Potent Cytotoxic Activity Research Articles

Bioactive Naphtho-α-Pyranones from Two Endophytic Fungi of the Genus Polyphilus.

In the course of our survey to study the metabolic potential of two species of a new helotialean genus Polyphilus, namely P. frankenii and P. sieberi, their crude extracts were obtained using different cultivation techniques, which led to the isolation and characterization of two new naphtho-α-pyranone derivatives recognized as a monomer (1) and its 6,6'-homodimer (2) together with two known diketopiperazine congeners, outovirin B (3) and (3S,6S)-3,6-dibenzylpiperazine-2,5-dione (4). The structures of isolated compounds were determined based on extensive 1D and 2D NMR and HRESIMS. The absolute configuration of new naphtho-α-pyranones was determined using a comparison of their experimental ECD spectra with those of related structural analogues. 6,6'-binaphtho-α-pyranone talaroderxine C (2) exhibited potent cytotoxic activity against different mammalian cell lines with IC50 values in the low micromolar to nanomolar range. In addition, talaroderxine C unveiled stronger antimicrobial activity against Bacillus subtilis rather than Staphylococcus aureus with MIC values of 0.52 µg mL-1 (0.83 µM) compared to 66.6 µg mL-1 (105.70 µM), respectively.

Chemical Composition, Antimicrobial, Nitric Oxide Inhibition and Cytotoxic Activity of Essential Oils from Zanthoxylum acanthopodium DC. Leaves and Stems from Vietnam.

This study was aimed to investigate the chemical composition and biological activities of leaf and stem essential oils of Zanthoxylum acanthopodium DC. from Vietnam. Their chemical composition was analyzed by GC/MS. Antimicrobial activities were evaluated by microdilution broth assay. Anti-inflammatory activity was evaluated by the ability to inhibit nitric oxide production in macrophage cells. Cytotoxic activity was evaluated using the sulforhodamine B assay on three human cancer cell lines. Forty-four compounds were identified in the leaf oil, among which dehydroaromadendrane (23.4 %), (E)-carpacin (17.6 %), 2-tridecanone (12.2 %), and 9-methyl-2-decanone (11.8 %) were the most abundant. The stem oil contained fifty-five identified constituents, mainly γ-gurjunene (51.1 %) and butyl acetate (11.8 %). Both oils exhibited inhibitory effects on three bacterial strains, namely S. aureus, E. coli, P. aeruginosa and a fungal strain C. albican, while showed insignificant effects on B. subtilis, L. fermentum, and S. enterica. Both oils showed weak NO production inhibition in LPS-induced RAW264.7 cells, but exhibited potent cytotoxic activity against all three tested cell lines SK-LU-1, MCF-7, and HepG2 with the IC50 values ranging from 16.03±0.77 to 35.60±1.62 μg/mL. This is the first report on the antimicrobial, anti-inflammatory and cytotoxic activities of essential oils from the leaves and stems of Z. acanthopodium.

Synthesis of phthalazine-based derivatives as selective anti-breast cancer agents through EGFR-mediated apoptosis: in vitro and in silico studies

The parent 2-(4-benzyl-1-oxophthalazin-2(1H)-yl)-acetohydrazide (4) has twenty-nine compounds. The starting material for their corresponding mono, dipeptides and reactions with active methylene compounds were produced by chemoselective N-alkylation of 4-Benzyl-2H-phthalazin-1-one (2) with ethyl chloroacetate to afford (4-benzyl-1-oxo-1H-phthalazin-2-yl) methyl acetate (3). The ester 3 was hydrazinolyzed to give hydrazide 4, then azide 5 coupled with amino acid ester hydrochloride and/or amines to produce several monopeptides, then the methyl (2-(4-benzyl-1-oxophthalazin-2(1H)-yl) acetyl) glycinate (7a) was hydrazinolyzed to produce corresponding hydrazide 2-(4-benzyl-1-oxophthalazin-2(1H)-yl)-N-(2-hydrazineyl-2-oxo ethyl) acetamide (8a). The hydrazide 8a under azide coupling method was coupled with amino acid ester hydrochloride and/or amines to produce several dipeptides, and the hydrazide 8a was also condensed and/or cyclized with several carbonyl compounds. The cytotoxicity of the synthesized compounds was tested using MTT assay, as well as apoptosis-induction through EGFR inhibition. Compounds 11d, 12c and 12d exhibited potent cytotoxic activities with IC50 values of 0.92, 1.89 and 0.57 μM against MDA-MB-231 cells compared to Erlotinib (IC50 = 1.02 μM). Interestingly compound 12d exhibited promising potent EGFR inhibition with an IC50 value 21.4 nM compared to Erlotinib (IC50 = 80 nM). For apoptosis, compound 12d induced apoptosis in MDA-MB-231 cells by 64.4-fold (42.5% compared to 0.66 for the control); hence, this compound may serve as a potential target-oriented anti-breast cancer agent. These results agreed with the molecular docking studies that highlighted the binding disposition of compound 12d towards EGFR protein. Hence, compound 12d may serve as a potential and selective anti-breast cancer agent.

Evaluating biological ethnopharmaceutical activities of fruit and root extracts of Solanum incanum L.

Solanum incanum L. is a plant that belongs to the Solanaceae family, growing in tropical climates all over the world. Despite the extensive use of the root and fruit sap extract of S. incanum in the agricultural and ethnopharmaceutical industries in Africa, there is minimal scientific documentation regarding its pesticide bioactive phytochemicals and efficacy. The study investigated the photochemical content (phenolics, flavonoids, saponins, terpenoids and alkaloids) of the methanol, ethyl acetate and hexane crude extracts of the root and fruit of S. incanum. The potential radical scavenging, (antioxidant), cytotoxicity, and efficacy activities of all crude extracts were examined using the 1, 1-diphenyl-2picrylhydrazyl (DPPH), propidium iodide (PI) and aphid leaf dip (ALD) assays respectively. The total phenolic, alkaloid, flavonoid, terpenoid and saponin content were highest in the methanol fruit (MFE), (3.49 ± 1.16 mg GAE/100 mg), steroidal fruit (SAE), (0.14±0.06 mg ATP/100 mg, hexane fruit (HFE), 3.62±1.23 mg QCT/100 mg, hexane root (Hroot), (1.19±0.47 mg LIN/100 mg and saponin (3.74±1.17 mg/100 mg). The aqueous extract of the ethyl acetate fruit had the highest antioxidant activity with an IC50 of 35.53±0.53 μg·mL-1 (p < 0.05) The methanol fruit and steroidal alkaloid extracts exhibited potent cytotoxicity against Vero cells demonstrating the highest cell mortality rate of 98% and 70% respectively at 100 μg·mL-1. Melphalan which was used as a positive control had a mortality rate of 75% cell at 100 μg/mL concentration. The methanol fruit extract exhibited the highest efficacy against the cabbage aphids with an LD50 of 13.16±3.78 μg·mL-1 (p < 0.05). The results indicated that the fruit and root of S. incanum have a variety of phytochemicals that may be considered for use as antioxidants and/or pesticides. By exhibiting the most potent cytotoxic activity against Vero cells, S. incanum roots have the greatest potential for the discovery of cytotoxic compounds necessary to develop anticancer drugs. The extracts with high potent efficacy against cabbage aphids need to be investigated further as pesticides to benefit the disadvantaged communities in the Southern African region. Key words: Antioxidant, cytotoxicity, lethal dose, mortality rate, phytochemicals, quantitative analysis

Panapophenanthrin, a Rare Oligocyclic Diterpene from Panus strigellus.

During the course of our search for biologically active secondary metabolites from fungal cultures, a new oligocyclic diterpenoidal derivative, panapophenanthrin (1), was isolated from Panus strigellus. In addition, two known metabolites, panepophenanthrin (2) and dihydrohypnophilin (3), were also obtained. The chemical structures of the isolated compounds were elucidated based on extensive 1D and 2D NMR spectral analyses together with high-resolution electrospray ionization mass spectrometry (HR-ESI-MS). The absolute configuration was determined through TDDFT-ECD calculations. All of the compounds were assessed for their antimicrobial and cytotoxic activities. Compounds 1 and 3 showed moderate to weak activities in the performed antimicrobial assays, while compound 1 exhibited potent cytotoxic activity against the mammalian cell lines mouse fibroblast (L929) and human endocervical adenocarcinoma (KB3.1).

The second-generation curcumin analogue RL71 elicits G2/M cell cycle arrest and apoptosis in canine osteosarcoma cells.

Canine osteosarcoma is an aggressive cancer, comprising 85% of canine bone neoplasms. Current treatment practices of surgery and chemotherapy increase 1-year survival by only 45%. The curcumin analogue RL71, has demonstrated potent in vitro and in vivo efficacy in several models of human breast cancer through increased apoptosis and cell cycle arrest. Thus, the present study aimed to investigate efficacy of curcumin analogues in two canine osteosarcoma cell lines. Osteosarcoma cell viability was assessed using the sulforhodamine B assay and mechanisms of action were determined by analysing the levels of cell cycle and apoptotic regulatory proteins via Western blotting. Further evidence was obtained using flow cytometry to detect cell cycle distribution and the number of apoptotic cells. RL71 was the most potent curcumin analogue with EC50 values of 0.64 ± 0.04 and 0.38 ± 0.009 μM (n = 3) in D-17 (commercial) and Gracie canine osteosarcoma cells, respectively. RL71 significantly increased the ratio of cleaved-caspase 3 to pro-caspase 3 and the level of apoptotic cells at the 2× and 5× EC50 concentration (p < 0.001, n = 3). Furthermore, at the same concentration, RL71 significantly increased the number of cells in the G2/M phase. In conclusion, RL71 has potent cytotoxic activity in canine osteosarcoma cells triggering G2/M arrest and apoptosis at concentrations achievable in vivo. Future research should further investigate molecular mechanisms for these changes in other canine osteosarcoma cell lines prior to in vivo investigation.

S-531011, a Novel Anti-Human CCR8 Antibody, Induces Potent Antitumor Responses through Depletion of Tumor-Infiltrating CCR8-Expressing Regulatory T Cells.

Although regulatory T cells (Treg) are inhibitory immune cells that are essential for maintaining immune homeostasis, Tregs that infiltrate tumor tissue promote tumor growth by suppressing antitumor immunity. Selective reduction of tumor-infiltrating Tregs is, therefore, expected to activate antitumor immunity without affecting immune homeostasis. We previously reported that selective Treg depletion targeted by a C-C motif chemokine receptor 8 (CCR8) resulted in induction of strong antitumor immunity without any obvious autoimmunity in mouse models. Thus, herein, we developed a novel humanized anti-CCR8 monoclonal antibody, S-531011, aimed as a cancer immunotherapy strategy for patients with cancer. S-531011 exclusively recognized human CCR8 among all chemokine receptors and showed potent antibody-dependent cell-mediated cytotoxicity activity toward CCR8+ cells and neutralization activity against CCR8-mediated signaling. We observed that S-531011 reduced tumor-infiltrating CCR8+ Tregs and induced potent antitumor activity in a tumor-bearing human-CCR8 knock-in mouse model. Moreover, combination therapy with S-531011 and anti-mouse programmed cell death 1 (PD-1) antibody strongly suppressed tumor growth compared with anti-PD-1 antibody alone with no observable adverse effects. S-531011 also depleted human tumor-infiltrating Tregs, but not Tregs derived from human peripheral blood mononuclear cells. These results suggest that S-531011 is a promising drug for inducing antitumor immunity without severe side effects in the clinical setting.

Antiproliferative and cell cycle arrest potentials of 3-O-acetyl-11-keto-β-boswellic acid against MCF-7 cells in vitro

IntroductionCancer is a major issue in medical science with increasing death cases every year worldwide. Therefore, searching for alternatives and nonorthodox methods of treatments with high efficiency, selectivity and less toxicity is the main goal in fighting cancer. Acetyl-11-keto-β-boswellic acid (AKBA), is a derivative pentacyclic triterpenoid that exhibited various biological activities with potential anti-tumoral agents. In this research, AKBA was utilized to examine the potential cytotoxic activity against MCF-7 cells in vitro and monitor the cellular and morphological changes with a prospective impact on apoptosis induction. MethodsThe cytotoxic activity of AKBA was measured by 3(4,5dimethylthiazole- 2-yl)-2,5 diphyneltetrazolium bromide (MTT) assay. A dose-dependent inhibition in MCF-7 cell viability was detected. The clonogenicity of MCF-7 cells was significantly suppressed by AKBA increment in comparison with untreated cells. ResultMorphologically, exposure of MCF-7 cells to high AKBA concentrations caused changes in cell nuclear morphology which was indicated by increasing in nuclear size and cell permeability intensity. The mitochondrial membrane potential (ΔΨm) was reduced by increasing AKBA concentration with a significant release of cytochrome c. Acridine orange/ethidium bromide dual staining experiment confirmed that MCF-7 cells treated with AKBA (IC50 concentration) displayed a late stage of apoptosis indicated by intense and bright reddish colour. ConclusionA significant increase in reactive oxygen species formation was observed. Caspase 8 and caspase 9 activities were estimated and AKBA activated the production of caspase 8 and caspase 9 in a dose-dependent pattern. Finally, the cell phase distribution analysis was conducted, and flow cytometric analysis showed that AKBA at 200 μg mL-1 significantly arrest MCF-7 cells at the G1 phase and triggered apoptosis.

A Facile Synthesis of Flower-like Iron Oxide Nanoparticles and Its Efficacy Measurements for Antibacterial, Cytotoxicity and Antioxidant Activity.

The objective of this study was to investigate the rhombohedral-structured, flower-like iron oxide (Fe2O3) nanoparticles that were produced using a cost-effective and environmentally friendly coprecipitation process. The structural and morphological characteristics of the synthesized Fe2O3 nanoparticles were analyzed using XRD, UV-Vis, FTIR, SEM, EDX, TEM, and HR-TEM techniques. Furthermore, the cytotoxic effects of Fe2O3 nanoparticles on MCF-7 and HEK-293 cells were evaluated using in vitro cell viability assays, while the antibacterial activity of the nanoparticles against Gram-positive and Gram-negative bacteria (Staphylococcus aureus, Escherichia coli, and Klebsiella pneumoniae) was also tested. The results of our study demonstrated the potential cytotoxic activity of Fe2O3 nanoparticles toward MCF-7 and HEK-293 cell lines. The antioxidant potential of Fe2O3 nanoparticles was evidenced by the 1,1-diphenyl-2-picrylhydrazine (DPPH) and nitric oxide (NO) free radical scavenging assays. In addition, we suggested that Fe2O3 nanoparticles could be used in various antibacterial applications to prevent the spread of different bacterial strains. Based on these findings, we concluded that Fe2O3 nanoparticles have great potential for use in pharmaceutical and biological applications. The effective biocatalytic activity of Fe2O3 nanoparticles recommends its use as one of the best drug treatments for future views against cancer cells, and it is, therefore, recommended for both in vitro and in vivo in the biomedical field.

Biological activities of extracts and compounds from Thai Kae-Lae (Maclura cochinchinensis (Lour.) Corner)

Background and aimsThe purpose of this study was to investigate the biological properties of Kae-Lae (Maclura cochinchinensis (Lour.) Corner), a traditional medicinal plant used in Ayurvedic recipes in Thailand. To achieve this objective, heartwood samples were collected from 12 sources across Thailand. Fractional extracts (n-hexane, ethyl acetate, and ethanol) and the dominant compounds (morin, resveratrol, and quercetin) were examined for their abilities on cytotoxicity, antioxidant, anti-inflammation, and antileukaemic activity (Wilms’ tumour 1 protein was used as a well-known biomarker for leukaemic cell proliferation).MethodsThe study used MTT to assess cytotoxicity in leukaemic cells (K562, EoL-1, and KG-1a). Antioxidant activities were evaluated using ABTS, DPPH, and FRAP assays. The anti-inflammatory activity was investigated by detecting IL-2, TNF-α, and NO using appropriate detection kits. Wilms’ tumour 1 protein expression was measured by Western blotting to determine the anti-leukaemic activity. The inhibition of cell migration was also analyzed to confirm anticancer progression.ResultsAmong the tested extract fraction, ethyl acetate No. 001 displayed strong cytotoxicity specifically in EoL-1 cells, while n-hexane No. 008 demonstrated this effect in three cell lines. Resveratrol, on the other hand, displayed cytotoxicity in all the tested cells. Additionally, the three major compounds, morin, resveratrol, and quercetin, exhibited significant antioxidant and anti-inflammatory properties. In particular, resveratrol demonstrated a noteworthy decreased Wilms’ tumour 1 protein expression and a reduction in cell proliferation across all cells. Moreover, ethyl acetate No. 001, morin, and resveratrol effectively inhibited MCF-7 cell migration. None of these compounds showed any impact on red blood cell haemolysis.ConclusionBased on these findings, it can be concluded that Kae-Lae has promising chemotherapeutic potential against leukaemic cells, with fractional extracts (ethyl acetate and n-hexane) and resveratrol exhibiting the most potent cytotoxic, antioxidant, anti-inflammatory, and anti-cell migration activities.

Chemical composition and potential antileishmanial and cytotoxic activity of Duguetia stelechantha (Diels) R.E.Fr. essential oil

Duguetia stelechantha (Diels) R.E.Fr., popularly known as “ata brava” in Brazil, belongs to the Annonaceae family. Biologically active monoterpenes and sesquiterpenes identified in this genus and family, comprising a source of new drugs against several conditions, including leishmaniasis. In this context, the aim of the present study was to extract and chemically characterize the essential oil (EO-DU) obtained from D. stelechantha for the first time. The potential antileishmanial activity and in vitro cytotoxicity of an EO microemulsion (EO-ME) formulated with Tween 80 and Transcutol P surfactants were also evaluated. Duguetia stelechantha leaves were submitted to a hydrodistillation process and their chemical composition was determined by GC/MS. The major identified EO components were β-pinene (46.17 %), α-pinene (20.2 %), and spathulenol (6.68 %). A headspace characterization indicated major EO-DU compounds present in the prepared ME, confirming incorporation. The extracted EO was moderately active against Leishmania (L.) amazonensis promastigotes (IC50 =138.3 µg/mL), while the EO-ME was determined as active, inhibiting these parasites at a lower concentration (IC50 =4.47 µg/mL) compared to the EO-DU, indicating high selectivity against L. (L) amazonensis promastigotes. The major compound α-pinene was also tested, and presented IC50 = 64.78 µg/mL, considering it active against the tested parasites. Considering that D. stelechantha is an abundant species in the Brazilian Legal Amazon and that the antileishmanial potential of the extracted EO was enhanced by EM incorporation, this assessment provides relevant perspectives for future studies focused on the bioeconomy.

Effect of denaturing agents on a lectin isolated from marine sponge Axinella donnaniand its potential cytotoxic activity

Marine sponges are oldest metazoans which were found to have structural and biologically diverse lectins. A lectin isolated from marine sponge Axinella donnani (ADL) were evaluated for its stability against denaturing agents such as Urea, Thiourea and Guanidine hydrochloride. Urea and Thiourea decreases the stability of ADL in higher concentration (5 mM) while Guanidine hydrochloride does not show any activity. Finally, cyt otoxicity of ADL at different concentrations (0.25 500 mg/mL) was tested against MCF 7, A431 and HeLa cell lines by MTT assay. ADL exhibited potential cytotoxicity against these cell lines after 24 hours in a dose dependent manner. Thus, ADL could be a pot ent cytotoxic agent in clinical applications.

Anti-imflammatory and cancer cell inhibitory activities of isolated compounds from Aspidistra triradiata N. Vislobokov

Background: The genus Aspidistra possesses biological activities such as antivirus, anti-cancer, anti-inflammation. The study aimed to isolate compounds, evaluate the anti-inflammatory and cytotoxic activities of A. triradiata. Materials and methods: The whole plant of A. triradiata was isolated by chromatographic methods, determined the structure of isolated compounds by NMR spectrum. The anti-inflammatory effect was evaluated by the inhibitory activity against nitric oxide production. The cytotoxic activity was determined by SRB method. Results: Four compounds were isolated from A. triradiata, including (25R)-spirostane-1β,2β,3β,4β,5β,6β-hexol (1), (25R)-17α-hydroxy-spirost-5-en-3β-yl α-L-rhamnopyranosyl-(1→4)-α-L-rhamnopyranosyl-(1→4)-β-D-glucopyranoside (2), 2-methoxy pancracin (3) and 2-methyl-3-(4,5,7-trihydroxy-8-hydroxymethyltetrahydro-6H-4-pyranyl)-2-propenoic acid (4). Compounds 1, 2 and 4 exhibited moderate anti-inflammatory activities with IC50 values in the range of 59.84 - 98.96 µg/mL. Compound 3 exhibited potent cytotoxicity against the LU-1 and KB cancer cell lines with IC50 values in the range of 0.95 - 0.98 µg/mL, compound 1 showed moderate activity with IC50 values ranging from 47.55 to 72.32 µg/mL. Conclusion: The chemical composition of A. triradiata has been elucidated and some isolated compounds possessing potential anti-inflammatory and cytotoxic activities were discovered. Key words: anti-inflammatory, nitric oxide, cancer, Aspidistra triradiata, NMR spectra.

In Vitro Antiproliferative Efficacy, Antioxidant Activity and LC MS Based Metabolite Profiling of Premna Barbata Stem Bark

Premna barbata Wall. ex Schauer is used traditionally as folkloric medicines for the treatment of differentpathological conditions. The first reported constituent from the bark of the plant was an iridoid glycoside premnosidic acid having antioxidant activity. Other species of this genus i.e., Premna latifolia, Premna tomentosa has shown to have antioxidant and cytotoxic activities. Despite the ethnomedicinal uses, no scientific evidence in support of antitumor activity on the stem bark of Premna barbata is reported so far. Hence, the current work aims to assess anticancer potentiality of different extracts of P. barbata on various cancer cell lines. Different extracts i.e., Petroleum ether extract (PBPE), Chloroform extract (PBCE), Ethyl acetate extract (PBEE) and Alcoholic extract (PBAE) were prepared and on each extract in-vitro antiproliferative activity was performed by using SRB assay. The most potent extract i.e., PBEE was then evaluated for antioxidant activity. Qualitative phytochemical investigation of different extracts indicates the presence of proteins, carbohydrates, steroids/triterpenoids, alkaloids, glycosides, flavonoids, and phenolic constituents. Ethyl acetate extract of Premna barbata gives potent cytotoxic activity in all cancer cell lines but more selectively to human colon cancer cell line (COLO-205) with GI 50 44.6 μg/ml. The phenolic and flavonoid content in ethyl acetate extract was 3.43±0.09 mg GE/g and 4.28±0.18mg QE/g respectively. Nineteen compounds were observed in positive (+) ESI mode chromatograms when LC-MS analysis was carried out. The LC-MS analysis by positive ionization mode, the predicted compounds such as Geniposidic acid (synonym: Premnosidic acid) and Rutin were detected. The cytotoxicity observed on cancerous cell lines in our study may be due to the presence of observed compounds. So, it can be concluded that Premna barbata stembark has remarkable cytotoxic activity against different tumor cell lines but the effect is more on colon cell lines as compared to others.

Abstract ND06: AMG 305, a dual targeting BiTE®molecule with selective activity for solid tumors that co-express CDH3 and MSLN

Abstract T cell engager (TCE) molecules are a targeted immune therapy that redirect a patient’s T cells to kill tumor cells. While several TCE molecules have now advanced to approval, clinical development has been challenging, especially in the solid tumor setting. There are few solid tumor surface antigens that are tumor-specific, and antigens with even low levels of expression in normal tissue can be recognized by a TCE and result in on-target off-tumor toxicity. To overcome this challenge, we have developed AMG 305, a first-in-class, dual targeting BiTE® (bispecific T cell engager) molecule that requires binding to both P-cadherin (CDH3) and mesothelin (MSLN) for potent cytotoxic activity. Immunohistochemistry analysis shows that CDH3 and MSLN are co-expressed in multiple solid tumor types. In normal tissues, immunostaining shows fewer tissues have overlapping co-expression than expression of just one or the other target. AMG 305 relies on an avidity-based approach to engage T cells to preferentially kill CDH3+MSLN+ tumor cells, with limited activity against normal cells that express only one of the target antigens. In vitro, AMG 305 induces potent cytotoxicity against tumor cells co-expressing CDH3 and MSLN, with greatly attenuated activity against cells expressing only CDH3 or MSLN. In vivo, AMG 305 demonstrates dose-dependent antitumor activity in a CDH3+MSLN+ xenograft tumor model. AMG 305 was clinically well-tolerated in a nonclinical safety study in cynomolgus monkey. Data from IND-enabling preclinical studies support initiation of the first-in-human study of AMG 305 in CDH3+MSLN+ solid tumors in 2023. Citation Format: Elizabeth Pham, Petra Lutterbuese, Petra Deegen, Natalie Mariano, Katja Matthes, Joachim Wahl, Pamela Bogner, Joan Lane, Kristin Lewis Wilson, Rodolfo Yabut, Virginie Naegele, Ines Ullrich, Stephanie Everts, Markus Muenz, Thomas Boehm, Sabine Stienen, Angela Coxon, Peter Kufer, Tobias Raum, Julie M. Bailis. AMG 305, a dual targeting BiTE®molecule with selective activity for solid tumors that co-express CDH3 and MSLN [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr ND06.

Potential Cytotoxic Activity of Methanol Extract, Ethyl Acetate, and n-Hexane Fraction from Clitoria ternatea L. on MCF-7 Breast Cancer Cell Line and Molecular Docking Study to P53

Breast cancer is a condition where the cells in breast tissue lose control and multiply uncontrollably. In this study, MCF-7 breast cancer cells were tested for cytotoxic activity using the MTT assay and the active compound's interaction with the p53 protein was tested in silico. The most active fraction was found to be the ethyl acetate fraction, with an IC50 value of 1.730 μg/mL and a selectivity index of 2.485. However, the selectivity index was less than 3, and Vero cells showed changes in morphology with the addition of the ethyl acetate fraction. GC-MS was used to identify 19 compounds in the ethyl acetate fraction, and in-silico tests were performed on 5 potential anticancer compounds. Lipinski's Rule of Five test showed that only 3 of these compounds could undergo molecular docking. The results indicated that Anethole compound can interact with p53 protein, while Cinnamaldehyde, (E)- can interact with p21 protein.

Cytotoxic Metabolites from Calophyllum tacamahaca Willd.: Isolation and Detection through Feature-Based Molecular Networking

Isocaloteysmannic acid (1), a new chromanone, was isolated from the leaf extract of the medicinal species Calophyllum tacamahaca Willd. along with 13 known metabolites belonging to the families of biflavonoids (2), xanthones (3-5, 10), coumarins (6-8) and triterpenes (9, 11-14). The structure of the new compound was characterized based on nuclear magnetic resonance (NMR), high-resolution electrospray mass spectrometry (HRESIMS), ultraviolet (UV) and infrared (IR) data. Its absolute configuration was assigned through electronic circular dichroism (ECD) measurements. Compound (1) showed a moderate cytotoxicity against HepG2 and HT29 cell lines, with IC50 values of 19.65 and 25.68 µg/mL, respectively, according to the Red Dye method. Compounds 7, 8 and 10-13 exhibited a potent cytotoxic activity, with IC50 values ranging from 2.44 to 15.38 µg/mL, against one or both cell lines. A feature-based molecular networking (FBMN) approach led to the detection of a large amount of xanthones in the leaves extract, and particularly analogues of the cytotoxic isolated xanthone pyranojacareubin (10).

Synthesis and cytotoxic activities of selenium nanoparticles incorporated nano-chitosan

AbstractNew system compromising of chitosan nanoparticles encapsulated pre-synthesized selenium nanoparticles in the presence of 5-fluorouracil was successfully prepared and used for cancer antiproliferation. Selenium nanoparticles were synthesized using ascorbic acid as reducing agent under mild condition. Chitosan nanoparticles were prepared via ionic gelation technique using sodium tri-polyphosphate. Characterization of the prepared nanoparticles was carried out using FTIR, TEM, XRD, TGA and dynamic light scattering (DLS). The results displayed the formation of selenium nanoparticles with an average size 20 nm and chitosan nanoparticles with an average size 207 and 250 nm for neat nano-chitosan and chitosan incorporated 5-fluorouracil/selenium nanoparticles, respectively. The encapsulated nanocomposites were tested for treatment of cancer cell of human colorectal carcinoma (HCT-116), human liver carcinoma (HepG-2), and human breast adenocarcinoma MCF-7. The results indicated the potent cytotoxic activities of all nanocomposite toward the tested cells with enhanced anticancer activity rather than the single drug or neat selenium nanoparticle. All composites were tested against non-tumor fibroblast-derived cell line (BJ) and demonstrated very low cytotoxicity.

Design and synthesis of 2,6-dihalogenated stilbene derivatives as potential anti-inflammatory and antitumor agents

In present study, three series of 2,6-dihalogenated stilbene derivatives were designed, synthesized, and assayed for anti-inflammatory and cytotoxic activities. All 62 compounds showed potential anti-inflammatory activity in zebrafish model in vivo, and the installation of halogens and pyridines led to significant improved effects. Among them, DHS2u and DHS3u with the substitution of pyridine showed more higher effects than positive drug indomethacin at 20 μM with inhibitory rate of 94.59% and 90.54%, respectively. Besides, DHS3g bearing 2,5-dimethoxy exhibited potent cytotoxic activity against K562 cells with IC50 values 3.12 μM along with a suitable selectivity on normal cell viability. These results showed that 2,6-dihalogenated stilbenes could serve as a bright starting point for the further development as anti-inflammatory and antitumor agents.

Abstract 6244: Design, synthesis, and structure-activity relationships of substituted pyrido[3,2-d]pyrimidines as microtubule targeting agents and anti-cancer agents

Abstract Microtubules (MTs) are composed of αβ-tubulin heterodimers and are essential components of the cellular cytoskeleton involved in critical cellular functions, including mitosis, cell migration and signaling, intracellular trafficking, and angiogenesis. Microtubule targeting agents (MTAs) are highly successful chemotherapeutic agents because they target MT dynamics and interfere with MT-dependent cellular processes. The clinical efficacy of MTAs is limited by multidrug resistance due to expression of the P-glycoprotein (Pgp) drug efflux pump or increased expression of βIII-tubulin. This necessitates the development of novel MTAs effective against cell lines expressing these forms of drug resistance, which could offer potential advantages in patients who fail to respond to current MTAs, such as paclitaxel. Previously, we reported colchicine site (CS) binding compound 1 with a pyrido[3,2-d]pyrimidine scaffold and a 2-H substitution and N4-4’-methoxyaniline substitution inhibited colchicine binding and tubulin assembly (87% inhibition at 5 µM and IC50 = 1.3 µM, respectively). Compounds 2-9 were designed with a 2-CH3 substitution to evaluate the structure-activity relationships at the 4-position by using conformational restriction and isosteric replacements. Compounds 2-9 were synthesized, and the biological evaluation showed that compounds 2-9 inhibited tubulin assembly (7, IC50 = 0.72 μM) and binding of colchicine to tubulin (7, 97% inhibition at 5 µM, 81% at 0.5 µM). Compound 7 was found to be highly potent in the MCF-7 breast cancer cell line with an IC50 of 2.5 nM which was ~3.5-fold better than combretastatin-A4 (CA4). Compound 7 inhibited the growth of the human ovarian cancer cell line OVCAR-8 with an IC50 = 3.0 nM. For the Pgp overexpressing cell line NCI/ADR-RES, 7 was equally potent (IC50 = 3.0 nM), whereas paclitaxel was almost inactive (IC50 = 1,500 nM). Thus, we have identified 2-CH3 substituted pyrido[3,2-d]pyrimidines as a novel structural scaffold for inhibition of tubulin assembly and colchicine binding that have potent cytotoxic activity against the breast cancer cell line MCF-7 and against both the parental ovarian cancer cell line OVCAR-8 and its derivative Pgp overexpressing cell line NCI/ADR-RES. These compounds thus merit further study as potential cancer chemotherapeutic agents. Citation Format: Yesha Vijaykumar Shah, Ruoli Bai, Ernest Hamel, Aleem Gangjee. Design, synthesis, and structure-activity relationships of substituted pyrido[3,2-d]pyrimidines as microtubule targeting agents and anti-cancer agents. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6244.