenols and related oxygen-containing heterocycles. These compounds demonstrated selective antitumor activity associated with the induction of cell apoptosis and inhibition of the process of glycolysis. In particular, bis(heteroaryl)methane containing two 4-hydroxy-6-methyl-2H-pyran-2-one moieties combine excellent in vitro antitumor efficacy with an IC50 of 1.7 µM in HuTu-80 human duodenal adenocarcinoma models with a high selectivity index of 73. Overall, this work highlights the therapeutic potential of dimeric compounds assembled from functionalized acetals and builds a starting point for the development of a new family of anticancer agents. [ABSTRACT FROM AUTHOR]

Lipophilicity is one of the principal parameters that describe the pharmacokinetic behavior of a drug, including its absorption, distribution, metabolism, elimination, and toxicity. In this study, the lipophilicity and other physicochemical, pharmacokinetic, and toxicity properties that affect the bioavailability of newly synthesized dialkylaminoalkyldiquinothiazine hybrids as potential drug candidates are presented. The lipophilicity, as RM0, was determined experimentally by the RP-TLC method using RP18 plates and acetone–TRIS buffer (pH 7.4) as the mobile phase. The chromatographic parameters of lipophilicity were compared to computationally calculated partition coefficients obtained by various types of programs such as iLOGP, XLOGP3, WLOGP, MLOGP, SILCOS-IT, LogP, logP, and milogP. In addition, the selected ADMET parameters were determined in silico using the SwissADME and pkCSM platforms and correlated with the experimental lipophilicity descriptors. The results of the lipophilicity study confirm that the applied algorithms can be useful for the rapid prediction of logP values during the first stage of study of the examined drug candidates. Of all the algorithms used, the biggest similarity to the chromatographic value (RM0) for certain compounds was seen with iLogP. It was found that both the SwissADME and pkCSM web tools are good sources of a wide range of ADMET parameters that describe the pharmacokinetic profiles of the studied compounds and can be fast and low-cost tools in the evaluation of examined drug candidates during the early stages of the development process. [ABSTRACT FROM AUTHOR]

Opinion Statement: Rhabdomyosarcoma, a soft tissue sarcoma commonly observed in childhood, requires multidisciplinary treatment, including surgical tumor resection, chemotherapy, and radiation therapy. Although long-term survival can be expected in patients with localized rhabdomyosarcoma, the clinical outcomes in patients with metastatic or unresectable rhabdomyosarcoma remain unsatisfactory. To improve the outcomes of rhabdomyosarcoma, it is important to explore effective systemic treatments for metastatic rhabdomyosarcoma. Currently, multiagent chemotherapy comprising vincristine, actinomycin D, and ifosfamide/cyclophosphamide remains standard systemic treatment for rhabdomyosarcoma. On the other hand, new treatment, such as immune checkpoint inhibitors and molecular targeted drugs, have demonstrated superior clinical outcomes compared to those of standard treatments in various type of malignancies. Therefore, it is necessary to assess the efficacies of these treatments in patients with rhabdomyosarcoma. Recent clinical studies have shown efficacies and safeties of temozolomide combined with vincristine/irinotecan, olaratumab combined with doxorubicin or vincristine/irinotecan, and long-term maintenance therapy. Furthermore, basic researches demonstrated new therapeutic targets. Future studies using these approaches are required to assess their clinical significances. [ABSTRACT FROM AUTHOR]

Abstract Kojic acid is a wonderful fungal secondary metabolite that has several applications in the food, medical, and agriculture sectors. Many human diseases become resistant to normal antibiotics and normal treatments. We need to search for alternative treatment sources and understand their mode of action. Aspergillus flavus ASU45 (OL314748) was isolated from the caraway rhizosphere as a non-aflatoxin producer and identified genetically using 18S rRNA gene sequencing. After applying the Box-Behnken statistical design to maximize KA production, the production raised from 39.96 to 81.59 g/l utilizing (g/l) glucose 150, yeast extract 5, KH2PO4 1, MgSO4.7H2O 2, and medium pH 3 with a coefficient (R 2 ) of 98.45%. Extracted KA was characterized using FTIR, XRD, and a scanning electron microscope. Crystalized KA was an effective antibacterial agent against six human pathogenic bacteria (Bacillus cereus, Staphylococcus aureus, Escherichia coli, Klebsiella pneumonia, Serratia marcescens, and Serratia plymuthica). KA achieves high inhibition activity against Bacillus cereus, K. pneumonia, and S. plymuthica at 100 μg/ml concentration by 2.75, 2.85, and 2.85 compared with chloramphenicol which gives inhibition zones 1, 1.1, and 1.6, respectively. Crystalized KA had anticancer activity versus three types of cancer cell lines (Mcf-7, HepG2, and Huh7) and demonstrated high cytotoxic capabilities on HepG-2 cells that propose strong antitumor potent of KA versus hepatocellular carcinoma. The antibacterial and anticancer modes of action were illustrated using the molecular docking technique. Crystalized kojic acid from a biological source represented a promising microbial metabolite that could be utilized as an alternative antibacterial and anticancer agent effectively.

Nano compounds, especially metal-organic frameworks (MOFs), have significant properties. Among the most important properties of these compounds, which depend on their specific surface area and porosity, are biological properties, such as anticancer and antibacterial properties. In this study, a new titanium/BTB metal-organic framework (Ti/BTB-MOF) was synthesized by using titanium nitrate and 1,3,5-Tris(4-carboxyphenyl)benzene (BTB) under microwave radiation. The structure of the synthesized Ti/BTB-MOF was characterized and confirmed using X-ray diffraction (XRD) patterns, X-ray photoelectron spectroscopy (XPS) analysis, Fourier transform infrared (FT-IR) spectra, energy- dispersive X-ray (EDAX) analysis mapping, scanning electron microscope (SEM) images, thermogravimetric analysis (TGA) curves, and Brunauer-Emmett-Teller (BET) analysis. The in vitro anticancer properties of Ti/BTB-MOF were evaluated using the MTT method against MG-63/bone cancer cells and A-431/skin cancer cells. The in vitro antibacterial activity was tested using the Clinical and Laboratory Standards Institute (CLSI) guidelines. In the anticancer activity, IC50 (half-maximal inhibitory concentration) values of 152 μg/mL and 201 μg/mL for MG-63/bone cancer cells and A-431/skin cancer cells, respectively, were observed. In the antibacterial activity, minimum inhibitory concentrations (MICs) of 2-64 μg/mL were observed against studied pathogenic strains. The antimicrobial activity of Ti/ BTB-MOF was higher than that of penicillin and gentamicin. Therefore, the synthesized Ti/BTB-MOF could be introduced as a suitable bioactive candidate. [ABSTRACT FROM AUTHOR]

Investigation pertaining to the design and synthesis of therapeutic drugs against lung cancer remains in high demand, considering the high fatality rate associated with this disease. Herein, a carboxyl and ester functionalization at the N3 position of the TZD (thiazolidine‐2,4‐dione) moiety in an indole‐TZD conjugate was envisaged and evaluated as a potential anticancer drug. Although TIA (thiazoindole acid) did not demonstrate significant effectiveness against the A549 human lung adenocarcinoma cell line, the ester analog TIE (thiazoindole ester) showed high cytotoxic potential against the A549 cell line in their monolayer and spheroid form. Further, preliminary mechanistic investigations, such as cell viability studies and nuclear staining, revealed typical apoptotic features, including chromatin condensation, cellular shrinkage, and the formation of horseshoe‐shaped nuclei. In addition, the TIE compound can disrupt the F‐actin protein, thereby decreasing cell migration. Moreover, the cell cycle analysis revealed a notable halt in the G2/M phase. Further docking studies elucidate the interaction between TIE and the (peroxisome proliferator‐activated receptor) PPAR‐γ receptor. In summary, the findings of our investigation suggest that TIE compounds possess considerable efficacy as an anti‐proliferative agent and hold promise for therapeutic applications in lung cancer treatment. [ABSTRACT FROM AUTHOR]

The Rutaceae family is one of the most studied plant families due to the large number of alkaloids isolated from them with outstanding biological properties, among them the quinoline-based alkaloids Graveoline 1 and Dubamine 2. The most common methods for the synthesis of alkaloids 1 and 2 and their derivatives involves cycloaddition reactions or metal-catalyzed coupling processes but with some limitations in scope and functionalization of the quinoline moiety. As a continuation of our current studies on the synthesis and chemical transformation of 2-aminochalcones, we are reporting here an efficient metal-free approach for the total synthesis of alkaloids 1 and 2 along with their analogues with structural diversity, through a two-step sequence involving intramolecular cyclization, oxidation/aromatization, N-methylation and oxidative C-C bond processes, starting from dihydroquinolin-4-ones as common precursors for the construction of the structures of both classes of alkaloids. [ABSTRACT FROM AUTHOR]

The medicinal plant Securinega virosa (Roxb ex. Willd) Baill., also known as Flueggea virosa (Roxb. ex Willd.) Royle, is commonly used in traditional medicine in Africa and Asia for the management of diverse pathologies, such as parasite infections, diabetes, and gastrointestinal diseases. Numerous alkaloids have been isolated from the twigs and leaves of the plant, notably a variety of oligomeric indolizidine alkaloids derived from the monomers securinine and norsecurinine which both display anticancer properties. The recent discovery that securinine can bind to tubulin and inhibit microtubule assembly prompted us to investigate the potential binding of two series of alkaloids, fluevirosines A–H and fluevirosinine A–J, with the tubulin dimer by means of molecular modeling. These natural products are rare high-order alkaloids with tri-, tetra-, and pentameric norsecurinine motifs. Despite their large size (up to 2500 Å3), these alkaloids can bind easily to the large drug-binding cavity (about 4800 Å3) on α-tubulin facing the β-tubulin unit. The molecular docking analysis suggests that these hydrophobic macro-alkaloids can form stable complexes with α/β-tubulin. The tubulin-binding capacity varies depending on the alkaloid size and structure. Structure-binding relationships are discussed. The docking analysis identifies the trimer fluevirosine D, tetramer fluevirosinine D, and pentamer fluevirosinine H as the most interesting tubulin ligands in the series. This study is the first to propose a molecular target for these atypical oligomeric Securinega alkaloids. [ABSTRACT FROM AUTHOR]

The main goal of this work was to elucidate the potential relevance of (radio)metal chelates of 99mTc and Re targeting Gquadruplex structures for the design of new tools for cancer theranostics. 99mTc provides the complexes with the ability to perform single-photon-emission computed tomography imaging studies, while the Re complexes should act as anticancer agents upon interaction with specific G4 DNA or RNA structures present in tumor tissues. Towards this goal, we have developed isostructural 99mTc(I) and Re(I) tricarbonyl complexes anchored by a pyrazolyl-diamine (Pz) chelator carrying a pendant pyridostatin (PDS) fragment as the G4-binding motif. The interaction of the PDF-Pz-Re (8) complex with different G4-forming oligonucleotides was studied by circular dichroism, fluorescence spectroscopy and FRET-melting assays. The results showed that the Re complex retained the ability to bind and stabilize G4-structures from different DNA or RNA sequences, namely those present on the SRC proto-oncogene and telomeric RNA (TERRA sequence). PDF-Pz-Re (8) showed low to moderate cytotoxicity in PC3 and MCF-7 cancer cell lines, as typically observed for G4-binders. Biodistribution studies of the congener PDF-Pz-99mTc (12) in normal mice showed that the complex undergoes a fast blood clearance with a predominant hepatobiliary excretion, pointing also for a high in vitro stability. [ABSTRACT FROM AUTHOR]

In this paper, we designed, synthesized, and biologically screened a series of methyl‐piperidine‐phenyl‐nicotinamide derivatives with the aim of novel derivatives as effective anticancer agents. Compounds (9 a), (9 e) and (9 k) exhibited potent anticancer activity with an IC50 value of 5.9 μM, 5.9 μM and 5.0 μM, respectively using MV411 (Acute Myeloid Leukemia) and K562 (Chronic Myeloid Leukemia) cell line. Our docking studies show good binding affinity of these compounds for ABL1 kinase. Furthermore, these compounds exhibited a favourable in silico ADME profile with good solubility and low clearance in Human Liver Microsomes (HLM). These derivatives represent a promising approach to initiate the development of new anticancer drugs in oncology programs. [ABSTRACT FROM AUTHOR]