Antiproliferative Studies Research Articles

Exploring the Biological Potential of Hydroxytyrosol and Derivatives: Synthetic Strategies and Evaluation of Antiproliferative, Antioxidant, and Antimicrobial Activities.

Phenolic compounds found in Extra Virgin Olive Oil (EVOO) have been associated with various health benefits. Bioavailability studies indicate that the phase I and II metabolites of these phenolic compounds can be detected in human urine and plasma following EVOO consumption. To contribute to the understanding of the biological potential of these phenolic compounds and their metabolites, this study delves into the synthesis, stability, and biological activities of hydroxytyrosol (HT), tyrosol (Tyr), and homovanillic alcohol (HVA), as well as their glucuronide, sulfate, and acetylated metabolites. For the first time, an effective synthesis was developed to allow the selective obtention of 3'- and 4'-glucuronides, as well as sulfates of HT. HT and its acetylated derivative emerged as the most potent compounds across antioxidant assessments, antiproliferative studies against human colorectal adenocarcinoma cell lines, and antimicrobial assays.

Design and synthesis of aminothiazole-benzazole based amide: antiproliferative, antimigration activity and molecular docking studies

Design and synthesis of aminothiazole-benzazole based amide: antiproliferative, antimigration activity and molecular docking studies

Analysis of Volatile Compounds in Caulerpa lentillifera for Anti-Proliferative Studies in HEPG2 Liver Cancer Cells and in silico Comparison

Analysis of Volatile Compounds in Caulerpa lentillifera for Anti-Proliferative Studies in HEPG2 Liver Cancer Cells and in silico Comparison

Heteroleptic complexes of hydrazone Scaffold of picolinoyl N- oxide and 2,4 dihydroxy phenyl moieties; evaluation of antioxidant activity, DNA and protein binding properties and in vitro antiproliferation studies

The present study deals with design and synthesis of new mononuclear Cu(II), Co(II), Ni(II) and Zn(II) metal complexes of hydrazone of 2-(2-(2,4-dihydroxybenzylidene)hydrazinecarbonyl)pyridine-1-oxide (H2L), in a view to study their potential relevance for the biological applications. Structural aspects of the title compound (H2L) and metal complexes synthesized were evaluated by spectral and analytical methods viz. 1H NMR, 13C NMR, LC-MS, FT-IR, UV–Visible, SEM, EDX, Powder XRD, ESR, TGA and DTA. Ligational properties of H2L were explored by employing pH metric equilibrium studies for recognizing metal ion binding potential donor sites, and further HyperChem 7.5 software for computing properties of frontier molecular orbitals to ascertain orientation of highest occupied molecular orbitals from which presumably electrons are donated to metal ion in complex formation. The affinity of all title compounds to bind with CT-DNA and the type of interaction, therein have been studied by conducting UV–VIS absorption and fluorescence emission titrations. The protein-binding ability of all metal complexes with two serum proteins (BSA and HSA) were explored by absorption titrations, and further fluorescence titrations for BSA binding were also performed. Antioxidant activity of the title compounds was carried out by the method of free radical scavenging using spectrophotometric technique. Additionally, cytotoxicity of all metal complexes and ligand was measured by CTG cell proliferation assay after treating them with MDA-MB-231 and SKOV-3 cell lines. The cell cycle arrest and apoptosis assay in above cell lines after treatment with title compounds were also investigated by flow cytometry. In addition, molecular docking studies at target CDK2 protein inferred binding affinity of the title compounds through non covalent bonding interactions.

Design and Synthesis of New Aminothiazole‐Benzazole Based Ureas: Antiproliferative and Antimigration Activity Studies

AbstractIn our quest to develop new treatments for cancer, we synthesized and tested a series of urea‐functionalized aminothiazole‐benzazole analogs. Our primary focus was assessing their ability to inhibit the growth of breast cancer (MCF‐7) and lung adenocarcinoma (A549) cells. Using 1H NMR, 13C NMR spectra, and high resolution mass spectrometry (HRMS), we confirmed the chemical structures of these compounds. Among them, compound 8a demonstrated significant cytotoxicity against MCF‐7 cells, achieving an IC50 value of 9.6±0.6 μM. Similarly, compound 8e exhibited potent cytotoxicity against A549 cells, with an IC50 value of 9.2±1.1 μM. We further investigated the antimigration properties of all compounds that showed promising antiproliferative effects in both MCF‐7 and A549 cells. Additionally, we evaluated how these compounds impact key apoptosis‐related proteins: Caspase‐7, PARP‐1, BAX, and Bcl‐2. These proteins play crucial roles in the regulation of programmed cell death. Overall, our findings suggest that these urea‐functionalized aminothiazole‐benzazole analogs hold promise as potential anticancer agents, warranting further exploration into their mechanisms of action and therapeutic potential.

Molecular docking, ADMET, molecular dynamic simulation, synthesis, and preliminary antiproliferative study of 1,2,4- thiadiazole derivatives as possible histone deacetylase inhibitors

Molecular docking, ADMET, molecular dynamic simulation, synthesis, and preliminary antiproliferative study of 1,2,4- thiadiazole derivatives as possible histone deacetylase inhibitors

Fractionated Leaf Extracts of Ocimum gratissimum Inhibit the Proliferation and Induce Apoptosis of A549 Lung Adenocarcinoma Cells.

Previous in vitro studies in our laboratory demonstrated that ethyl acetate (P2) and water- soluble (PS/PT1) fractionated leaf extracts of Ocimum gratissimum inhibit the proliferation of prostate cancer cells. It has been reported that the crude aqueous extract induces apoptosis in lung adenocarcinoma cells; however, the efficacy of the fractionated extracts against these cells remains unclear. In the present study, we hypothesized that the ability of the fractionated extracts to inhibit proliferation and induce apoptosis is associated with the activation of pro-apoptotic proteins and induction of DNA condensation in A549 cells. Ocimum gratissimum was cultivated and its leaves were harvested, extracted, and fractionated to produce fractions P2 and PS/PT1. Anti-proliferative activity was assessed by direct cell count. For morphological characterization of apoptosis, 4',6-diamidino-2-phenylindole staining was employed. Western blot analysis was performed to evaluate the apoptotic activity of the fractionated extracts. In data generated from anti-proliferation studies, P2 significantly inhibited cell proliferation in a concentration-dependent manner; PS/PT1 elicited a decrease in the viability of cells, occurring at 500 µg/mL. 4',6-diamidino-2-phenylindole staining revealed the induction of apoptosis, as evidenced by the formation of apoptotic bodies. Increased levels of pro-apoptotic proteins were observed as the concentrations of the fractionated extracts increased. These results suggest that fractionated leaf extracts of Ocimum gratissimum inhibit the proliferation and induce apoptosis of A549 cells.

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.

Selective Antineoplastic Potential of Fractionated Caribbean Native Ganoderma Species Extracts on Triple-Negative Breast Cancer Cells.

Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by the absence of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor type 2 expression. It is known for its high malignancy, invasiveness, and propensity for metastasis, resulting in a poor prognosis due to the absence of beneficial therapeutic targets. Natural products derived from mushrooms have gained significant attention in neoplastic therapy due to their potential medicinal properties. The therapeutic potential of Ganoderma lucidum in breast cancer has been highlighted by our group, suggesting its use as an adjuvant treatment. The present study aims to assess the potential antineoplastic capacity of two Caribbean native Ganoderma species found in Puerto Rico, Ganoderma multiplicatum (G. multiplicatum) and Ganoderma martinicense (G. martinicense). Antiproliferative studies were conducted via cell viability assays after cultivation, harvesting, and fractionation of both species. The obtained results indicate that most of the fractions show some cytotoxicity against all cell lines, but 33% of the fractions (F1, F2, F7, F12) display selectivity towards cancer cell models. We demonstrate for the first time that native Ganoderma species can generate metabolites with anti-TNBC properties. Future avenues will focus on structure elucidation of the most active fractions of these Ganoderma extracts.

Click—ferrocenyl nucleotides—synthesis, electrochemistry, and antiproliferative activity studies

The copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction was used as a major tool for the synthesis of the artificial 5ʹ-T-click(Fc)-T-clickʹ(Fc)-A-3ʹtrinucleotide and its dinucleotide congeners. The synthesized nucleotides are redox-active. Their CVs in DMSO show irreversible redox processes, attributed to the Fe2+/Fe3+ oxidation–reduction of the ferrocenyl unit and the oxidation–reduction processes associated with the follow-up reaction products with the solvent. One of obtained dinucleotides was more active than cisplatin against lung cancer A549 cells. It also showed less toxic effect in non-tumoral human HEK293T cells than cisplatin drug.

Ag(I)-NHC/TBHP promoted aqueous synthesis of some new quinoline-aromatic amides; Anti-proliferative, Anti-VEGFR-2 and Molecular docking studies

Herein, we synthesized some new quinoline-aromatic amides (5a-5o) as VEGFR-2 targeting anti-proliferative agents via Ag(I)-NHC/TBHP promoted oxidative amidation of 4-(((quinolin-4-ylmethylene)amino)methyl)benzaldehyde (3) with several anilines (4a-4o) in benign water solvent. The anti-proliferative activity of derivatives (5a-5o) over two human cancer cell lines such as HepG-2 and MCF-7 revealed that majority of derivatives had selectively better activity against HepG2. In specific, compound 5o displayed higher activity against two cells than the Sorafenib with IC50 values <3 μM. Also, compound 5g showed almost similar activity (IC50; 2.5–4.2 μM) against two cell lines with the positive control (IC50; 2.2–3.4 μM). Active compounds 5d-5g 5i-5j, 5l and 5o found in anti-proliferative activity were then evaluated for their VEGFR-2 inhibitory activities and observed that compound 5o showed higher inhibition (IC50 = 33.5 nM) than the Sorafenib (IC50 = 35.6 nM), while, compound 5g had comparable inhibition (IC50 = 36.1 nM) with the positive control. In silico molecular docking studies revealed the important binding interactions of compounds 5e, 5g, 5l, 5o and Sorafenib with VEGFR-2 (pdb id 3VHE) and compounds 5e, 5g, 5l and 5o displayed encouraging binding energies and inhibition constants than the Sorafenib. Finally, the results of in silico SWISSADME showed that compounds 5e, 5g, 5l and 5o followed Lipinski, Ghose, Veber, Egan and Muegge rules without any deviation and showed high gastrointestinal (GI) absorption.

Anti-proliferative, Morphological and Molecular Docking Studies of New Thiophene Derivatives and their Strategy in Ionic Liquids Immobilized Reactions.

A number of research were conducted on the pyran and thiophene derivatives, which were attributed to have a wide range of biological activities, including anti-plasmodial, as well as acting as caspase, hepatitis C and cancer inhibitors. The multicomponent reactions of the 5-acetyl-2-amino-4-(phenylamino)-thiophene-3-carbonitrile produced biologically active target molecules like pyran and their fused derivatives. Comparison between regular catalytic multi-component reactions and solvent-free ionic liquids immobilized multicomponent was studied. The multicomponent reactions in this work were carried out not only under the reflux conditions using triethylamine as a catalyst but also in solvent-free ionic liquids immobilized magnetic nanoparticles (MNPs) catalysts. Through this work, thirty-one new compounds were synthesized and characterized and were evaluated toward the six cancer cell lines, namely A549, HT-29, MKN-45, U87MG, and SMMC-7721 and H460. The most active compounds were further screened toward seventeen cancer cell lines classified according to the disease. In addition, the effect of compound 11e on the A549 cell line was selected to make further morphological changes in the cell line. The Molecular docking studies of 11e and 11f were carried and promising results were obtained. The synthesis of heterocyclic compounds derived from thiophene derivatives has been receiving significant attention. After a detailed optimizing study, it has been found that the solvent-free ionic liquids immobilized multi-component syntheses afforded a high yield of compounds, opening a greener procedure for this synthetically relevant transformation. Many of the synthesized compounds can be considered anticancer agents, enhancing further studies.

In vitro and in vivo antiproliferative activity on lung cancer of two acylhydrazone based zinc(II) complexes

Two acylhydrazone based zinc(II) complexes [Zn(HL)2Cl2(CH3OH)2] (Zn1) and [ZnL(AC)]2 (Zn2) were synthesized from 3-(1-(salicyloylhydrazono)ethyl) pyridine (HL). Single crystal X-ray structure analyses showed that complexes Zn1 and Zn2 have a zero-dimensional monomer or dimer structure. Antiproliferative activity studies revealed that Zn1 and Zn2 are both more effective against A549 cells than cisplatin. The results of the reactive oxygen species (ROS) generation assay on A549 cells showed that both Zn1 and Zn2 induced apoptosis through ROS accumulation. The apoptosis-inducing and cell cycle arrest effects of Zn1 and Zn2 on A549 cells indicated that the antitumor effect was achieved through apoptosis induction and inhibition of DNA synthesis by blocking the G0/G1 phase of the cell cycle. What’s more, the results of wound-healing assay showed that Zn1 and Zn2 could inhibit the migration of A549 cells. Western blot analysis further demonstrated that Zn1 and Zn2 induced cell apoptosis through the mitochondrial pathway, in which process, the expression level of cytochrome C, cleaved-PARP, cleaved-caspase 3 and cleaved-caspase 9 proteins increased while pro-caspase 3 and pro-caspase 9 expression decreased. In vivo anticancer evaluation demonstrated that both Zn1 and Zn2 complexes effectively inhibited tumor growth without causing significant toxicity in systemic organs.

Synthesis and Characterization of Piano-Stool Ruthenium(II)-Arene Complexes of Isatin Schiff Bases: Cytotoxicity and DNA Intercalation.

A series of aryl-isatin Schiff base derivatives (3a-d) and their piano-stool ruthenium complexes (4a-d) were synthesized and characterized via 1H and 13C NMR and Fourier transform infrared (FTIR) spectroscopy. In addition, the purity of all of the compounds (3a-c and 4a-d) was determined via elemental analysis. Complex 4d was analyzed using X-ray crystallography. An in vitro antiproliferative study of the compounds (3a-c and 4a-d) against human hepatocellular carcinoma (HEPG2), human breast cancer (MCF-7), human prostate cancer (PC-3), and human embryonic kidney (HEK-293) cells exhibited their considerable antiproliferative activity. 4d exhibited effective cytotoxicity against HEPG2 and MCF-7. It displayed higher cytotoxicity than the reference metallo-drug cisplatin. Moreover, the stability of 4d was studied via 1H NMR spectroscopy, and the binding model between 4d and DNA was investigated via ultraviolet-visible spectroscopy. The lipophilicity of the synthesized complexes was determined using an extraction method.

Abstract 5746: Tris(4-methoxyphenyl) methanol conjugates of triptorelin as cell-penetrating anti-cancer prodrugs

Abstract Triptorelin® (TRP) is an anti-cancer drug used for the treatment of a wide range of hormone-responsive cancers, including prostate cancer. The increase in testosterone levels, known as the flare effect, is a major side effect of cancer chemotherapy when TRP is used in a combination regimen. Reports indicate that enhancing the cellular uptake and retention of TRP can improve its biological activity. In this study, TRP conjugates of tris(4-methoxyphenyl) methanol derivatives (TPMs) with optimized hydrophobicity were synthesized by reacting 2-substituted methoxybenzenes with 1,3,5-trioxane, followed by conjugation with TRP and sebacic acid to produce TRP-TPMs derivatives. The hydrophobicity of TRP was optimized by using the appropriate hydrophobic linker attached to the respective TPM to improve cellular uptake. The aim of the current studies was to evaluate the respective antiproliferative effects of the newly synthesized TRP-TPMs, physical mixtures of TPMs and TRP using different cell lines. Our hypothesis was that exposure of cells to TRP-TPMs derivatives can enhance the antiproliferative activities in cells in comparison to respective the physical mixtures and TRP. Antiproliferative studies in human acute lymphoblastic leukemia (CCRF-CEM), human ovarian adenocarcinoma (SK-OV-3), and mouse preadipocytes (3T3-L1) were carried out following exposure to the respective compounds. Our findings indicate that TRP-TPMs conjugates, at a concentration of 50 µM, significantly inhibited cell proliferation in CCRF-CEM, SK-OV-3, and 3T3-L1 cells by 21-37%, 24-73%, and 37-56%, respectively, following 72-hour incubation in comparison to the respective physical mixtures and TRP. Conjugation of TRP with the respective derivative of TPMs enhanced antiproliferative activities in all the cells (with no significant differences in cytotoxicity) compared to the physical mixtures of TPMs and TRP. The findings in the current studies suggest that TRP-TPMs can be used as potential prodrugs, to enhance the cells biological activity, and cellular uptake of TRP. Citation Format: Ryan Beni, William Boadi, Jawzah Alnakhli, Samiyah Alhamed. Tris(4-methoxyphenyl) methanol conjugates of triptorelin as cell-penetrating anti-cancer prodrugs [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 5746.

Anti-proliferative and morphological studies of 2-(benzo[d]thiazol-2-yl) derivatives together with their strategy in ionic liquids immobilized reactions

Anti-proliferative and morphological studies of 2-(benzo[d]thiazol-2-yl) derivatives together with their strategy in ionic liquids immobilized reactions

Cynara cardunculus L. var. scolymus L. Landrace "Carciofo Ortano" as a Source of Bioactive Compounds.

The preservation of agricultural biodiversity and socioeconomic development are relevant both to enhance domestic production and to support innovation. In the search for new biomolecules, we have focused on the "Carciofo Ortano" landrace, growth in the northern part of the Lazio region. Artichoke cultivation generates substantial by-products, including leaves, stems, and roots, which could serve as valuable sources of biomolecules and prebiotic dietary fiber. To valorize the leaf waste of the "Carciofo Ortano" landrace, a multidisciplinary approach was applied. Chemical analysis using HPLC-DAD identified mono-O- and di-O-caffeoylquinic acids and the sesquiterpene cynaropicrin in all artichoke leaf extracts. SPME-GC/MS analyses detected aliphatic alcohols in the fresh leaf samples. Antiproliferative and cytotoxic studies on cancer (SH-SY5Y, MCF-7, MDA) and normal (MCF-10A) human cell lines revealed that leaf extracts induced a selective dose and time-dependent biological effect. While showing slight activity against environmental bacterial strains, artichoke leaf extracts exhibited significant antifungal activity against the phytopathogenic fungus Alternaria alternata. Overall, the results highlight the potential of "Carciofo Ortano" cultivation by-products as a rich source of biomolecules with versatile applications in humans, animals, and the environment.

Synthesis, Characterization, Docking Studies and in vitro Response of New Camptothecin Derivatives towards Oral Squamous Cell Carcinoma

Evidence suggests heterocyclic rings as the essential component of various available chemotherapeutics. Present study was aimed to carry out the molecular docking, synthesis, characterization and response of new camptothecin derivatives (NCDs) towards OSCC cell lines. To achieve the aim of the study, new camptothecin derivatives were designed to perform molecular docking against the target protein Human DNA Topoisomerase-1 (1T8I). Molecules 2 and 3 with high docking scores were subjected to synthesis. In current investigation, NCDs were synthesized by cyclization of imino analogue (2) into a new azetidinone derivative (3) on treatment with triethylamine and chloroacetyl chloride. Synthesized NCDs were characterized using IR, NMR and mass analysis. The NCDs were further subjected to antiproliferation study using CAL-27 (OSCC), followed by in vitro DNA relaxation assay and cell cycle analysis. The results of the docking of CPT-11 against Human DNA Topoisomerase-1 Duplex (PDB ID: 1T8I) in present study revealed compound 2 and 3 exhibited high docking score among all camptothecin analogues. Present study successfully synthesized and elucidated the structures of NCD 2 and 3. The antiproliferation study results revealed that NCD 2 and NCD 3 offered an IC50 of 34.73 µg/mL and 62.5 µg/mL, respectively. The DNA relaxation assay exhibited the inhibition action of synthesized NCDs (IC50 concentration) against topoisomerase enzyme. Moreover, the cell cycle analysis revealed that both NCDs arrested cancer cells in ‘S’ phase. Though the present study highlights the potential of NCDs against oral squamous cell carcinoma, however, the present study also recommends that the synthesized NCDs must be further evaluated for preclinical and clinical significance.

Molecular modelling, Synthesis and Antiproliferative Evaluation of New Phenyldiazenyl)-Pyrazol Schiff Base Derivatives

Lung cancer is the most prevalent worldwide. In addition, it is also the most common cause of cancer-related deaths worldwide, with around 1.8 million new cases annually. With a 5-year survival rate of fewer than 20%. Cytotoxic medicines are commonly employed in cancer treatment. Although the medicine improves patients' quality of life, several disadvantages diminish its efficacy. This necessitates developing new effective strategies that target tumors with minimal adverse effects. This research aims to overcome these issues by synthesizing a new series of phenyldiazenyl)-pyrazol schiff base derivatives by utilizing the molecular docking (GOLD) suite program and the pharmacokinetic properties determination by utilizing (Swiss) ADME suite; The most appropriate-fitting compounds were subsequently produced and confirmed using spectrum analysis (FTIR, 1HNMR, and 13 CNMR). MTT in vitro assay were performed to assess of antiproliferative activities against A549 lung cancer cell lines. The antiproliferative study showed that compound 3a had an inhibitory concentration (IC50 of 17.37 µM) on lung cancer cells (A549), which was significantly higher inhibitory activity than Erlotinib (IC50 = 25.06 µM). While compound 3b had an inhibitory activity comparable to the reference drug's, The IC50 values for compounds 3c, 3d, and 3e were 47.48, 45.56, and 33.05 µM, respectively

Styryl carbamate backbones for the discovery of TME-disrupting agents

Twenty-one styryl carbamates have been designed, synthetized and characterized by their physical properties. Afterwards, their potential activity as tumor microenvironment disruptors has been evaluated. First, antiproliferative studies on tumor cell lines HT-29, A-549 and MCF-7 and on non-tumor cell line HEK-293 were carried out. Then, the antiproliferative activity of some selected compounds was evaluated on co-cultures of A-549 and immune cells, Jurkat T or monocytes THP-1. To determine their potential as oncoinflammation regulators, the secretion levels of IL-6, TNF-α and SAA-1 were, also, determined from these co-culture assays. Then, the effect on the expression levels of anticancer targets PD-L1 in both A-549 and monocytes THP-1 were established and, finally, the expression of CD80 and CD11b in THP-1. Compounds 9–13 bearing halophenyl carbamate units exhibited promising results as TME disruptors and inflammation regulators.