Tested Cancer Cell Research Articles

Madecassic acid analogues with a five-membered A-ring and their cytotoxic activity

The structural modification of madecassic acid focused on the contraction of the six-membered A-ring to a five-membered ring, combined with the dehydration of 6-OH to form a new double bond and formation of the esterification or amidation at C-28. The synthesised structures were identified based on the analysis of their NMR and EIS-MS data. Eighteen new madecassic acid analogues were tested in vitro for their cytotoxicity against three cancer cell lines, including human mouth carcinoma (KB), human hepatocellular carcinoma (HepG2), and human lung carcinoma (A549) using the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay. Among them, compounds 5 and 12 exhibited potent and selective cytotoxic activity in KB and HepG2 cell lines, with IC50 values ranging from 3.57 to 6.32 µM. The results also indicated that analogues with a 5-membered A-ring containing an α,β-unsaturated aldehyde esterified at C-23 showed a decrease in their cytotoxic activity compared to precursors in the tested cancer cells.

New vatalanib analogs: Design, synthesis, in silico study and biological evaluation for anticancer activity

In our attempts to improve pharmacokinetics and pharmacodynamics characters of vatalanib, four strategies of the drug design were applied to design and synthesis new quinoxaline based vatalanib analogs. Antiproliferative activities of the synthesized compounds were investigated against two tumor cell lines (HepG2 and HCT‐116) using vatalanib as a positive control. The new candidates showed promising anticancer activity against two tested cancer cell lines with IC50 values ranging from 6.04 ± 0.19 to 100.15 ± 3.26 µM, in particular compounds 11b and 11c which were more potent than vatalanib. The most potent was the 4-benzoylquinoxaline derivative 11b (IC50 = 6.04 ± 0.19 µM and 15.58 ± 0.58 µM) compared to vatalanib (IC50 of 25.27 ± 0.84 µM and 43.91 ± 1.64 µM) against HepG2 and HCT116, respectively. The selectivity indices of 11b were found to be approximately 14 and 5 towards HepG2 and HCT116, respectively. While vatalanib showed selectivity indices of about 5 and 3 towards HepG2 and HCT116, respectively. The most promising compound 11b was further investigated in HepG‐2 cells for its apoptotic effect, cell cycle arrest and in vitro VEGFR-2 inhibitory activity as the main mechanisms of cell death. It was found that 11b can induce apoptosis and arrest the cell cycle at the at G1 phase in addition to, compound 11b showed effective inhibition of VEGFR-2 with IC50 of 0.918 ± 0.033 µM compared to vatalanib (IC50 of 0.265 ± 0.009 µM). Deep computational studies were created for the designed compounds including molecular docking, physicochemical properties, profiling pharmacokinetics, ADMET studies, and toxicity predictions to evaluate the prospective drug candidates. The results of the docking study were consistent with biological testing, furthermore, in silico ADMET study revealed the superior pharmacokinetics characters of the new candidates over vatalanib. So, the current work suggests that the 4-benzoylquinoxaline-1-yl-acetamide derivatives, especially 11b, can serve as lead molecules for development of new effective anticancer drugs.

Synthesis of bis-Chalcones Based on Green Chemistry Strategies and Their Cytotoxicity Toward Human MeWo and A375 Melanoma Cell Lines.

Chalcone is an aromatic ketone that forms the central core of many important biological compounds. Chalcone derivatives show various biological activities, especially anti-inflammatory, antibacterial, antioxidant, and anticancer activities, and also inhibit melanoma cell growth. In this study, we synthesized chalcone compounds with bis-chalcone's chemical structure under microwave (MW) and microwave-ultrasound (MW-US) conditions and compared them to chalcones produced using the classical synthesis method. All bis-chalcones were synthesized with terephthalaldehyde and an appropriate aromatic ketone as substrates in Claisen-Schmidt condensation. All the obtained compounds were tested regarding their roles as potential anticancer agents. The cytotoxic effect of the bis-chalcones against human MeWo and A375 melanoma cell lines was investigated through colorimetric MTT and SRB assays. The data were analyzed statistically. In the case of the synthesis of bis-chalcones, it was determined that the use of green conditions supported by the MW or MW-US factors led to an increase in the yield of the final products and a reduction in the reaction time compared to the classic method. The biological results showed the high cytotoxic effect of bis-chalcones. The present results show the compounds' high antiproliferative and cytotoxic potential, especially for the two selected bis-chalcone derivatives (3b and 3c), in particular, at concentrations of 50 μM-200 μM at 24, 48 h, and 72 h of incubation. The use of MW and US for the synthesis of bis-chalcones significantly improved the process compared to the classical method. The derivatives containing two hydroxy and two methoxy groups were the most effective against the tested cancer cells.

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.

Ursolic Acid Conjugates: A New Frontier in Anticancer Drug Development.

New Ursolic Acid (UA) conjugates were synthesized using optimized synthetic protocols through the molecular hybridization approach at C-3 and C-28. This resulted in the targeted molecules being produced in good yields. Some of the synthesized conjugates showed significantly relevant bioactivity against mammalian cells and in animal models of cancers. Selected UA conjugates were tested against bladder and breast cancer cell lines. The conjugates showed moderate to significantly enhanced antiproliferative activities against Triple Negative Breast Cancer (TNBC; MDA-MB 231), which is an aggressive tumor making up about 10-15 % of all breast cancers and bladder (T24 and 5637) cancer cell lines. These properties were superior to the parent UA. Among all the synthesized compounds, 18 c and 18 d have exhibited promising antiproliferative and cytotoxic properties against all tested cancer cell lines. However, 18 d has proved to be exceptionally selective for cancer cell lines, showing more cytotoxicity towards them than normal epithelial cells (MCF-12A). Compound 18 d has demonstrated cytotoxicity against tumor cells, including those intrinsically resistant to chemotherapy drugs such as 2-difluoro-deoxy cytidine (Gemcitabine). The activity of the UA conjugates on tumor cells was mediated by multiple cytotoxic mechanisms, including drug-induced cytotoxic autophagy and programmed cell death, indicating a novel possibility of combination therapy.

Combining lavendustin C and 5-arylidenethiazolin-4-one-based pharmacophores toward multitarget anticancer hybrids

Lavendustin C, a natural-product derived anticancer lead compound, was modified at its carboxylic group by esterification or amidation (compounds 6–10) and at its amino group by introducing 5-arylidenethiazolin-4-ones (14a–c to 17a–c, 18a and 18b). Two strategies were used to combine these moieties and to optimize the yield. These new compounds were evaluated for their antiproliferative activities against a panel of nine cancer cell lines. The results clearly show that 5-arylidenethiazolin-4-one moiety contributes substantially to the activity. Also, methyl esters are more potent than amides, while N-ethylamides are the most potent among amides. 14b showed the highest potency against all tested cancer cell lines with IC50 1.4–2.5 µM, while against normal cell line IC50 > 50 µM. It showed arrest of HeLa cells at G0/G1, S phases and reduction of the percent of cells in G2/M. Moreover, 14b triggered death of HeLa cancer cells via apoptosis induction. EGFR inhibitory potency of 14b was found to be comparable to that of erlotinib. Computational docking and in silico pharmacokinetic studies were performed and discussed. In conclusion, 14b might serve as a multitarget lead compound for further development of anticancer agents.

New naphtho[2,1-b]furan-2,5-dione and isocoumarin derivatives from bambusicolous fungus Gelatinomyces siamensis

Two new compounds, 6-hydroxy-1-(4-hydroxyphenyl)naphtho[2,1-b]furan-2,5-dion (1) and 3-methyl-6-α-L-rhamnopyranosyl-2H-chromen-2-one (2), along with three known compounds (3-5) were isolated from the rare bambusicolous fungus Gelatinomyces siamensis. The structures were elucidated through the analysis of IR, NMR and HRESIMS spectrographic data. Compound 1 exhibited cytotoxicity against HeLa, HT29, MCF-7 and PC-3 cells, but was not toxic against normal Vero cells. The most abundant metabolite, oosporein (5), exhibited significant cytotoxic effects against all tested cancer cells.

A Dual Action Platinum(IV) Complex with Self-assembly Property Inhibits Prostate Cancer through Mitochondrial Stress Pathway.

Platinum(IV) prodrugs are highly promising anticancer agents because they can selectively target tumors and minimize the adverse effects associated with their PtII congeners. In this study, we synthesized dual action PtIV complexes by linking oxoplatin with lithocholic acid. The synthesized compounds, designated as PL-I, PL-II, and PL-III, can spontaneously self-assemble in water, resulting in the formation of spherical shape nanoparticles. Among the developed complexes, PL-III appeared to be the most potent compound against all the tested cancer cell lines, with 10 fold higher cytotoxicity compared to cisplatin in PC3 cells. The complex arrests the cell cycle in the S and G2 phases and induces DNA damage. Additional mechanistic investigations demonstrate that PL-III predominantly localizes within the mitochondria and cytoplasm. Consequently, PL-III disrupts mitochondrial membrane potential, increases ROS production, and perturbs mitochondrial bioenergetics in PC3 cells. The complex induces apoptosis through the mitochondrial pathway by upregulating pro-apoptotic protein expression and downregulating anti-apoptotic protein expression from the BCl-2 protein family. These results demonstrate that higher cellular uptake and reduction of PL-III by biological reductants in PC3 cells resulted in a synergistic effect of lithocholic acid and cisplatin, which can be easily observed due to its unique cytotoxic mechanism. This further underscores the significance of dual-action PtIV complexes in enhancing the efficacy of cancer therapy.

Wee1 inhibitor optimization through deep-learning-driven decision making

Deep learning has gained increasing attention in recent years, yielding promising results in hit screening and molecular optimization. Herein, we employed an efficient strategy based on multiple deep learning techniques to optimize Wee1 inhibitors, which involves activity interpretation, scaffold-based molecular generation, and activity prediction. Starting from our in-house Wee1 inhibitor GLX0198 (IC50 = 157.9 nM), we obtained three optimized compounds (IC50 = 13.5 nM, 33.7 nM, and 47.1 nM) out of five picked molecules. Further minor modifications on these compounds led to the identification of potent Wee1 inhibitors with desirable inhibitory effects on multiple cancer cell lines. Notably, the best compound 13 exhibited superior cancer cell inhibition, with IC50 values below 100 nM in all tested cancer cells. These results suggest that deep learning can greatly facilitate decision-making at the stage of molecular optimization.

Sesquiterpene Coumarins, Chromones, and Acetophenone Derivatives with Selective Cytotoxicities from the Roots of Ferula caspica M. Bieb. (Apiaceae).

In search of selective cytotoxic compounds from Ferula species as potential leads for the treatment of various cancer diseases, a bioactivity-guided isolation study was performed on the roots of Ferula caspica M. Bieb. COLO 205 (colon), K-562 (leukemia), and MCF-7 (breast) cancer cell lines were used to monitor the cytotoxic activity of column fractions and determine the IC50 value of the active compounds. In addition to the seven known (5-11) compounds, four previously unknown compounds: kayserin A (1), kayserin B (2), 8'-epi-kayserin B angelate (3), and 3-epi-ferulin D (4) were isolated from the dichloromethane extract of the roots of F. caspica. Structure elucidation of the isolated compounds was carried out by extensive spectroscopic analyses such as 1D- and 2D-NMR spectroscopy, High-Resolution Mass Spectroscopy (HRMS), IR spectroscopy, and UV spectroscopy. Although all of the isolated compounds showed various degrees of cytotoxic activity on COLO 205, K-562, and MCF-7 cancer cell lines, the most potent compounds were identified in the following order: 1-Hydroxy-1-(1'-farnesyl)-4,6-dihydroxyacetophenone (HFDHAP, 11), 3-epi-ferulin D (3EFD, 4), and 7-desmethylferulin D (7DMFD, 6). The cytotoxic activities of all three compounds were more potent than that of the reference compound cisplatin (Cis) against all tested cancer cell lines. Still, only HFDHAP (11) was more potent than the reference compound doxorubicin (Dox) against the MCF-7 cancer cell line. The mechanism of action of these three compounds was investigated on the COLO 205 cell line. The results indicated that compounds 4, 6, and 11 trigger caspase-3/8/9 activation and suppress the anti-apoptotic protein, Bcl-xL. Molecular docking studies confirmed the interactions of the three cytotoxic molecules with the active site of the Bcl-xL protein.

Potent drug candidature of copper-coordinated metallodrug: Experimental study, spectroscopic insights, anticancer activity, apoptosis analysis, cell cycle, theoretical calculations, and molecular docking studies

The biological properties of the thiocarbohydrazone, pyrazole, and copper ions are well-known, thus copper complexes incorporated with pyrazole-thiocarbohydrazone hybrid ligands have potential medical applications. In this study, copper complex [Cu(PMT)2(Cl)2] derived from pyrazole-thiocarbohydrazone hybrid chelator (PMT) was successfully synthesized. With the help of several fundamental techniques, including elemental and thermal studies, molar conductivity, and magnetic moment measurements, the structure and coordination behavior of the PMT chelator and its Cu(PMT) nanocomplex were examined. In addition, records of ESR, FT-IR, and UV–Vis spectroscopy were obtained. The powder X-ray diffraction data has identified significant information about the crystalline forms of the Cu(PMT) chelate. The findings demonstrated that producing octahedral, mono-species of chelate and chelation occurs through the N, and S donor sites of neutral chelator. The cytotoxicity assessment of the PMT and its Cu(PMT) chelate was further evaluated against human ovary cancer cells (SKOV3), human breast cancer cells (MCF-7), and human colon cancer cells (HCT116) by using SRB assay. The Cu(PMT) chelate displayed promising results regarding standard doxorubicin. Furthermore, the apoptosis analysis of the Cu(PMT) chelate strongly induced the late-apoptotic cell population against the tested cancer cells. Also, the cell-cycle distribution of the Cu(PMT) complex arrests cell proliferation at the G1, S, and G2 phases. PMT and its Cu(PMT) were also studied using computational simulations and the DFT approach. Different chemical quantum parameters were determined from the optimized structure. The interaction between copper chelate and the CDK8 kinase active site was examined using docking studies.

Design, Synthesis and In-Vitro Antimicrobial and Cytotoxic Activity Screening of 5-Carboxamide Substituted 3, 4-Dihydropyrimidine-2 (1H) Ones

This paper describes the synthesis and in vitro biological evaluation of new compounds designated as 5(a-h) and 8(a-f). These compounds were synthesized by the reaction of thiazole derivative (3) or thiadiazole derivative (7) with urea and various aromatic aldehydes 4(a-h) in ethanol. The structures of the synthesized compounds were checked by IR,1H,13C NMR, and Mass spectroscopy. The antibacterial and antifungal activities of the compounds were evaluated against Escherichia coli (Gram-negative), Staphylococcus aureus (Gram-positive), and Candida albicans (fungus) using agar well diffusion, minimum inhibitory concentration (MIC), and minimum bactericidal/fungicidal concentration methods. The cytotoxic activities of these compounds against HT-29 and A-549 cancer cell lines were assessed in vitro by the MTT method. Our studies showed compounds 8c and 8f to have the most expressed antibacterial activity against S. aureus, while compounds 8c and 8d were the most potent against E. coli. Compounds 5h and 8e showed the highest antifungal activity against C. albicans, and compound 5f showed the most potent activity against the tested cancer cell lines.

Antibacterial and Anticancer Properties of Endophenazines from Streptomyces prasinus ZO16, an Endophyte in Zingiber officinale Rosc.

<b>Background and Objective:</b> This study investigated a bacterial strain, ZO16, isolated from ginger (<i>Zingiber officinale</i>) roots. Analysis of its 16S ribosomal DNA (rDNA), along with chemical and physical properties, revealed it to be <i>Streptomyces prasinus</i>. This study aimed to isolate and characterize the main bioactive compounds from ZO16, evaluating their antibacterial and anticancer properties. <b>Materials and Methods:</b> Techniques like column chromatography and thin-layer chromatography (TLC) were used to purify the key compounds from ZO16's culture extract. Nuclear Magnetic Resonance (NMR) spectroscopy and mass spectrometry were utilized to confirm the identities of the purified compounds as endophenazine A (compound 1) and endophenazine B (compound 2). The antibacterial and anticancer properties of these compounds were then evaluated. <b>Results:</b> The isolated compounds displayed antibacterial activity against <i>Staphylococcus aureus</i> ATCC 25923 and Methicillin-Resistant <i>Staphylococcus aureus</i> (MRSA). The minimum inhibitory concentration (MIC) of the isolated compounds against bacteria ranged from 8 to 32 μg/mL, while the minimum bactericidal concentration (MBC) was between 32 and 128 μg/mL. These compounds exhibited effectiveness against tested cancer cells with IC<sub>50</sub> values ranging from 30.40 to 32.51 μg/mL for cervical cancer (HeLa), 78.32 to 86.45 μg/mL for liver cancer (HepG2) and 23.41 to 28.26 μg/mL for breast cancer (MDA-MB-231) cells. However, these compounds also showed moderate toxicity towards non-cancerous Vero cells (IC<sub>50</sub> = 317.44-328.63 μg/mL). <b>Conclusion:</b> The findings of this study suggest that <i>Streptomyces prasinus</i> strain ZO16 produces compounds with antibacterial and anticancer properties. Further investigation of these compounds has the potential to contribute to the development of improved methods for controlling and treating bacterial infections and some cancers.

Bone sialoprotein stimulates cancer cell adhesion through the RGD motif and the αvβ3 and αvβ5 integrin receptors.

Being implicated in bone metastasis development, bone sialoprotein (BSP) expression is upregulated in patients with cancer. While BSP regulates cancer cell adhesion to the extracellular matrix, to the best of our knowledge, the specific adhesive molecular interactions in metastatic bone disease remain unclear. The present study aimed to improve the understanding of the arginine-glycine-aspartic acid (RGD) sequence of BSP and the integrin receptors αvβ3 and αvβ5 in BSP-mediated cancer cell adhesion. Human breast cancer (MDA-MB-231), prostate cancer (PC-3) and non-small cell lung cancer (NSCLC; NCI-H460) cell lines were cultured on BSP-coated plates. Adhesion assays with varying BSP concentrations were performed to evaluate the effect of exogenous glycine-arginine-glycine-aspartic acid-serine-proline (GRGDSP) peptide and anti-integrin antibodies on the attachment of cancer cells to BSP. Cell attachment was assessed using the alamarBlue® assay. The present results indicated that BSP supported the adhesion of cancer cells. The RGD counterpart GRGDSP peptide reduced the attachment of all tested cancer cell lines to BSP by ≤98.4%. Experiments with anti-integrin antibodies demonstrated differences among integrin receptors and cancer cell types. The αvβ5 antibody decreased NSCLC cell adhesion to BSP by 84.3%, while the αvβ3 antibody decreased adhesion by 14%. The αvβ3 antibody decreased PC-3 cell adhesion to BSP by 46.4%, while the αvβ5 antibody decreased adhesion by 9.5%. Adhesion of MDA-MB-231 cells to BSP was inhibited by 54.7% with αvβ5 antibody. The present results demonstrated that BSP-induced cancer cell adhesion occurs through the binding of the RGD sequence of BSP to the cell integrin receptors αvβ3 and αvβ5. Differences between cancer types were found regarding the mediation via αvβ3 or αvβ5 receptors. The present findings may explain why certain cancer cells preferentially spread to the bone tissue, suggesting that targeting the RGD-integrin binding interaction could be a promising novel cancer treatment option.

Synthesis and Anticancer Activity of Palladium‐Butadienyl Complexes Bearing Picolyl‐NHC and Phosphine Ligands

AbstractThis work presents the synthesis and full characterization of Pd(II)‐butadienyl complexes incorporating picolyl‐NHC or phosphine ligands (PPh3 or PTA). These complexes were evaluated against four different cancer cell lines and human lung fibroblasts. Our findings indicate a slightly lower antiproliferative activity of picolyl‐NHC Pd(II)‐butadienyl complexes compared to recently published ones featuring N−N, P−P, and C−C ligands but, above all, they exhibited selectivity for ovarian cancer cells. Additionally, trans‐[PdX (phosphine)2C4(COOMe)4Y)] derivatives (X=Br, Cl and Y=CH3, Br) proved excellent anticancer activity across all tested cancer cell lines, especially the bisPTA complexes. Importantly, the IC50 values suggest minimal impact from the halide coordinated to palladium or that present in the butadienyl terminal position. Furthermore, the low activity observed towards non‐cancerous cells underscores the potential of these synthesized Pd(II)‐butadienyl compounds as promising candidates for further investigation in anticancer research.

Insights into free radicals scavenging, α-Amylase inhibition, cytotoxic and antifibrotic activities unveiled by Peganum harmala extracts

BackgroundPeganum harmala L. is used in traditional medicine to treat several health ailments. Hence, the present work aimed to investigate the DPPH free radical scavenging, α-amylase, cytotoxic, and antifibrotic effects of the hydrophilic extract and fixed oil obtained from P. harmala seeds.MethodsThe hydrophilic extract and fixed oil of P. harmala were assessed for their abilities to scavenge DPPH free radicals and inhibit α-amylase using reference bioassays. The cytotoxicity was assessed on several cancer and normal cell lines, including B16F1, Caco-2, COLO205, HeLa, Hep 3B and Hep G2, MCF-7, and HEK-293 T cells. The MTS assay was used to evaluate the antifibrotic capabilities utilizing the human hepatic stellate (LX-2) cell line.ResultsP. harmala plant fixed oil has potent DPPH free radical scavenging activity with an IC50 dose of 79.43 ± 0.08 µg/ml. Besides, the hydrophilic extract has a poor anti-α-amylase effect compared with the antidiabetic drug Acarbose, with IC50 doses of 398 ± 0.59 and 25.11 ± 1.22 µg/ml, respectively. In addition, the growth of MCF-7, Hep3B, HepG2, HeLa, COLO205, CaCo2, B16F1, and HeK293t was inhibited by P. harmala hydrophilic extract with IC50 doses of 121.34 ± 1.71, 268.3 ± 0.75, 297.20 ± 1.00, 155.60 ± 1.14, 150.01 ± 0.51, 308.35 ± 0.53, 597.93 ± 1.36, and 5.38 ± 0.99 µg/ml, respectively. In addition, at 1000 µg/ml, 5-Fluorouracil reduced fibrosis cells by 0.089%, while the hydrophilic extract decreased the number of LX-2 cells by 5.81%.ConclusionP. harmala plant-fixed oil exhibits potential antioxidant properties. While the hydrophilic extract showed limited effectiveness as an anti-α-amylase agent and demonstrated notable cytotoxic effects against various tested cancer cell lines. Furthermore, this extract significantly reduces the number of LX-2 fibrotic cells. These findings emphasize the therapeutic potential of these products in managing various health disorders and warrant further investigation into their mechanisms of action and clinical applications.

Talazoparib enhances resection at DSBs and renders HR-proficient cancer cells susceptible to Polθ inhibition

Background and purposeThe PARP inhibitor (PARPi), Talazoparib (BMN673), effectively and specifically radiosensitizes cancer cells. Radiosensitization is mediated by a shift in the repair of ionizing radiation (IR)-induced DNA double-strand breaks (DSBs) toward PARP1-independent, alternative end-joining (alt-EJ). DNA polymerase theta (Polθ) is a key component of this PARP1-independent alt-EJ pathway and we show here that its inhibition can further radiosensitize talazoparib-treated cells. The purpose of the present work is to explore mechanisms and dynamics underpinning enhanced talazoparib radiosensitization by Polθ inhibitors in HR-proficient cancer cells. Methods and MaterialsRadiosensitization to PARPis, talazoparib, olaparib, rucaparib and veliparib was assessed by clonogenic survival. Polθ-proficient and −deficient cells were treated with PARPis and/or with the Polθ inhibitors ART558 or novobiocin. The role of DNA end-resection was studied by down-regulating CtIP and MRE11 expression using siRNAs. DSB repair was assessed by scoring γH2AX foci. The formation of chromosomal abnormalities was assessed as evidence of alt-EJ function using G2-specific cytogenetic analysis. ResultsTalazoparib exerted pronounced radiosensitization that varied among the tested cancer cell lines; however, radiosensitization was undetectable in normal cells. Other commonly used PARPis, olaparib, veliparib, or rucaparib were ineffective radiosensitizers under our experimental conditions. Although genetic ablation or pharmacological inhibition of Polθ only mildly radiosensitized cancer cells, talazoparib-treated cells were markedly further radiosensitized. Mechanistically, talazoparib shunted DSBs to Polθ-dependent alt-EJ by enhancing DNA end-resection in a CtIP- and MRE11-dependent manner – an effect detectable at low, but not high IR doses. Chromosomal translocation analysis in talazoparib-treated cells exposed to Polθ inhibitors suggested that PARP1- and Polθ-dependent alt-EJ pathways may complement, but also back up each other. ConclusionWe propose that talazoparib promotes low-dose, CtIP/MRE11-dependent resection and increases the reliance of irradiated HR-proficient cancer cells, on Polθ-mediated alt-EJ. The combination of Polθ inhibitors with talazoparib suppresses this option and causes further radiosensitization. The results suggest that Polθ inhibition may be exploited to maximize talazoparib radiosensitization of HR-proficient tumors in the clinic.

Exploring the Potential of Oleanolic Acid Dimers-Cytostatic and Antioxidant Activities, Molecular Docking, and ADMETox Profile.

The presented work aimed to explore the potential of oleanolic acid dimers (OADs): their cytostatic and antioxidant activities, molecular docking, pharmacokinetics, and ADMETox profile. The cytostatic properties of oleanolic acid (1) and its 14 synthesised dimers (2a-2n) were evaluated against 10 tumour types and expressed as IC50 values. Molecular docking was performed with the CB-Dock2 server. Antioxidant properties were evaluated with the CUPRAC method. ADMETox properties were evaluated with the ADMETlab Manual (2.0) database. The results indicate that the obtained OADs can be effective cytostatic agents, for which the IC50 not exceeded 10.00 for many tested cancer cell lines. All OADs were much more active against all cell lines than the mother compound (1). All dimers can inhibit the interaction between the 1MP8 protein and cellular proteins with the best results for compounds 2f and 2g with unsaturated bonds within the linker. An additional advantage of the tested OADs was a high level of antioxidant activity, with Trolox equivalent for OADs 2c, 2d, 2g-2j, 2l, and 2m of approximately 0.04 mg/mL, and beneficial pharmacokinetics and ADMETox properties. The differences in the DPPH and CUPRAC assay results obtained for OADs may indicate that these compounds may be effective antioxidants against different radicals.

Acylphloroglucinol derivatives from the aerial parts of Syzygium borneense and their cytotoxic activities

Four new acylphloroglucinol derivatives, borneensinones A-D (1–4) along with five known compounds (5-9) were isolated from the aerial parts of Syzygium borneense. Their structures were elucidated based on the interpretation of spectrometric and spectroscopic data (HRESI-MS, 1D- and 2D-NMR) and by comparison with literature data for known compounds. All acylphloroglucinol derivatives (1–6) were tested for their cytotoxic activities against four human cancer cell lines (KB, MCF-7, HepG-2, and A549). Among the six tested compounds, compound 6 exhibited the strongest inhibitory activity against four tested cancer cell lines, with IC50 values ranging from 6.21 to 26.96 μM. Compound 1 was more active against KB and HepG2 comparing to the A549 and MCF7 cells. Compound 5 had a moderate cytotoxicity with IC50 values ranging from 27.71 to 97.32 μM.

Design, synthesis and cytotoxic evaluation of new thieno[2,3-d]pyrimidine analogues as VEGFR-2/AKT dual inhibitors, apoptosis and autophagy inducers

Novel thieno[2,3-d]pyrimidine analogues were designed, synthesized and evaluated for anti-proliferative activity against HepG-2, PC-3 and MCF-7 cancer cell lines. In addition, WI-38 normal cell line was used to explore the safety of all the tested compounds. Compounds 2 (IC50 = 4.29 µM HePG-2, 10.84 µM MCF-7), 6 (IC50 = 14.86 μM HePG-2, 8.04 μM PC-3 and 12.90 μM MCF-7) and 17 (IC50 = 9.98 μM HePG-2, 33.66 μM PC-3 and 14.62 μM MCF-7) were the most promising candidates on the tested cancer cells with high selective toxicity-sparing normal cells. A further mechanistic evaluation revealed promising kinase inhibitory activity, where compound 2 inhibited VEGFR-2 and AKT at IC50 = 0.161 and 1.06 μM, respectively, Furthermore, derivative 6 inhibited VEGFR-2 and AKT at IC50 = 0.487 and 0.364 μM, respectively, while compound 17 showed IC50 = 0.164 and 0.452 μM, respectively. Moreover, compounds 2, 6 resulted in G1 phase cell cycle arrest while candidate 17 arrest cell cycle at G2/M phase. Similar to the apoptosis results, compound 17 showed the highest autophagic induction among the evaluated derivatives. Finally, docking studies were conducted to assess the binding patterns of these active derivatives. The results showed that the binding patterns inside the active sites of both the VEGFR-2 and AKT-1 (allosteric pocket) crystal structures were identical to the reference ligands.