Significant Antiproliferative Activity Research Articles

Design, Synthesis, and Antiproliferative Activity of Benzopyran-4-One-Isoxazole Hybrid Compounds.

The biological significance of benzopyran-4-ones as cytotoxic agents against multi-drug resistant cancer cell lines and isoxazoles as anti-inflammatory agents in cellular assays prompted us to design and synthesize their hybrid compounds and explore their antiproliferative activity against a panel of six cancer cell lines and two normal cell lines. Compounds 5a-d displayed significant antiproliferative activities against all the cancer cell lines tested, and IC50 values were in the range of 5.2-22.2 μM against MDA-MB-231 cancer cells, while they were minimally cytotoxic to the HEK-293 and LLC-PK1 normal cell lines. The IC50 values of 5a-d against normal HEK-293 cells were in the range of 102.4-293.2 μM. Compound 5a was screened for kinase inhibitory activity, proteolytic human serum stability, and apoptotic activity. The compound was found inactive towards different kinases, while it completely degraded after 2 h of incubation with human serum. At 5 μM concentration, it induced apoptosis in MDA-MB-231 by 50.8%. Overall, these findings suggest that new benzopyran-4-one-isoxazole hybrid compounds, particularly 5a-d, are selective anticancer agents, potentially safe for human cells, and could be synthesized at low cost. Additionally, Compound 5a exhibits potential anticancer activity mediated via inhibition of cancer cell proliferation and induction of apoptosis.

Pt(IV) and Au(III) complexes with tridentate-benzothiazole based ligand: synthesis, characterization, biological applications (antibacterial, antifungal, antioxidant, anticancer and molecular docking) and DFT calculation

A novel tridentate azo dye ligand, 2-[2′-(6-methoxybenzothiazolyl)azo]-5-dimethylamino benzoic acid (6-MBTADB) and its Pt(IV) and Au(III) metal complexes have been synthesized. The proposed structures were defined from elemental analysis, molar conductivity, magnetic susceptibility, atomic absorption spectrophotometry,1H NMR, 13C NMR, FT-IR, UV–Vis, mass spectra, X-ray diffraction analysis (XRD), thermal analysis (TGA/DTA) and field emission scanning electron microscopy (FE-SEM). Based on analytical and spectroscopic data, suitable geometry has been suggested for all complexes. The 6-MBTADB ligand acts as a tridentate via NNO donors towards the metal ions inside octahedral geometry with Pt(IV), and square planner with Au(III) ion. Quantum chemical calculations were performed on the compounds using density functional theory DFT/B3LYP, 6–311G (d,p), and LanL2DZ basis sets. Moreover, the synthesized compounds showed greater antimicrobial activity when tested biologically against Escherichia coli, Staphylococcus aureus, and Aspergillus niger. The results of their tests show that the metal complexes are more effective against several bacterial and fungal strains. Further, the free radical scavenging activity of the free ligand and metal complexes has been determined by their interaction with the stable DPPH free radical. The combined molecular docking study evaluates the binding energies of anticancer agents, providing the binding property with the receptor. The results of the molecular docking show that the ligand and its complexes have a good affinity with the protein kinase (1HK7). Finally, all the compounds exhibited significant antiproliferative activity against the human breast cancer (MCF-7) and normal HUVECs cell lines, showing that Pt(IV) chelate the most potent against MCF-7 cell line based on IC50 and selective indices (SI) values. This research may provide knowledge that is an excellent backdrop for the rational design of promising drugs.

Biochemical, molecular and anti-tumor characterization of L-methionine gamma lyase produced by local Pseudomonas sp. in Egypt

A soil inhabiting Pseudomonas sp. has been examined for producing L- methionine gamma-lyase enzyme. The identity of the tested bacteria was verified by VITEK2, and MALDI-TOF analysis in addition to molecular confirmation by 16S rDNA sequence and submitted in Genbank under accession number ON993898.1. Production of the targeted enzyme was done using a commercial medium including L-methionine, as the main substrate. This obtained enzyme was precipitated using acetone (1:1v/v) followed by purification with Sephadex G100 and sepharose columns. The specific activity of the purified enzyme (105.8 µmol/ mg/min) increased by 1.89 folds after the purification steps. The peptide fingerprint of the native MGL was verified from the proteomics analysis, with identical conserved active site domains with database-deposited MGLs. The molecular mass of the pure MGL denatured subunit was (>40 kDa) and that of the native enzyme was (>150 kDa) ensuring their homotetrameric identity. The purified enzyme showed absorption spectra at 280 nm and 420 nm for the apo-MGL and PLP coenzyme, respectively. Amino acids suicide analogues analysis by DTNB, hydroxylamine, iodoacetate, MBTH, mercaptoethanol and guanidine thiocyanate reduced the relative activity of purified MGL. From the kinetic properties, the catalytic effectiveness (Kcat/km) of Pseudomonas sp. MGL was 10.8 mM -1 S-1 for methionine and 5.51 mM -1 S-1 for cysteine, respectively. The purified MGL showed highly significant antiproliferative activity towards the liver carcinoma cell line (HEPG-2) and breast carcinoma cell line (MCF-7) with half inhibitory concentration values (IC50) 7.23 U/ml and 21.14 U/ml, respectively. No obvious signs of toxicity on liver and kidney functions in the examined animal models were observed.

Discovery of a Novel Class of PROTACs as Potent and Selective Estrogen Receptor α Degraders to Overcome Endocrine-Resistant Breast Cancer In Vitro and In Vivo.

The estrogen receptor (ER) is a well-established target for endocrine therapies of ER-positive breast cancer (ER+ BC), but endocrine resistance limits the efficacy of clinical drugs. Using proteolysis targeting chimera (PROTAC) technology to degrade ERα may be an effective alternative to endocrine therapies. Herein, we disclose a novel series of potent and selective ERα PROTACs based on an oxabicycloheptane sulfonamide (OBHSA) scaffold, with no associated ERβ degradation. These PROTACs showed significant antiproliferation and ERα degradation activities against a broad spectrum of ER+ BC cells including tamoxifen-resistant and ERα mutant cell lines. Genomics analysis confirmed that these PROTACs inhibited the nascent RNA synthesis of ERα target genes and impaired genome-wide ERα binding. Compound ZD12 exhibited excellent antitumor potency and ERα degradation activity in both tamoxifen-sensitive and -resistant BC mice models, which are superior to fulvestrant. This study demonstrates the potential of these PROTACs as novel drug candidates for endocrine-resistant BC treatment.

Design, synthesis, and biological evaluation of novel dihydropteridone derivatives possessing oxadiazoles moiety as potent inhibitors of PLK1

Polo like kinase 1 (PLK1) is a serine/threonine kinase that is widely distributed in eukaryotic cells and plays an important role in multiple phases of the cell cycle. Its importance in tumorigenesis has been increasingly recognized in recent years. Herein, we describe the optimization of a series of novel dihydropteridone derivatives (13a-13v and 21g-21l) possessing oxadiazoles moiety as potent inhibitors of PLK1. Compound 21g exhibited improved PLK1 inhibitory capability with an IC50 value of 0.45 nM and significant anti-proliferative activities against four tumor-derived cell lines (MCF-7 IC50 = 8.64 nM, HCT-116 IC50 = 26.0 nM, MDA-MB-231 IC50 = 14.8 nM and MV4-11 IC50 = 47.4 nM) with better pharmacokinetic characteristics than BI2536 in mice (AUC0-t = 11 227 ng h mL−1vs 556 ng h mL−1). Moreover, 21g exhibited moderate liver microsomal stability and excellent pharmacokinetic profile (AUC0-t = 11227 ng h mL−1, oral bioavailability of 77.4%) in Balb/c mice, acceptable PPB, improved PLK1 inhibitory selectivity, and no apparent toxicity was observed in the acute toxicity assay (20 mg/kg). Further investigation showed that 21 g could arrest HCT-116 cells in G2 phase and induce apoptosis in a dose-dependent manner. These results indicate that 21g is a promising PLK1 inhibitor.

Augmentation of Docetaxel-Induced Cytotoxicity in Human PC-3 Androgen-Independent Prostate Cancer Cells by Combination With Four Natural Apoptosis-Inducing Anticancer Compounds.

Docetaxel (DTX) is the treatment of choice for metastatic castration-resistant prostate cancer. However, developing drug resistance is a significant challenge for achieving effective therapy. This study evaluated the anticancer and synergistic effects on DTX of four natural compounds (calebin A, 3'-hydroxypterostilbene, hispolon, and tetrahydrocurcumin) using PC-3 androgen-resistant human prostate cancer cells. We utilized the CellTiter-Glo® luminescent cell viability assay and human PC-3 androgen-independent prostate cancer cells to determine the antiproliferative effects of the four compounds alone and combined with DTX. Cytotoxicity to normal human prostate epithelial cells was tested in parallel using normal immortalized human prostate epithelial cells (RWPE-1). We used cell imaging and quantitative caspase-3 activity to determine whether these compounds induce apoptosis. We also measured the capacity of each drug to inhibit TNF-α-induced NF-kB using a colorimetric assay. Our results showed that all four natural compounds significantly augmented the toxicity of DTX to androgen-resistant PC-3 prostate cancer cells at IC50. Interestingly, when used alone, each of the four compounds had a higher cytotoxic activity to PC-3 than DTX. Mechanistically, these compounds induced apoptosis, which we confirmed by cell imaging and caspase-3 colorimetric assays. Further, when used either alone or combined with DTX, the four test compounds inhibited TNF-α-induced NF-kB production. More significantly, the cytotoxic effects on normal immortalized human prostate epithelial cells were minimal and non-significant, suggesting prostate cancer-specific effects. In conclusion, the combination of DTX with the four test compounds could effectively enhance the anti-prostate cancer activity of DTX. This combination has the added value of reducing the DTX effective concentration. We surmise that calebin A, 3'-hydroxypterostilbene, hispolon, and tetrahydrocurcumin were all excellent drug candidates that produced significant antiproliferative activity when used alone and synergistically enhanced the anticancer effect of DTX. Further in vivo studies using animal models of prostate cancer are needed to confirm our in vitro findings.

Guided Isolation of New Cytotoxic Cassane Diterpenoids from Caesalpinia sappan.

Guided by an MS/MS-based molecular networking, six undescribed cassane diterpenoids and three known ones were isolated and identified from the seeds of Caesalpinia sappan. Their structures were unequivocally elucidated by extensive spectroscopic analyses and electronic circular dichroism (ECD) calculations. Cytotoxic evaluation showed that phanginin JA exhibited significant antiproliferative activities against human non-small cell lung cancer (A549) cells with IC50 values of 16.79±0.83 μM. Further flow cytometry analysis revealed that phanginin JA could exert apoptotic effect of A549 cells by arresting cell cycle in G0/G1 phase.

Proteolysis Targeting Chimeras (PROTACs) Based on Imatinib Induced Degradation of BCR‐ABL in K562 Cells

AbstractThe proteolysis targeting chimera (PROTAC) technology is widely explored in cancer research and utilized in the treatment of various tumors and malignancies. In the design and optimization of PROTAC, linker is not only critical to the degradation activity of PROTACs, but also greatly affects the membrane permeability, metabolic stability and drug availability. In this study, fifteen new PROTACs based on Imatinib were designed, synthesized, and assessed for their anticancer activity against K562 cells. The CCK‐8 assay results showed that a new PROTAC with a 2‐oxoethyl linker (PROTAC 1) exhibited significant antiproliferative activity against K562 (IC50=0.62±0.02 μM) cells. Western blot analysis showed that PROTAC 1 regulated the protein levels of BCR‐ABL in a dose‐dependent manner and induced degradation of BCR‐ABL in a ubiquitin‐proteasome‐dependent manner in K562 cells. This study provides further evidence for the importance of linker selection in PROTAC design.

Interactions between curcumin and human salt-induced kinase 3 elucidated from computational tools and experimental methods.

Natural products are widely used for treating mitochondrial dysfunction-related diseases and cancers. Curcumin, a well-known natural product, can be potentially used to treat cancer. Human salt-induced kinase 3 (SIK3) is one of the target proteins for curcumin. However, the interactions between curcumin and human SIK3 have not yet been investigated in detail. In this study, we studied the binding models for the interactions between curcumin and human SIK3 using computational tools such as homology modeling, molecular docking, molecular dynamics simulations, and binding free energy calculations. The open activity loop conformation of SIK3 with the ketoenol form of curcumin was the optimal binding model. The I72, V80, A93, Y144, A145, and L195 residues played a key role for curcumin binding with human SIK3. The interactions between curcumin and human SIK3 were also investigated using the kinase assay. Moreover, curcumin exhibited an IC50 (half-maximal inhibitory concentration) value of 131nM, and it showed significant antiproliferative activities of 9.62 ± 0.33µM and 72.37 ± 0.37µM against the MCF-7 and MDA-MB-23 cell lines, respectively. This study provides detailed information on the binding of curcumin with human SIK3 and may facilitate the design of novel salt-inducible kinases inhibitors.

Abstract 3829: Antioxidant and antiproliferative activities of Ipomoea cairica extracts on three breast cancer cell lines

Abstract Introduction: Breast cancer was the top cause of cancer deaths in 2020 with a death toll of 685 000 worldwide. Breast cancer treatments are based on drug specificity for unique receptors on the surface of some breast cancer types, there is a search for alternative treatments that are inclusive of different breast cancer types. Evidence suggests that antioxidants offer a protective effect against certain cancers. Studies on Ipomoea cairica have reported potential anticancer activity, hence this study aimed to assess the antioxidant and antiproliferative potentials of the extracts of Ipomoea cairica on three breast cancer cell lines. Materials and Methods- The study protocol was approved by the University of the Free State Health Sciences Research Ethics Committee (HSREC), with approval number: UFS-HSD2022/0353/2607-0001. Ipomoea cairica stem and leaves were harvested and identified by Prof. H. Baijnath, Department of Conservation Science, School of Life Sciences, University of KwaZulu-Natal, Durban, South Africa, with specimen number 29 30 DD housed at the Ward Herbarium. The dried plant was extracted sequentially using organic solvents ranging from non-polar to polar and water. The extracts were filtered and concentrated using a rotary evaporator and then evaporated to dryness/lyophilized. Cells were cultured according to standard established procedure. The extracts were subjected to phytochemical analyses. FRAP, DPPH, and ABTS assays were done to examine antioxidant activity and MTT assays were used to evaluate the antiproliferative/cytotoxicity of the extracts against normal (Vero) and breast cancer cell lines (MCF-7, MDA-MB-231, and 4T1). Results and Discussion- Extracts of Ipomoea cairica possess alkaloids, saponins, phenols, flavonoids, phytosterols, tannins, triterpenoids, and anthraquinones. The results from the DPPH and ABTS assays revealed that the methanol and ethyl acetate fractions had significantly the highest antioxidant potentials while the methanol stem extract exhibited the most significant antioxidant activity in the FRAP assay. The DCM stem extract showed the highest antiproliferative activity against all tested cell lines. Conclusion- Extracts of I. cairica possess significant antioxidant properties and antiproliferative activities against a wide array of breast cancer types including the most challenging triple-negative breast cancer. The plant would make for a strong herbal candidate for adjuvant therapy with breast cancer medication. Citation Format: Ayodeji Mathias Adegoke, Doreen Kulabako Kyagaba, Nomonde Hadebe, Nandi Mabaso, Relebohile Patricia Lefojane, Himansu Baijnath, Oyeronke Adunni Odunola, Mamello Patience Sekhoacha. Antioxidant and antiproliferative activities of Ipomoea cairica extracts on three breast cancer cell lines. [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 3829.

Discovery of novel benzenesulfonamides incorporating 1,2,3-triazole scaffold as carbonic anhydrase I, II, IX, and XII inhibitors

Sulfonamides are among the most promising potential inhibitors for carbonic anhydrases (CAs), which are pharmaceutically relevant targets for treating several disease conditions. Herein, a series of benzenesulfonamides bearing 1,2,3-triazole moiety as inhibitors of human (h) α-CAs (hCAs) were designed using the tail approach. The design method combines a benzenesulfonamide moiety with a tail of oxime and a zinc-binding group on a 1,2,3-triazole scaffold. Among the synthesized derivatives, the naphthyl (6m, KI of 68.6 nM, SI of 10.3), and methyl (6a, KI of 56.3 nM, SI of 11.7) derivatives (over hCA IX) and propyl (6c, KI of 95.6 nM, SI of 2.7), and pentyl (6d, KI of 51.1 nM, SI of 6.6) derivatives (over hCA XII) displayed a noticeable selectivity for isoforms hCA I and II, respectively. Meanwhile, derivative 6e displayed a potent inhibitory effect versus the cytosolic isoform hCA I (KI of 47.8 nM) and tumor-associated isoforms hCA IX and XII (KIs of 195.9 and 116.9 nM, respectively) compared with the reference drug acetazolamide (AAZ, KIs of 451.8, 437.2, and 338.9 nM, respectively). Derivative 6b showed higher potency (KI of 33.2 nM) than AAZ (KI of 327.3 nM) towards another cytosolic isoform hCA II. Nevertheless, substituting the lipophilic large naphthyl tail to the 1,2,3-triazole linked benzenesulfonamides (6a-n) raised inhibitory effect versus hCA I and XII and selectivity towards hCA I and II isoforms over hCA IX. Evaluation of the cytotoxic potential of the synthesized derivatives was conducted in L929, MCF-7, and Hep-3B cell lines. Several compounds in the series demonstrated significant antiproliferative activity and minimal cytotoxicity. In the molecular docking study, the sulfonamide moiety interacted with the zinc-ion and neatly fit into the hCAs active sites. The extension of the tail was found to participate in diverse hydrophilic and hydrophobic interactions with adjacent amino acids, ultimately influencing the effectiveness and specificity of the derivatives.

Discovery of novel CDK2 inhibitors using multistage virtual screening and in vitro melanoma cell lines.

Cyclin-dependent kinases 2 (CDK2) is a serine/threonine-protein kinase, which plays a key role in the regulation of cell cycle and is related to the occurrence and development of melanoma. In this study, we identified potent inhibitors for CDK2 by combining a multistage virtual screening strategy with bioassay validations. The biochemical activity of compounds was validated with ADP-Glo™ Kinase assay in vitro, and the results indicated that the biochemical activity of compound 1 (C1) was better than other selected compounds. Cell viability assay showed that the minimum inhibition concentration of C1 for CDK2 was lower than 4μM. Further functional test results showed that C1 exerted significant antiproliferative, pro-apoptosis, and anti-migration activity in melanoma cell lines (A375 cells, WM35 cells, and A875 cells). Our findings suggested that the C1, virtually screened from compound libraries, as the novel inhibitor of CDK2, may be further developed as an effective therapeutic agent in the treatment of melanoma lines.

Discovery of novel N-benzylarylamide-dithiocarbamate based derivatives as dual inhibitors of tubulin polymerization and LSD1 that inhibit gastric cancers

In this work, N-benzylarylamide-dithiocarbamate based derivatives were designed, synthesized, and their biological activities as anticancer agents were explored. Some of the 33 target compounds displayed significant antiproliferative activities with IC50 values at the double-digit nanomolar level. The representative compound I-25 (also named MY-943) not only showed the most effective inhibitory effects on three selected cancer cells MGC-803 (IC50 = 0.017 μM), HCT-116 (IC50 = 0.044 μM) and KYSE450 (IC50 = 0.030 μM), but also exhibited low nanomolar IC50 values from 0.019 to 0.253 μM against the other 11 cancer cells. Compound I-25 (MY-943) effectively inhibited tubulin polymerization and suppressed LSD1 at the enzymatic levels. Compound I-25 (MY-943) could act on the colchicine binding site of β-tubulin, thus disrupting the construction of cell microtubule network and affecting the mitosis. In addition, compound I-25 (MY-943) could dose-dependently induce the accumulation of H3K4me1/2 (MGC-803 and SGC-7091 cells) and H3K9me2 (SGC-7091 cells). Compound I-25 (MY-943) could induce G2/M phase arrest and cell apoptosis, and suppress migration in MGC-803 and SGC-7901 cells. In addition, compound I-25 (MY-943) significantly modulated the expression of apoptosis- and cycle-related proteins. Furthermore, the binding modes of compound I-25 (MY-943) with tubulin and LSD1 were explored by molecular docking. The results of in vivo anti-gastric cancer assays using in situ tumor models showed that compound I-25 (MY-943) effectively reduced the weight and volume of gastric cancer in vivo without obvious toxicity. All these findings suggested that the N-benzylarylamide-dithiocarbamate based derivative I-25 (MY-943) was an effective dual inhibitor of tubulin polymerization and LSD1 that inhibited gastric cancers.

Role of Bromodomain and Extraterminal (BET) Proteins in Prostate Cancer

Introduction The bromodomain and extraterminal (BET) family of proteins are epigenetic readers of acetylated histones and are critical activators of oncogenic networks across many cancers. Therapeutic targeting of BET proteins has been an attractive area of clinical development for metastatic castration-resistant prostate cancer. In recent years, many structurally diverse BET inhibitors have been discovered and tested. Preclinical studies have demonstrated significant antiproliferative activity of BET inhibitors against prostate cancer. However, their clinical success as monotherapies has been limited by treatment-associated toxicities, primary and acquired drug resistance, and a lack of predictive biomarkers of benefit. Areas covered This review provides an overview of advancements in BET inhibitor design, preclinical research, and conclusions from clinical trials in prostate cancer. We speculate on incorporating BET inhibitors into combination regimens with other agents to improve the therapeutic index of BET inhibition in treating prostate cancer. Expert opinion The therapeutic potential of BET inhibitors for prostate cancer has been demonstrated in preclinical studies. However, further research is needed to identify biomarkers that can predict sensitivity to BET inhibitors and to develop novel, highly selective inhibitors to reduce toxicities. Finally, BET inhibitors are likely to hold the most clinical potential in combination with other agents.

Extraction, structure characterization and biological activity of polysaccharide from coconut peel

Taking coconut peel as raw material, the extraction process of coconut peel polysaccharide (CPP) was optimized by boiling water extraction. The coconut peel polysaccharide was characterized by UV, IR, SEM, 1D NMR and 2D NMR spectra. At the same time, the molecular weight and monosaccharide component were analyzed by gel chromatography and ion chromatography, respectively. Antioxidant activity of coconut peel polysaccharide and its derivatives in vitro was evaluated by scavenging ABTS and DPPH radicals and O2−·, and the anti HepG2 proliferation activity in vitro was also carried out. The results showed that the molecular weight of coconut peel polysaccharide was 1.20 × 105 Da, which was mainly composed of arabinose (Ara), galactose (Gal), glucose (Glu), xylose (Xyl) and galacturonic acid (Gal-A). The main chain structure of polysaccharides detected by 1D and 2D NMR spectrum was → 4)-α-D-Glcp (1 → . In vitro antioxidant test showed that coconut peel polysaccharide and its derivatives had a certain scavenging effect on ABTS and DPPH free radical and O2−·. With the increase of polysaccharide concentration, the scavenging ability was gradually increased. In addition, coconut peel polysaccharide and its derivatives showed significant antiproliferative activity against HepG2 cells in vitro.Graphical

The Diatom Cylindrotheca closterium and the Chlorophyll Breakdown Product Pheophorbide a for Photodynamic Therapy Applications

Microalgae, eukaryotic unicellular plants that are distributed worldwide, have been shown to exert anti-proliferative and anticancer activities on various human cancer cell lines. An example of a microalgal bioactive compound is a chlorophyll breakdown product named Pheophorbide a (Ppa), which has been reported to have anti-proliferative properties against various cell lines. This compound has also been tested with light exposure in photodynamic therapy for cancer treatment. In this paper, we screened eleven marine microalgae against a panel of cancer cells, and evaluated the synergistic anti-proliferative effect with Pheophorbide a, with and without photo-activation. The results showed significant anti-proliferative activity against melanoma cells when Ppa was combined with fraction E of the diatom Cylindrotheca closterium plus 1 h photo-activation. Its activity was also analyzed using gene expression and Western blot experiments. Altogether, these data give new insights into the possible application of microalgae for photodynamic therapy.

Structure and Bonding in the Complex of Zinc with 4,4’-Diacetylcurcumin

Revised 28 March 2022; Accepted 14 July 2022
 Abstract: The structure and bonding situation in the complex of zinc with 4,4’-diacetylcurcumin and methanol ligands, [Zn(L)2(CH3OH)2], were examined by DFT calculations with the levels of TPSSH/def2-SVP and TPSSH/def2-TZVP in gas phase and methanol solvation. For each phase, four isomers with octahedral geometrical structures were found. The complexes were stabilized by Zn-O metal-ligand bondings and the support of hydrogen bondings. The bonding characters were analyzed in detail by the QTAIM and NBO theories. The study contributes to a deeper understanding of the structure and electron properties of the [Zn(L)2(CH3OH)2] complex that was experimentally synthesized and predicted to have significant antiproliferative activities for the human MCF-7 breast and HepG2 liver cancer cells.

Coumarin derivatives with potential anticancer and antibacterial activity: Design, synthesis, VEGFR-2 and DNA gyrase inhibition, and in silico studies.

A series of coumarin derivatives were designed, synthesized, and evaluated for their antiproliferative activity. Compound 3e exhibited significant antiproliferative activity and was further evaluated at five doses at the National Cancer Institute. It effectively inhibited vascular endothelial growth factor receptor-2 (VEGFR-2) with an IC50 value of 0.082 ± 0.004 µM compared with sorafenib. While compound 3e significantly downregulated total VEGFR-2 and its phosphorylation, it markedly reduced the HUVEC's migratory potential, resulting in a significant disruption in wound healing. Furthermore, compound 3e caused a 22.51-fold increment in total apoptotic level in leukemia cell line HL-60(TB) and a 6.91-fold increase in the caspase-3 level. Compound 3e also caused cell cycle arrest, mostly at the G1/S phase. Antibacterial activity was evaluated against Gram-positive and Gram-negative bacterial strains. Compound 3b was the most active derivative, with the same minimum inhibitory concentration and minimum bactericidal concentration value of 128 μg/mL against K. pneumonia and high stability in mammalian plasma. Moreover, compounds 3b and 3f inhibited Gram-negative DNA gyrase with IC50 = 0.73 ± 0.05 and 1.13 ± 0.07 µM, respectively, compared to novobiocin with an IC50 value of 0.17 ± 0.02 µM. The binding affinity and pattern of derivative 3e toward the VEGFR-2 active site and compounds 3a-c and 3f in the DNA gyrase active site were evaluated using molecular modeling. Overall, ADME studies of the synthesized coumarin derivatives displayed promising pharmacokinetic properties.

Synthesis, Antiproliferative Evaluation, and Molecular Docking Study of Novel Longifolene-Derived Tetraline Fused Thiazole-Amide Derivatives.

Twenty novel longifolene-derived tetraline fused thiazole-amide compounds were synthesized from longifolene, a renewable natural resource. Their structures were characterized by FT-IR, NMR, ESI-MS, and elemental analysis. The in vitro antiproliferative activity of these compounds against SK-OV-3 ovarian cancer cell lines, MCF-7 human breast cancer cell lines, HepG2 human liver cancer cell lines, A549 human lung adenocarcinoma cell lines, and T-24 human bladder cancer cell lines was tested by MTT assay. Compounds 6a-6c displayed significant and broad-spectrum antiproliferative activity against almost the tested cancer cell lines with IC50 in the range of 7.84 to 55.88 μM, of which compound 6c exhibited excellent antiproliferative activities with 7.84 μM IC50 against SKOV-3, 13.68 μM IC50 against HepG2, 15.69 μM IC50 against A549, 19.13 μM IC50 against MCF-7, and 22.05 μM IC50 against T-24, showing better and broad-spectrum antiproliferative effect than that of the positive control 5-FU. Furthermore, the action model was analyzed by the molecular docking study. Some intriguing structure-activity relationships were found and discussed herein by DFT theoretical calculation.

Antioxidant and antiproliferative potentials of phenolic-rich extracts from biotransformed grape pomace in colorectal Cancer

BackgroundColorectal carcinoma is one of the most commonly diagnosed malignancies worldwide. Consumption of dietary supplements and nutraceuticals such as phenolic compounds may help combat colorectal carcinoma. The effect of two phenolic-rich extracts prepared from biotransformed grape pomace on the antioxidant properties and antiproliferative activity against two colorectal cancer cell lines (Caco-2 and SW620) were investigated.MethodsA 15-day solid-state fermentation with the white-rot fungi Phanerochaete chrysosporium and Trametes gibbosa was used to biotransform grape pomace. Solid-liquid extraction was then performed to extract bioactive compounds. The extract was analyzed for the determination of phenolic compounds by ultra-high performance liquid chromatography and in vitro assays of biological activities (antioxidant activity, antiproliferative activity, cell cycle analysis).ResultsThe 4 days of solid-state fermentation proved to be the optimal period to obtain the maximum yield of phenolic compounds. The tested extracts showed significant antioxidant and antiproliferative activities. Grape pomace treated with P. chrysosporium and T. gibbosa reduced cancer cell growth by more than 60% at concentrations (solid/liquid ratio) of 1.75 mg/mL and of 2.5 mg/mL, respectively. The cell cycle perturbations induced by the grape pomace extracts resulted in a significant increase in the number of cells in the S (9.8%) and G2/M (6.8%) phases of SW620 exposed to T. gibbosa after 48 hours, while P. chrysosporium increased the percentage of cells in the G1 phase by 7.7%. The effect of grape pomace extracts on Caco-2 was less pronounced.ConclusionsThe obtained results suggest the presence of bioactive compounds in biotransformed grape pomace as a residue from winemaking, which could be used to prevent colon cancer.