Significant Antiproliferative Activity Research Articles

Design, Synthesis, and Anti-Cervical Cancer and Reversal of Tumor Multidrug Resistance Activity of Novel Nitrogen-Containing Heterocyclic Chalcone Derivatives.

This study involved the design and synthesis of 21 new nitrogen-containing heterocyclic chalcone derivatives utilizing the active substructure splicing principle, with glycyrrhiza chalcone serving as the lead compound. The targets of these derivatives were VEGFR-2 and P-gp, and their efficacy against cervical cancer was evaluated. Following preliminary conformational analysis, compound 6f ((E)-1-(2-hydroxy-5-((4-hydroxypiperidin-1-yl)methyl)-4-methoxyphenyl)-3-(4-((4-methylpiperidin-1-yl)methyl)phenyl)prop-2-en-1-one) exhibited significant antiproliferative activity against human cervical cancer cells (HeLa and SiHa) with IC50 values of 6.52 ± 0.42 and 7.88 ± 0.52 μM, respectively, when compared to other compounds and positive control drugs. Additionally, this compound demonstrated lower toxicity towards human normal cervical epithelial cells (H8). Subsequent investigations have demonstrated that 6f exerts an inhibitory impact on VEGFR-2, as evidenced by its ability to impede the phosphorylation of p-VEGFR-2, p-PI3K, and p-Akt proteins in HeLa cells. This, in turn, results in the suppression of cell proliferation and the induction of both early and late apoptosis in a concentration-dependent manner. Furthermore, 6f significantly curtails the invasion and migration of HeLa cells. In addition, 6f had an IC50 of 7.74 ± 0.36 μM against human cervical cancer cisplatin-resistant HeLa/DDP cells and a resistance index (RI) of 1.19, compared to 7.36 for cisplatin HeLa cells. The combination of 6f and cisplatin resulted in a significant reduction in cisplatin resistance in HeLa/DDP cells. Molecular docking analyses revealed that 6f exhibited binding free energies of -9.074 and -9.823 kcal·mol-1 to VEGFR-2 and P-gp targets, respectively, and formed hydrogen bonding forces. These findings suggest that 6f has potential as an anti-cervical cancer agent and may reverse cisplatin-resistant activity in cervical cancer. The introduction of the 4-hydroxy piperidine and 4-methyl piperidine rings may contribute to its efficacy, and its mechanism of action may involve dual inhibition of VEGFR-2 and P-gp targets.

Photo-Uncaging by C(sp3)-C(sp3) Bond Cleavage Restores β-Lapachone Activity.

β-Lapachone is an ortho-naphthoquinone natural product with significant antiproliferative activity but suffers from adverse systemic toxicity. The use of photoremovable protecting groups to covalently inactivate a substrate and then enable controllable release with light in a spatiotemporal manner is an attractive prodrug strategy to limit toxicity. However, visible light-activatable photocages are nearly exclusively enabled by linkages to nucleophilic functional sites such as alcohols, amines, thiols, phosphates, and sulfonates. Herein, we report covalent inactivation of the electrophilic quinone moiety of β-lapachone via a C(sp3)-C(sp3) bond to a coumarin photocage. In contrast to β-lapachone, the designed prodrug remained intact in human whole blood and did not induce methemoglobinemia in the dark. Under light activation, the C-C bond cleaves to release the active quinone, recovering its biological activity when evaluated against the enzyme NQO1 and human cancer cells. Investigations into this report of a C(sp3)-C(sp3) photoinduced bond cleavage suggest a nontraditional, radical-based mechanism of release beginning with an initial charge-transfer excited state. Additionally, caging and release of the isomeric para-quinone, α-lapachone, are demonstrated. As such, we describe a photocaging strategy for the pair of quinones and report a unique light-induced cleavage of a C-C bond. We envision that this photocage strategy can be extended to quinones beyond β- and α-lapachone, thus expanding the chemical toolbox of photocaged compounds.

Synthesis and Cytotoxicity Assessment against Human Colorectal Cancer Cell Lines of Quaternary 8-Dichloromethyl Protoberberine Alkaloids.

Twenty-two quaternary 8-dichloromethylprotoberberine alkaloids were synthesized from unmodified quaternary protoberberine alkaloids (QPAs) to improve their physical and chemical properties and to obtain selectively anticancer derivatives. The synthesized derivatives showed more appropriate octanol/water partition coefficients by up to values 3-4 compared to unmodified QPA substrates. In addition, these compounds exhibited significant antiproliferative activity against colorectal cancer cells and lower toxicity on normal cells, resulting in more significant selectivity indices than unmodified QPA compounds in vitro. The IC50 values of antiproliferative activity of quaternary 8-dichloromethyl-pseudoberberine 4-chlorobenzenesulfonate and quaternary 8-dichloromethyl-pseudopalmatine methanesulfonate against colorectal cancer cells are 0.31 μM and 0.41 μM, respectively, significantly stronger than those of other compounds and positive control 5-fluorouracil. These findings suggest that 8-dichloromethylation can be used as one of the modification strategies to guide the structural modification and subsequent investigation of anticancer drugs for CRC based on QPAs.

Mechanistic insights into the anti-tumor and anti-metastatic effects of Patrinia villosa aqueous extract in colon cancer via modulation of TGF-β R1-smad2/3-E-cadherin and FAK-RhoA-cofilin pathways

BackgroundPatrinia villosa, a traditional medicinal herb commonly used for treating intestinal-related diseases, has been commonly prescribed by Chinese medicine practitioners as a key component herb to treat colon cancer, although its anti-tumor effect and mechanisms of action have not been fully elucidated. Hypothesis/purposeThis study aimed to investigate the anti-tumor and anti-metastatic effects of Patrinia villosa aqueous extract (PVW), and its underlying mechanisms. MethodThe chemical profile of PVW was analysed by high-performance liquid chromatography with photodiode-array detection (HPLC-DAD) method. Cell-based functional assays MTT, BrdU, scratch, and transwell were conducted to evaluate the effects of PVW on human colon cancer HCT116 and murine colon26-luc cells, assessing cytotoxicity, cell proliferation, motility, and migration, respectively. Western blotting was performed to assess the effect of PVW on the expression of key intracellular signaling proteins. In vivo studies were conducted using zebrafish embryos and tumor-bearing mice to evaluate the anti-tumor, anti-angiogenesis, and anti-metastatic effects of PVW in colon cancer. ResultsFive chemical markers were identified and quantified in PVW. PVW exhibited significant cytotoxicity and anti-proliferative activity, as well as inhibitory effects on cell motility and migration in both HCT116 and colon 26-luc cancer cells via modulating protein expressions of TGF-β R1, smad2/3, snail, E-cadherin, FAK, RhoA, and cofilin. PVW (0.01–0.1 mg/ml) could significantly decrease the length of subintestinal vessels of zebrafish embryos through decreasing mRNA expressions of FLT1, FLT4, KDRL, VEGFaa, VEGFc, and Tie1. PVW (> 0.05 mg/ml) also significantly suppressed colon cancer cells migration in the zebrafish embryos. Furthermore, oral administration of PVW (1.6 g/kg) significantly inhibited tumor growth by decreasing the expressions of tumor activation marker Ki-67 and CD 31 in tumor tissues of HCT116 tumor-bearing mice. PVW could also significantly inhibit lung metastasis in colon 26-luc tumor-bearing mice by modulating their tumor microenvironment, including immune cells populations (T cells and MDSCs), levels of cytokines (IL-2, IL-12, and IFN-γ), as well as increasing the relative abundance of gut microbiota. ConclusionThis study revealed for the first time the anti-tumor and anti-metastatic effects of PVW through regulation of TGF-β-smad2/3-E-cadherin, and FAK-cofilin pathways in colon cancer. These findings provide scientific evidence to support the clinical use of P. villosa in patients with colon cancer.

Phytochemical profile and biological activities of the essential oils in the aerial part and root of Saposhnikovia divaricata

The dried root of Saposhnikovia divaricata (Turcz.) Schischk. is popular as a good medicinal material, however the abundant aerial part is often discarded, which caused the waste of resources. In order to exploit resources, the essential oils of the plant aerial part and root were extracted, separately called as VOA and VOR, their chemicals were identified. The tumor necrosis factor-α, interleukin-6, nitric oxide and interleukin-1β were detected to evaluate the oils anti-inflammatory activities. Then, the oils free radical scavenging rates were measured with DPPH, ABTS and hydroxyl free radical. The oils antitumor activities were evaluated with HeLa and HCT-8 cancer cell lines. The results showed the concentrations of VOA and VOR were separately 0.261% and 0.475%. Seventeen components of VOA were identified, accounting for 80.48% of VOA, including phytol, spathulenol, phytone, 4(15),5,10(14)-Germacratrien-1-ol, neophytadiene, etc. Seven components of VOR were determined, representing 90.73% of VOR, consisted of panaxynol, β-bisabolene, etc. VOA and VOR significantly inhibited the secretion of nitric oxide, interleukin-1β, interleukin‐6 and tumor necrosis factor-α, effectively scavenged the DPPH, ABTS and hydroxyl free radicals, and showed significant antiproliferative activity against HeLa and HCT-8. The two oils presented important biological activity, which provided a hopeful utilized basis, and helped to reduce the waste of the aerial non-medicinal resources of S. divaricata.

Study of Ceramide-Flavone Analogs Showing Self-Fluorescence and Anti-Proliferation Activities.

Many current anti-cancer drugs used to treat breast cancer mediate tumor cell death through the induction of apoptosis. Cancer cells, however, often acquire multidrug-resistance following prolonged exposure to chemotherapeutics. Consequently, molecular pathways involved in tumor cell proliferation have become potential targets for pharmacological intervention. Ceramides are tumor suppressor lipids naturally found in the cell membrane, and are central molecules in the sphingolipid signalling pathway. Our lab has targeted the ceramide signaling pathway for potential pharmacological intervention in the treatment of breast cancer. Previously, we have shown that certain ceramide analogs have therapeutic potential in the treatment of chemo-sensitive and multidrug-resistant breast cancers. Using the most active analog from our previous studies as the lead compound, new analogs containing a flavone moiety were designed and synthesized. In general, flavone derivatives often show interesting pharmacological properties, and compounds based on these molecules have been found useful in many different therapeutic areas including anti-tumor, anti-coagulants, and anti-HIV therapy. Synthesis and biological evaluation of five new flavonoid ceramide analogs are reported here. These compounds were also shown to be self-fluorescent, which can be useful when investigating their distribution and action in cancer cells. Four out of the five flavone ceramide analogs in this study showed significant anti-proliferation activities in the three cell lines studied, MDA-MB-232, MCF-7, and MCF-7TN-R; some showing varying degrees of selectivity. The mechanisms involved in cell proliferation inhibition are complicated and further studies are needed.

The effect of Lavandula Coronopifolia essential oil on the biophysical properties of desensitization and deactivation gating currents in ionotropic receptors

The rising incidence of cancer and the lack of effective therapeutic interventions for many neurological illnesses like Alzheimer's and epilepsy has prompted us to investigate the composition and effects of the Lavandula coronopifolia oil from Palestine on cancer cells and AMPA receptor subunits in the brain due to the vast range of beneficial properties of Lavandula coronopifolia essential oil (EO). GC/MS was used to analyze L. coronopifolia's EO chemistry. EO's cytotoxicity and biophysical effects on AMPA receptors were investigated using MTS and electrophysiological techniques. The GC–MS results revealed that L. coronopifolia EO has a high content of eucalyptol (77.23%), β-pinene (6.93%), and α-pinene (4.95%). The EO showed more significant antiproliferative selectivity activities against HepG2 cancer cell lines than HEK293T cell lines with IC50 values of 58.51 and 133.22 µg/mL, respectively. The EO of L. coronopifolia affected AMPA receptor kinetics (desensitization and deactivation) and preferred homomeric GluA1 and heteromeric GluA1/A2 receptors. These findings indicate the potential therapeutic use of L. coronopifolia EO in the selective treatment of HepG2 cancer cell lines and neurodegenerative diseases.

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.