Selected Cancer Cell Research Articles

Multifunctional Indomethacin Conjugates for the Development of Nanosystems Targeting Cancer Treatment.

It is well known that the nonsteroidal anti-inflammatory drug (NSAID) indomethacin (IND) exhibits significant anticancer potential reported not only by in vitro and in vivo studies, but also in clinical trials. Despite promising results, IND is not widely used as an adjunctive agent in cancer therapy due to the occurrence of several gastrointestinal side effects, primarily after oral administration. Therefore, this study aimed to develop a nanosystem with reduced toxicity and risk of side effects for the delivery of IND for cancer treatment. IND was encapsulated in nanostructured lipid carriers (NLC) in the form of a phospholipid conjugate, where a covalent bond exists between the drug and phosphatidylcholine skeleton. For this purpose, seven new hybrid molecules were synthesized, and subsequently evaluated as anticancer agents in an in vitro model against selected cancer cell lines. Biological studies demonstrated that the synthesized conjugates possessed excellent antiproliferative effects, exhibiting a 2.7-fold to even 100-fold higher activity against selected cancer cells, while remaining non-toxic to healthy cells. Based on biological studies and molecular calculations, heterosubstituted phosphatidylcholine containing IND and oleic acid (IND-OA-PC) in the sn-1 and sn-2 positions, respectively, was identified as the most potent molecule. Subsequently, IND-OA-PC was encapsulated in nanostructured lipid carriers (IND-OA-PC-NLC). The results revealed that IND-OA-PC-NLC has a spherical shape with an average diameter of 155 nm and a negatively charged surface (-17.4 ± 0.49 mV). In this study, it was proven that the encapsulated conjugate of indomethacin with PC exhibits high activity against triple-negative (TNBC, Her2-, PR-, and ER-) breast cancer cells MDA-MB-468. While free IND was active at a concentration of 270.5μM, in the form of the phospholipid conjugate (IND-OA-PC), it inhibited the growth of cancer cells at 67.5μM and after conjugate encapsulation (IND-OA-PC-NLC) it was effective at only 10.3μM. Our study revealed that the conjugation of NSAID with phosphatidylcholine and its combination with nanotechnology techniques create opportunities to repurpose well-known drugs from this group for new therapeutic applications.

A New Proton Transfer Complex Between 3,4-Diaminopyridine Drug and 2,6-Dichloro-4-nitrophenol: Synthesis, Spectroscopic Characterization, DFT Studies, DNA Binding Analysis, and Antitumor Activity.

The proton transfer (PT) complexation reaction between 3,4-diaminopyridine (3,4-DAP), an important drug, and 2,6-dichloro-4-nitrphenole (DCNP) was investigated experimentally and theoretically. The experimental results indicated a chemical reaction occurred because of a hydrogen bonding, followed by proton transfer from the DCNP to the 3,4-DAP in different polar media. The Benesi-Hildebrand equation was used to estimate the formation constant (Kf), molar absorptivity (εPT), and other physical parameters. The formed PT complex was characterized using FTIR, 1H, and 13C NMR spectra. In addition, the nanocrystalline structure, particle sizes, and surface morphology of the complex were investigated by XRD and SEM-EDX. The structure of the 1:1 PT complex was calculated theoretically in the gas phase and the presence of solvent effects. Using TD-DFT calculations, the band observed at 406 nm (Calc. 379.5 nm) and 275 nm (Calc. 272.3 nm) could be assigned to the HOMO→LUMO transition (99%), and HOMO→L+3 transition (87%), respectively. The DNA binding ability of the PT complex was investigated, revealing an intercalative binding mechanism with a binding constant Kb of 4.6 × 104 M-1. Based on the results of the Ct-DNA binding study, the binding free energy of the PT complex with the receptor of human DNA (PDB ID:1BNA) is found to be -7.2 kcal/mol. The cytotoxic effects of the PT complex were evaluated on selected cancer cell lines, demonstrating significant antitumor activity against A-549 and MCF-7 cancer cell lines.

Synthesis of New Xanthene and Acridine Derivatives from Cyclohexan-1,3-dione and the Study of their Antiproliferative Activities

Background: Ionic immobilized liquids and multi-component reactions are integral to green chemistry, facilitating the synthesis of biologically active compounds, such as xanthene and acridine derivatives. These approaches have garnered significant attention in recent years. Objective: The aim of this study was to synthesize novel xanthene and acridine derivatives with diverse substituents and heterocyclic rings. Furthermore, the research sought to evaluate their anticancer activity against various cancer cell lines and analyze their structure-activity relationships (SAR) to determine how structural modifications impact their biological effectiveness. Method: The core compounds in this study were synthesized from cyclohexane-1,3-dione and triethoxymethane under two distinct reaction conditions. The first involved the use of a solvent with either Et₃N or NH₄OAc as a catalyst, while the second employed a solvent-free approach using an ionic liquid catalyst (ILs). Results: The anti-proliferative activity of all synthesized compounds was evaluated against six selected cancer cell lines, revealing that many compounds exhibited significant inhibitory effects. Furthermore, their inhibitory potential against tyrosine kinases and Pim-1 kinases was assessed, along with an investigation of their mechanism of action on tyrosine kinases. Conclusion: The anti-proliferative activity of the newly synthesized compounds was evaluated against six cancer cell lines. Many of the compounds exhibited strong inhibitory effects not only against the tested cancer cell lines but also against tyrosine kinases and Pim-1 kinases.

Dipicolinate‐Ruthenium‐NHC/trpy Complexes: Pincer Ligand Induced Hemilability of Dipicolinate and Enhancement of Cytotoxic Property

AbstractA ruthenium(II) aquo complex [Ru(dipic)(PPh3)2(OH2)], (1 A), bearing O,N,O‐coordinated 2,6‐dipicolinate was synthesized via reaction of [Ru(PPh3)3Cl2] with 2,6‐dipicolinic acid. Crystal structure of 1 A was determined. Utilizing 1 A as a synthon, three new complexes were synthesized. Reaction of 1 A with a bidentate NHC‐ligand, viz. 1‐methyl‐3‐(2′‐pyridyl)imidazole (IMeCN), afforded [Ru(dipic)(IMeCN)(PPh3)], (2 A). Similar reactions of 1 A with two pincer ligands, viz. 2,6‐bis(1′‐methyl imidazolyl)pyridine (IMeCNC) and 2,2′;6′,2“‐terpyridine (trpy), respectively yielded [Ru(dipic)(IMeCNC)(PPh3)], (3 A) and [Ru(dipic)(trpy)(PPh3)], (3 B). Structure of 2 A was optimized by DFT method. Structures of 3 A and 3 B were determined by X‐ray crystallography. In both 3 A and 3B the 2,6‐dipicolinate ligand was found to be N,O‐coordinated with one carboxy end remaining unbound to the metal center. Anticancer property of 2 A, 3 A and 3 B was studied and compared. Cytotoxicity of 3 A, studied against three selected cancer cell lines, viz. chronic myelogenous leukemia cell line (K562), hepatocellular carcinoma cell line (HepG2) and breast adenocarcinoma cell line (MCF7), was found to be the most promising. It displayed the best activity against K562, while it did not have any appreciable effect on its normal counterpart, viz. the human peripheral blood mononuclear cells (hPBMC). The comparative cytotoxicity studies indicated that presence of the C,N,C‐coordinated pincer NHC ligand in 3 A, together with presence of the free carboxylate end of N,O‐coordinated dipic ligand, are presumably responsible for its superior cytotoxic behavior.

Anticancer Properties Against Select Cancer Cell Lines and Metabolomics Analysis of Tender Coconut Water.

Tender Coconut Water (TCW) is a nutrient-rich dietary supplement that contains in bioactive secondary metabolites and phytohormones with anti-oxidative and anti-inflammatory properties. Studies on TCW's anti-cancer properties are limited and the mechanism of its anti-cancer effects have not been defined. In the present study, we investigate TCW for its anti-cancer properties and, using untargeted metabolomics, we identify components form TCW with potential anti-cancer activity. Cell viability assay, BrdU incorporation assay, soft-agar assay, flow-cytometery, and Western blotting were used to analyze TCW's anticancer properties and to identify mechanism of action. Liquid chromatography- Tandem Mass Spectroscopy (LC-MS/MS) was used to identify TCW components. TCW decreased the viability and anchorage-independent growth of HepG2 hepatocellular carcinoma (HCC) cells and caused S-phase cell cycle arrest. TCW inhibited AKT and ERK phosphorylation leading to reduced ZEB1 protein, increased E-cadherin, and reduced N-cadherin protein expression in HepG2 cells, thus reversing the 'epithelial-to-mesenchymal' (EMT) transition. TCW also decreased the viability of Hep3B hepatoma, HCT-15 colon, MCF-7 and T47D luminal A breast cancer (BC) and MDA-MB-231 and MDA-MB-468 triplenegative BC cells. Importantly, TCW did not inhibit the viability of MCF-10A normal breast epithelial cells. Untargeted metabolomics analysis of TCW identified 271 metabolites, primarily lipids and lipid-like molecules, phenylpropanoids and polyketides, and organic oxygen compounds. We demonstrate that three components from TCW: 3-hydroxy-1-(4-hydroxyphenyl)propan-1-one, iondole-3-carbox aldehyde and caffeic acid inhibit the growth of cancer cells. TCW and its components exhibit anti-cancer effects. TCW inhibits the viability of HepG2 hepatocellular carcinoma cells by reversing the EMT process through inhibition of AKT and ERK signalling.

An efficient synthesis, characterization, and in silico studies of novel chromenes, thiophenes, pyrazolo[1,5-a]pyrimidines, and pyrimidines as potential antimicrobial and anticancer agents using the bio-buffer tris(hydroxymethyl)aminomethane (THAM)

Novel 2-imino-6-(aryldiazenyl)-2H-chromene-3-carboxamides 6a–e, 2-amino-4H-cyclopenta or benzo[b]thiophene-3-carboxamides 10a,b, 2,7-diaminopyrazolo[1,5-a]pyrimidine-6-carboxamides 13a–e, pyrimidine-5-carboxamides 14, 15 and 3-amino-1H-pyrazole-4-carboxamide 16 were synthesized from the reaction of 2-cyano-N-(1,3-dihydroxy-2-(hydroxyl-methyl) propan-2-yl) acetamide 2 with 4-arylazosalicylaldehydes 5a-e, cyclopentanone and/or cyclohexanone, guanidine derivatives and hydrazine hydrate, respectively. Some new compounds were evaluated for antibacterial activity in vitro, and exhibited good efficacy compared to gentamicin. Compound 4c showed greater activity against gram negative bacteria (Klebsiella pneumonia and Pseudomonas aeruginosa) than standard antibiotic. Compound 4c with two withdrawing groups also showed the higher activity (38.7 ± 0.6) against fungi (Candida albicans) than the Nystatin (20 ± 0.5). On the other hand, compounds 13a, 13c, and 13e have strong cytotoxic activity among the tested compounds in the three selected cancer cell lines (HePG2, MCF7 and Hela). Physicochemical characterization by Swiss ADME predication was also performed for some synthesized compounds exhibiting better biological and antimicrobial properties.

The Cytotoxic Effects of Turkish Bee Venom (Apis mellifera) on Selected Cancer Cell Lines

The Cytotoxic Effects of Turkish Bee Venom (Apis mellifera) on Selected Cancer Cell Lines

Ionic Liquids Immobilized Synthesis of New Xanthenes Derivatives and their Antiproliferative, Molecular Docking, and Morphological Studies.

Xanthenes and benzoxanthenesare are highly valuable compounds in organic chemistry and medicinal chemistry. Xanthene derivatives were found to have many applications in medicinal chemistry. This work aims to explore the synthesis of xanthene derivatives with various substituents and find the possibility of their uses as anticancer agents. The basic starting compound through this work was the 2,3-dihydro-1H-xanthen-1-one (3), which was synthesized from the reaction of cyclohexan-1,3-dione and 2-hydroxybenzaldehyde. Compound 3 was used to synthesize new thiophene, pyrimidine, isoxazole, and thiazole derivatives based on the xanthenes nucleus. Fused xanthene derivatives were obtained through further heterocyclization reactions. Multicomponent reactions expressed in this work were carried out in the presence of solvent catalyzed by Et3N and in solvent-free ionic liquid immobilized catalyst. Cytotoxicity for the newly synthesized compounds toward cancer cell lines was measured, and the results revealed that many compounds exhibited high inhibitions. The antiproliferative activity of the synthesized compounds was studied on six selected cancer cell lines. The nature of the heterocyclic ring and the variations of substituted groups showed a high effect through the inhibitions of the tested compound.

Molecular Hybrid Design, Synthesis, In Vitro Cytotoxicity, In Silico ADME and Molecular Docking Studies of New Benzoate Ester-Linked Arylsulfonyl Hydrazones.

In this paper, we present the synthesis and characterization of two known sulfonyl hydrazides (1 and 2) and their new sulfonyl hydrazone derivatives (9-20), as well as in vitro and in silico investigations of their cytotoxic properties against human lung (A549) and human breast (MCF-7) cancer cell lines. The target compounds (9-20) obtained in high yields were synthesized for the first time by a multi-step reaction, and their structures were confirmed by elemental analysis and various spectral techniques, including FT-IR, 1H-, and 13C-NMR. The antiproliferative profiles of these compounds (1, 2, and 9-20) in this study were determined at concentrations of 200, 100, 50, and 25 µM against selected cancer cell lines for 72 h using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) method. Except for compounds 1 and 2, other compounds (9-20) demonstrated cytotoxic activity at concentrations lower than 200 µM. The newly synthesized compounds (9-20) demonstrated antiproliferative activities at a micromolar level, with IC50 values in the range of 29.59-176.70 μM for the A549 cell line and 27.70-170.30 μM for the MCF-7 cell line. Among these compounds, compound 15 (IC50 = 29.59 μM against A549 cell line and IC50 = 27.70 μM against MCF-7 cell line) showed the highest cytotoxic activity against these two cancer cell lines compared to the reference drug cisplatin (IC50 = 22.42 μM against A549 cell line and IC50 = 18.01 μM against MCF-7 cell line). From docking simulations, to establish a plausible binding mode of compounds, we noticed that compound 15 demonstrated the highest affinity (-6.8508 kcal/mol) for estrogen receptor-beta (ERbeta) compared to others, suggesting promising ERbeta binding potential. Most compounds followed Lipinski's rule of five, with acceptable logP values. Additionally, all had mixed gastrointestinal absorption and limited blood-brain barrier permeability. Overall, our study proposed new sulfonyl hydrazones as a potential class of anticancer agents.

Evaluation of Anticancer Activity of Nucleoside-Nitric Oxide Photo-Donor Hybrids.

Herein, we report the synthesis of a new hybrid compound based on a 2'-deoxyuridine nucleoside conjugated with a NO photo-donor moiety (dU-t-NO) via CuAAC click chemistry. Hybrid dU-t-NO, as well as two previously reported 2'-deoxyadenosine based hybrids (dAdo-S-NO and dAdo-t-NO), were evaluated for their cytotoxic and cytostatic activities in selected cancer cell lines. dAdo-S-NO and dAdo-t-NO hybrids displayed higher activity with respect to dU-t-NO. All hybrids showed effective release of NO in the micromolar range. The photochemical behavior of the newly reported hybrid, dU-t-NO, was studied in the RKO colon carcinoma cell line, whereas the dAdo-t-NO hybrid was tested in both colon carcinoma RKO and hepatocarcinoma Hep 3B2.1-7 cell lines to evaluate the potential effect of NO released upon irradiation on cell viability. A customized irradiation apparatus for in vitro experiments was also designed.

Synthesis, Docking, and Machine Learning Studies of Some Novel Quinolinesulfonamides-Triazole Hybrids with Anticancer Activity.

In the presented work, a series of 22 hybrids of 8-quinolinesulfonamide and 1,4-disubstituted triazole with antiproliferative activity were designed and synthesised. The title compounds were designed using molecular modelling techniques. For this purpose, machine-learning, molecular docking, and molecular dynamics methods were used. Calculations of the pharmacokinetic parameters (connected with absorption, distribution, metabolism, excretion, and toxicity) of the hybrids were also performed. The new compounds were synthesised via a copper-catalysed azide-alkyne cycloaddition reaction (CuAAC). 8-N-Methyl-N-{[1-(7-chloroquinolin-4-yl)-1H-1,2,3-triazol-4-yl]methyl}quinolinesulfonamide was identified in in silico studies as a potential strong inhibitor of Rho-associated protein kinase and as a compound that has an appropriate pharmacokinetic profile. The results obtained from in vitro experiments confirm the cytotoxicity of derivative 9b in four selected cancer cell lines and the lack of cytotoxicity of this derivative towards normal cells. The results obtained from silico and in vitro experiments indicate that the introduction of another quinolinyl fragment into the inhibitor molecule may have a significant impact on increasing the level of cytotoxicity toward cancer cells and indicate a further direction for future research in order to find new substances suitable for clinical applications in cancer treatment.

Dendrimer Platforms for Targeted Doxorubicin Delivery-Physicochemical Properties in Context of Biological Responses.

The unique structure of G4.0 PAMAM dendrimers allows a drug to be enclosed in internal spaces or immobilized on the surface. In the conducted research, the conditions for the formation of the active G4.0 PAMAM complex with doxorubicin hydrochloride (DOX) were optimized. The physicochemical properties of the system were monitored using dynamic light scattering (DLS), circular dichroism (CD), and fluorescence spectroscopy. The Quartz Crystal Microbalance with Dissipation Monitoring (QCM-D) method was chosen to determine the preferential conditions for the complex formation. The highest binding efficiency of the drug to the cationic dendrimer was observed under basic conditions when the DOX molecule was deprotonated. The decrease in the zeta potential of the complex confirms that DOX immobilizes through electrostatic interaction with the carrier's surface amine groups. The binding constants were determined from the fluorescence quenching of the DOX molecule in the presence of G4.0 PAMAM. The two-fold way of binding doxorubicin in the structure of dendrimers was visible in the Isothermal calorimetry (ITC) isotherm. Fluorescence spectra and release curves identified the reversible binding of DOX to the nanocarrier. Among the selected cancer cells, the most promising anticancer activity of the G4.0-DOX complex was observed in A375 malignant melanoma cells. Moreover, the preferred intracellular location of the complexes concerning the free drug was found, which is essential from a therapeutic point of view.

Oleanolic Acid Dimers with Potential Application in Medicine-Design, Synthesis, Physico-Chemical Characteristics, Cytotoxic and Antioxidant Activity.

The present work aimed to obtain a set of oleanolic acid derivatives with a high level of cytotoxic and antioxidant activities and a low level of toxicity by applying an economical method. Oleanolic acid was alkylated with α,ω-dihalogenoalkane/α,ω-dihalogenoalkene to obtain 14 derivatives of dimer structure. All of the newly obtained compounds were subjected to QSAR computational analysis to evaluate the probability of the occurrence of different types of pharmacological activities depending on the structure of the analysed compound. All dimers were tested for cytotoxicity activity and antioxidant potential. The cytotoxicity was tested on the SKBR-3, SKOV-3, PC-3, and U-87 cancer cell lines with the application of the MTT assay. The HDF cell line was applied to evaluate the tested compounds' Selectivity Index. The antioxidant test was performed with a DPPH assay. Almost all triterpene dimers showed a high level of cytotoxic activity towards selected cancer cell lines, with an IC50 value below 10 µM. The synthesised derivatives of oleanolic acid exhibited varying degrees of antioxidant activity, surpassing that of the natural compound in several instances. Employing the DPPH assay, compounds 2a, 2b, and 2f emerged as promising candidates, demonstrating significantly higher Trolox equivalents and highlighting their potential for pharmaceutical and nutraceutical applications. Joining two oleanolic acid residues through their C-17 carboxyl group using α,ω-dihalogenoalkanes/α,ω-dihalogenoalkenes resulted in the synthesis of highly potent cytotoxic agents with favourable SIs and high levels of antioxidant activity.

Green synthesis of silver nanoparticle prepared with Ocimum species and assessment of anticancer potential

Silver nanoparticles (AgNPs) have gained much attention due to their unique physical, and chemical properties. Integration of phytochemicals in nanoformulation might have higher applicability in healthcare. Current work demonstrates the synthesis of green AgNPs with O. gratissimum (gr-AgNPs) O. tenuiflorum (te-AgNPs) and O. americanum (am-AgNPs) followed by an evaluation of their antimicrobial and anticancer properties. SEM analysis revealed spherical-shaped particles with average particle sizes of 69.0 ± 5 nm for te-AgNPs, 46.9 ± 9 nm for gr-AgNPs, and 58.5 ± 18.7 nm for am-AgNPs with a polydispersity index below 0.4. The synthesized am-AgNPs effectively inhibited Klebsiella pneumonia, Escherichia coli, Staphylococcus aureus, Aspergillus niger, and Candida albicans with 23 ± 1.58 mm, 20 ± 1.68 mm, 22 ± 1.80 mm, 26 ± 1.85 mm, and 22 ± 1.40 nm of zone of inhibition respectively. Synthesized AgNPs also induced apoptotic cell death in MCF-7 in concentration-dependent manner. IC50 values for am-AgNPs, te-AgNPs, and gr-AgNPs were 14.78 ± 0.89 µg, 18.04 ± 0.63 and 15.41 ± 0.37 µg respectively which suggested that am-AgNPs were the most effective against cancer. At higher dose size (20 µg) AgNPs were equally effective to commercial standard Doxorubicin (DOX). In comparison to te-AgNPs and gr-AgNPs, am-AgNPs have higher in vitro anticancer and antimicrobial effects. The work reported Ocimum americanum for its anticancer properties with chemical profile (GCMS) and compared it with earlier reported species. The activity against microbial pathogens and selected cancer cells clearly depicted that these species have distinct variations in activity. The results have also emphasized on higher potential of biogenic silver nanoparticles in healthcare but before formulation of commercial products, detailed analysis is required with human and animal models.

Anticancer efficacy triggered by synergistically modulating the homeostasis of anions and iron: Design, synthesis and biological evaluation of dual-functional squaramide-hydroxamic acid conjugates

Targeting the homeostasis of anions and iron has emerged as a promising therapeutic approach for the treatment of cancers. However, single-targeted agents often fall short of achieving optimal treatment efficacy. Herein we designed and synthesized a series of novel dual-functional squaramide-hydroxamic acid conjugates that are capable of synergistically modulating the homeostasis of anions and iron. Among them, compound 16 exhibited the most potent antiproliferative activity against a panel of selected cancer cell lines, and strong in vivo anti-tumor efficacy. This compound effectively elevated lysosomal pH through anion transport, and reduced the levels of intracellular iron. Compound 16 could disturb autophagy in A549 cells and trigger robust apoptosis. This compound caused cell cycle arrest at the G1/S phase, altered the mitochondrial function and elevated ROS levels. The present findings clearly demonstrated that synergistic modulation of anion and iron homeostasis has high potentials in the development of promising chemotherapeutic agents with dual action against cancers.

Design, Synthesis, and Cytotoxicity of 1H‐1,2,3‐Triazole Tethered‐Benzophenone Based Derivatives as Potent Candidate Anti‐Breast Cancer Agents

AbstractThe process of developing potential anticancer molecules comprises the cautious selection of core moiety and tethering pharmacologically active chemical functionalities to biologically active pharmacophores. Here, we report a library of ten 1H‐1,2,3‐triazole tethered‐benzophenone derivatives. Protein‐ligand interaction studies through molecular docking of our synthesised compounds were carried out with a novel epigenetic oncogene‐enhancer of zeste homolog2 (EZH2). Molecular docking studies disclosed that our synthesized compounds showed potent inhibition against EZH2 and in‐vitro validation assays through MTT assay, Trypan blue dye exclusion and in‐vitro methylation assays, these studies revealed the synthesized compounds‐9 c, 9 f, 9 i showed potent inhibition on EZH2. The anticipated anti‐cancer activity of library molecules was assessed in in‐vitro against breast and lung cancer (MCF7 and A549) cell lines, supported by in‐vitro assays and molecular docking binding studies. Among all ten compounds, 9 c, 9 f, 9 i are exerted potential anti‐cancer activity against the selected cancer cell line in in‐vitro. The results were supported by in‐silico docking studies. Further validation studies in in‐vivo models will pave a way for developing potent inhibitors against breast cancer and lung cancer.

Abstract 4488: Newly developed organoiridium(III) complexes containing N,P-ligands possess antiproliferative activity in selected cancer cell lines

Abstract In conventional cancer treatment, platinum-based cytostatics are considered as standard therapy; however, they possess severe side effects. This fact leads to a constant effort to develop new non-platinum metallodrugs with different mechanism of action (MoA). In our study we developed new half-sandwich organoiridium(III) complexes, of general formulas [Ir(η5-Cp*)Cl(LNP)]PF6 (1-3) and [Ir(η5-Cpph)Cl(LNP)]PF6 (4-6) involving three different N,P-donor phosphinoalkylamines (LNP), which we tested on 2D and 3D cancer models; HCp* = pentamethylcyclopentadiene, HCpph= (2,3,4,5-tetramethylcyclopenta-2,4-dien-1-yl)benzene. The most effective complexes 3 and 6 bearing 3-(diphenylphosphanyl)propan-1-amine had the highest cytotoxic effect against various cancer cell lines (THP-1, HeLa, SW982, A549, MOR) including a cisplatin-resistant lung carcinoma cell line (MOR/CPR) with IC50 values between 3.1 and 9.1 μM for specific cell lines. The cytotoxic effect was further demonstrated on 3D spheroids of lung cancer cells that revealed anti-cancer and anti-migration potential of complexes 3 and 6. Cell cycle and cell death analysis showed a different mechanism compared to the effect of cisplatin. Moreover, complex 3 did not decrease cell viability of non-cancerous cells (peripheral blood mononuclear cells and porcine chondrocytes) under 50% at a concentration of 20 µM. In addition, we report for the first time that organoiridium complexes showed high cytotoxic activity on cancer cell lines, including cisplatin-resistant cell line, with different MoA from cisplatin. They trigger expression of stress-related genes associated with oxidative stress, DNA damage, and endoplasmic reticulum stress and, moreover, complex 3 showed cytotoxic selectivity towards cancer cells. This work was supported by the Czech health research council of the Ministry of Health of the Czech Republic (AZV Project NU22-08-00236). Citation Format: Renata Hezova, Jan Hosek, Nicol Strakova, Pavlina Simeckova, Josef Masek, Simona Kajabova, Pavel Starcha. Newly developed organoiridium(III) complexes containing N,P-ligands possess antiproliferative activity in selected cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4488.

RNA-seq transcriptome and pathway analysis of the medicinal mushroom Lignosus tigris (Polyporaceae) offer insights into its bioactive compounds with anticancer and antioxidant potential

Ethnopharmacological relevanceMedicinal mushrooms belonging to the Lignosus spp., colloquially known as Tiger Milk mushrooms (TMMs), are used as traditional medicine by communities across various regions of China and Southeast Asia to enhance immunity and to treat various diseases. At present, three Lignosus species have been identified in Malaysia: L. rhinocerus, L. tigris, and L. cameronensis. Similarities in their macroscopic morphologies and the nearly indistinguishable appearance of their sclerotia often lead to interchangeability between them. Hence, substantiation of their traditional applications via identification of their individual bioactive properties is imperative in ensuring that they are safe for consumption. L. tigris was first identified in 2013. Thus far, studies on L. tigris cultivar sclerotia (Ligno TG-K) have shown that it possesses significant antioxidant activities and has greater antiproliferative action against selected cancer cells in vitro compared to its sister species, L. rhinocerus TM02®. Our previous genomics study also revealed significant genetic dissimilarities between them. Further omics investigations on Ligno TG-K hold immense potential in facilitating the identification of its bioactive compounds and their associated bioactivities. Aim of studyThe overall aim of this study was to investigate the gene expression profile of Ligno TG-K via de novo RNA-seq and pathway analysis. We also aimed to identify highly expressed genes encoding compounds that contribute to its cytotoxic and antioxidant properties, as well as perform a comparative transcriptomics analysis between Ligno TG-K and its sister species, L. rhinocerus TM02®. Materials and methodsTotal RNA from fresh 3-month-old cultivated L. tigris sclerotia (Ligno TG-K) was extracted and analyzed via de novo RNA sequencing. Expressed genes were analyzed using InterPro and NCBI-Nr databases for domain identification and homology search. Functional categorization based on gene functions and pathways was performed using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Clusters of Orthologous Genes (COG) databases. Selected genes were subsequently subjected to phylogenetic analysis. ResultsOur transcriptomics analysis of Ligno TG-K revealed that 68.06% of its genes are expressed in the sclerotium; 80.38% of these were coding transcripts. Our analysis identified highly expressed transcripts encoding proteins with prospective medicinal properties. These included serine proteases (FPKM = 7356.68), deoxyribonucleases (FPKM = 3777.98), lectins (FPKM = 3690.87), and fungal immunomodulatory proteins (FPKM = 2337.84), all of which have known associations with anticancer activities. Transcripts linked to proteins with antioxidant activities, such as superoxide dismutase (FPKM = 1161.69) and catalase (FPKM = 1905.83), were also highly expressed. Results of our sequence alignments revealed that these genes and their orthologs can be found in other mushrooms. They exhibit significant sequence similarities, suggesting possible parallels in their anticancer and antioxidant bioactivities. ConclusionThis study is the first to provide a reference transcriptome profile of genes expressed in the sclerotia of L. tigris. The current study also presents distinct COG profiles of highly expressed genes in Ligno TG-K and L. rhinocerus TM02®, highlighting that any distinctions uncovered may be attributed to their interspecies variations and inherent characteristics that are unique to each species. Our findings suggest that Ligno TG-K contains bioactive compounds with prospective medicinal properties that warrant further investigations. ClassificationSystems biology and omics

Determination of the optimal pH for doxorubicin encapsulation in polymeric micelles

HypothesisThe anticancer drug doxorubicin hydrochloride (DX) shows a high solubility in aqueous media thanks to the positive charge in the ammonium group. This feature, however, affects the drug encapsulation in the hydrophobic domains of polymeric micelles (PMs) used for the targeted delivery of the drug. At basic pH, DX deprotonates but also acquires a negative charge in the phenolic groups of the anthracycline structure. Both the efficiency and the rate of encapsulation will be increased by choosing an appropriate pH such that the drug molecule is in neutral form. ExperimentsAn optimal pH for the encapsulation of the DX in PMs based on commercial poloxamers and on the diblock copolymer methoxy-poly(ethylene glycol)17-b-poly(ε-caprolactone)9 was determined by fluorescence spectroscopy, following the time evolution of both the intensity ratio of the first and the second emission bands of DX and its fluorescence lifetime, both sensitive to the environment polarity. Intracellular delivery of PMs encapsulated drug was followed by Confocal Scanning Laser Microscopy (CSLM). Cell viability was assessed with the sulforhodamine B (SRB) assay. FindingsBy adjusting pH to 8.1 a high yield of incorporation of DX in the PMs was achieved coupled to an appreciable increase (one order of magnitude) in the drug encapsulation rate. In-vitro tests in selected cancer cell lines showed the slow release of the drug and a delay in the cytotoxic response in comparison to free DX as detected by CSLM and SRB assay. The proposed methodology paves the way for a greener, faster and more efficient encapsulation of DX in PMs.

New approaches for the synthesis of chromene and quinoline derivatives and their anti-proliferative, morphological studies

This work aimed to evaluate the anticancer potential of the novel 5,6,7,8-tetrahydro-4H-chromenes against selected six cancer cell lines together with the prostate cancer cell line PC-3. A novel series of substituted 5,6,7,8-tetrahydro-4H-chromenes were synthesized through feasible synthetic strategy. The synthetic schemes involve firstly the multi-component reactions of dimedone with the aromatic aldehydes and ethyl acetoacetate to produce the 5,6,7,8-tetrahydro-4H-chromenes derivatives. On the other hand, carrying the same reactions using NH4OAc produced the hexahydroquinoline compounds. Anti-proliferative evaluations and inhibitions for all synthesized compounds toward selected cancer cell lines were carried out and the results revealed that many of them exhibited high inhibitions. Morphology of A549 cell line by the effect of compounds 14f and 16c was performed.
 KEY WORDS: Anti-proliferative activity, Chromene derivatives, Morphology, Multi-component reactions
 Bull. Chem. Soc. Ethiop. 2024, 38(3), 775-798. 
 DOI: https://dx.doi.org/10.4314/bcse.v38i3.18