Cell Antiproliferative Activity Research Articles

Discovery of novel Macrocyclic small molecules Based on 2-Amino-4-thiazolylpyridineas selective EGFR inhibitors with high Blood-Brain barrier penetration for the treatment of glioblastoma

Because epidermal growth factor receptor (EGFR) is the most commonly mutated oncogene in glioblastoma (GBM), the development of EGFR inhibitors has become a promising direction for the treatment of GBM. However, due to factors such as limited blood–brain barrier (BBB) permeability and pathway compensation mechanisms, current EGFR inhibitors targeting GBM are not satisfactory. In the previous study, we obtained compound 10c with strong anti-cell proliferation activity. Since macrocyclization can effectively change the physical and chemical properties of molecules, and optimize their selectivity. Therefore, a series of 2-amino-4-thiazolyl pyridine scaffold macrocyclic derivatives were designed and synthesized using compound 10c as the lead compound in this study. Compound 3a, which inhibited the growth of glioblastoma cell lines U87MG and U87-EGFRVIII, had average IC50 values of 4.69 µM and 4.98 µM, respectively. Compound 3a was highly selective to 9 kinases in the ErbB family, including ErbB2 and ErbB4. In addition, compound 3a demonstrated good blood–brain barrier permeability in mice, the blood–brain concentration of the drug remained above 20 % within 5–60 min following intravenous administration in mice. In conclusion, compound 3a is a promising candidate for novel EGFR inhibitors targeting GBM.

Discovery of a Highly Potent and Selective Inhibitor Targeting Protein Lysine Methyltransferase NSD2.

The histone lysine methyltransferase NSD2 has been recognized as an attractive target for cancer treatment, due to the functional implication of its dysregulation in the initiation and progression of many cancers. Although considerable efforts have been made to develop NSD2 small-molecule inhibitors, highly potent and selective ones are still rarely available till now. Here, we report the discovery of a series of novel NSD2 inhibitors via an extensive SAR exploration of the privileged quinazoline scaffold within compound 8. The most promising compound 42 showed excellent NSD2 enzymatic inhibitory activity and good antiproliferative activity in cells. In addition, it demonstrated favorable pharmacokinetic properties and significantly inhibited the tumor growth in a RS411 tumor xenograft model with good safety. Taken together, compound 42 could be a promising NSD2 inhibitor and deserves further investigation.

Antioxidant, Antiproliferative and Antibacterial Activity of Phoradendron californicum Extracts; a Parasitic Plant from Northwestern Mexico

Phoradendron californicum is a plant native of northwestern Mexico that has been used as a therapeutic alternative. In the present study, methanolic and chloroformic extracts of P. californicum were prepared and evaluated for their antioxidant activities, phenolic and flavonoid content, as well as their antiproliferative activity in cancer cells and antibacterial activity. The methanolic extract presented higher antioxidant activity (IC50: 47.62 ± 2.90 μg/mL) and higher total phenol content (186.45 ± 4.58 μg/mL) compared to the chloroformic extract (IC50: ˃400 ug/mL and 13.54 ± 1.57 μg/mL, respectively), both extracts presented similar content of total flavonoids (19.92 ± 1.84 and 25.55 ± 0.73 μg/mL, respectively). On the other hand, the chloroformic extract presented higher antiproliferative activity in the cell lines evaluated (HeLa, PC3 and L929) compared to the methanolic extract, meanwhile, in the antibacterial activity the chloroformic extract presented higher activity against Escherichia coli and Listeria monocytogenes, while the methanolic extract was more active against Salmonella enterica. The clear difference in the biological activities of both extracts may be due to differences in the chemical composition of each due to the extraction method used. P. californicum has potential for the search of new compounds with biological activity

Synthesis, cancer cell antiproliferative and antibacterial activity of zinc hydroxybenzoate complexes of substituted terpyridines

Terpyridine metal complexes are well known for their wide range of biological activities, among which the anticancer effect has received increasing attention. In this paper, nine zinc terpyridine complexes were synthesized by using zinc o/m/p-hydroxybenzoate and three 4′-(substituted phenyl)-2,2′:6′,2″-terpyridine ligands, and the structures of these complexes were characterized by elemental analysis, infrared spectroscopy, single crystal X-ray diffraction,11H NMR spectroscopy and ESI-MS.. In order to study their antiproliferative activities, four cell lines were selected for in vitro cellular experiment: human esophageal cancer cell line (Eca-109), human breast cancer cell line (MCF-7), human hepatocellular carcinoma cell (Bel-7402) and human normal liver cells (HL-7702). The results show that they possess standout inhibitory effect on the proliferation activity against the cancer cells but less cytotoxicity to normal cells, being superior to cisplatin, a commonly used drug in clinical practice. Bacteriostatic experiment also shows that most complexes have a good inhibitory effect on Staphylococcus aureus, with the minimum bacteriostatic concentration is as low as 20 μg/mL. The strong affinity between these complexes and CT-DNA was verified by UV spectrum, and the main binding mode of intercalation was found by circular dichroism. Molecular docking study reveals that these complexes bind to the double-stranded DNA mainly by intercalation, giving the binding capacity sequence as ATAT < GCGC. And they bind to G-quadruplex mainly through electrostatic force, with the binding capacity of 2A5R > 2KKA > 1CN0.

The Autoxidized Mixture of (-)-Epicatechin Contains Procyanidins and Shows Antiproliferative and Apoptotic Activity in Breast Cancer Cells.

For this study, procyanidins generated through the autoxidation of (-)-epicatechin (Flavan-3-ol) under mildly acidic conditions (pH = 6.0) were characterized with ultra high-performance liquid chromatography (UHPLC) coupled with tandem mass spectrometry (MS/MS). Two procyanidins (types A and B) and a mix of oligomers were generated through the autoxidation of (-)-epicatechin. The antiproliferative activity of this mixture of procyanidins on MDA-MB-231, MDA-MB-436, and MCF-7 breast cancer cells was evaluated. The results indicate that the procyanidin mixture inhibited the proliferation of breast cancer cells, where the activity of the procyanidin mixture was stronger than that of (-)-epicatechin. Moreover, the mechanism underlying the antiproliferative activity of procyanidins was investigated. The resulting data demonstrate that the procyanidins induced apoptotic cell death in a manner selective to cancerous cells. In particular, they caused the activation of intrinsic and extrinsic apoptotic pathways in the breast cancer cells. The findings obtained in this study demonstrate that the generation of procyanidins in vitro by the autoxidation of (-)-epicatechin has potential for the development of anti-breast cancer agents.

Cereblon-based Bifunctional Degrader of SOS1, BTX-6654, Targets Multiple KRAS Mutations and Inhibits Tumor Growth.

Mutations within the oncogene KRAS drive an estimated 25% of all cancers. Only allele-specific KRAS G12C inhibitors are currently available and are associated with the emergence of acquired resistance, partly due to upstream pathway reactivation. Given its upstream role in the activation of KRAS, son of sevenless homolog 1 (SOS1), has emerged as an attractive therapeutic target. Agents that target SOS1 for degradation could represent a potential pan-KRAS modality that may be capable of circumventing certain acquired resistance mechanisms. Here, we report the development of two SOS1 cereblon-based bifunctional degraders, BTX-6654 and BTX-7312, cereblon-based bifunctional SOS1 degraders. Both compounds exhibited potent target-dependent and -specific SOS1 degradation. BTX-6654 and BTX-7312 reduced downstream signaling markers, pERK and pS6, and displayed antiproliferative activity in cells harboring various KRAS mutations. In two KRAS G12C xenograft models, BTX-6654 degraded SOS1 in a dose-dependent manner correlating with tumor growth inhibition, additionally exhibiting synergy with KRAS and MEK inhibitors. Altogether, BTX-6654 provided preclinical proof of concept for single-agent and combination use of bifunctional SOS1 degraders in KRAS-driven cancers.

Targeting the Subpocket Enables the Discovery of Thiadiazole-Pyridazine Derivatives as Glutaminase C Inhibitors.

As glutaminase C (GAC) has become an attractive target for cancer treatment by regulating glutaminolysis, thus, interest in GAC inhibitors has risen in recent years. Herein, a potential binding subpocket comprising basic residues was identified, and through extensive structure-activity relationship studies, promising inhibitors 11 and 39 were identified with robust GAC inhibitory activity and A549 cell antiproliferative activity. X-ray crystallography of the 11-GAC and 27-GAC complexes revealed a novel binding mode against GAC. The potency of 11 and 27 against GACK320A further highlighted the importance of the binding. Notably, compounds 11 and 39 regulated the cellular metabolite, thereby increasing reactive oxygen species by blocking glutamine metabolism. Compound 11 also exhibited excellent antiproliferative activity in the A549 cell xenograft model. We further proved that 11 is a safe GAC allosteric inhibitor. A basic subpocket is proposed that might provide new strategies for the development of novel GAC inhibitors in the future.

Analytical Investigation of Forced Oxidized Anti-VEGF IgG Molecules: A Focus on the Alterations in Antigen and Receptor Binding Activities

Alterations in the biological activity of the molecules under stress conditions have not been documented as widely in the literature yet. This study was designed to reveal the functional impacts of various oxidation conditions on a model mAb, a commercial anti-VEGF IgG molecule. The responses to antigen binding, cell proliferation, FcRn receptors, and C1q binding, which rarely appear in the current literature, were investigated. The authors report peptide mapping data, post-translational modification (PTM) analysis, cell proliferation performance, and antigen (VEGF), C1q, and FcRn binding activities of the mAb under various stress conditions. The oxidation-prone site of the mAb was determined as Met252 in the DTLMISR peptide. The VEGF binding activity and anti-cell proliferation activity of the mAbs did not alter, while C1q and FcRn binding capacity significantly decreased under oxidative stress conditions. The full report is vital for many scientific and industrial processes about mAbs. The authors recommend performing functional analyses in addition to the structural studies while investigating the impacts of stress factors on therapeutic mAbs.

Abstract 4008: TAS2940, a novel brain-penetrable pan-ERBB inhibitor, exhibits tumor regression and prolongs survival in intracranial models bearing ERBB aberrations

Abstract Background: Primary and metastatic brain tumors have significant unmet medical needs as few drugs can penetrate the blood-brain barrier (BBB). Brain metastasis is more common in non-small cell lung cancer (NSCLC) and breast cancer than in other cancers. Genetic alterations in ERBB family genes are frequently observed in those cancers, with about half of HER2/EGFR aberrations metastasizing in the brain. EGFR aberrations have been also observed in glioblastoma. Several pan-ERBB inhibitors are clinically available or under clinical development, such as afatinib, neratinib, and poziotinib. However, none are highly brain-penetrable as they are pumped out via the BBB. Here, we report TAS2940 as a novel potent pan-ERBB inhibitor that elicits brain penetrability and anti-tumor effects in brain metastasis models. Methods: The kinase selectivity of TAS2940 was evaluated in a panel of 257 kinases. Autophosphorylation of wild-type and mutant ERBB in stably expressing cell lines was evaluated using a quantitative immunofluorescence assay. The growth inhibitory effect on cell lines expressing HER2/EGFR aberrations was evaluated based on quantitation of the cellular ATP concentration. Cell lines were transplanted subcutaneously or intracranially in BALB/cAJcl-nu/nu mice. HER2 tyrosine kinase inhibitors, including TAS2940, were then orally administered once daily followed by evaluation of tumor volume and body weight. Results: TAS2940 showed potent and selective inhibition against ERBB family proteins over more than 250 kinases on enzymatic assay. TAS2940 also showed preferential cytotoxicity in cells harboring HER2/EGFR genetic alterations in vitro, while sparing cells without ERBB genetic aberrations. TAS2940 showed potent anti-proliferative activity in cells containing HER2 genetic alterations or EGFR exon 20 insertions, commonly found in NSCLC or breast cancer, as well as EGFRvIII alterations, frequently observed in glioblastoma. In vivo xenograft tumor models with various EGFR genetic alterations showed that TAS2940 exerted anti-tumor effects, such as growth retardation or regression. We further examined brain penetration by assessing the brain to blood concentration of TAS2940 in mice with intact BBBs, showing higher brain penetrability compared to other ERBB inhibitors. Evaluation of TAS2940 in intracranial brain metastasis mouse models resulted in tumor regression and prolonged survival. Conclusion: TAS2940 is a novel potent and selective pan-ERBB inhibitor with high brain penetrability in vivo. These results support the clinical development of TAS2940 in primary and metastatic brain tumors driven by ERBB genetic aberrations. Citation Format: Kei Oguchi, Hikari Araki, Shingo Tsuji, Masayuki Nakamura, Akihiro Miura, Kaoru Funabashi, Akiko Osada, Sakiho Tanaka, Takamasa Suzuki, Shinji Mizuarai. TAS2940, a novel brain-penetrable pan-ERBB inhibitor, exhibits tumor regression and prolongs survival in intracranial models bearing ERBB aberrations. [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 4008.

Identification of New Purpuroine Analogues from the Arctic Echinodermata Pteraster militaris That Inhibit FLT3-ITD+ AML Cell Lines.

Isolation of bioactive products from the marine environment is considered a very promising approach to identify new compounds that can be used for further drug development. In this work we have isolated three new compounds from the purpuroine family by mass-guided preparative HPLC; purpuroine K-M. These compounds where screened for antibacterial- and antifungal activity, antibiofilm formation and anti-cell proliferation activity. Additionally, apoptosis-, cell cycle-, kinase binding- and docking studies were performed to evaluate the mechanism-of-action. None of the compounds showed activity in antibacterial-, antibiofilm- or antifungal assays. However, one of the isolated compounds, purpuroine K, showed activity against two cell lines, MV-4-11 and MOLM-13, two AML cell lines both carrying the FTL3-ITD mutation. In MV-4-11 cells, purpuroine K was found to increase apoptosis and arrest cells cycle in G1/G0, which is a common feature of FLT3 inhibitors. Interactions between purpuroine K and the FLT3 wild type or FLT3 ITD mutant proteins could however not be elucidated in our kinase binding and docking studies. In conclusion, we have isolated three novel molecules, purpuroine K-M, one of which (purpuroine K) shows a potent activity against FLT3-ITD mutated AML cell lines, however, the molecular target(s) of purpuroine K still need to be further investigated.

Insilco and Invitro approaches identify novel dual PI3K/AKT pathway inhibitors to control acute myeloid leukemia cell proliferations.

Acute myeloid leukemia (AML) is characterized by disruption of intracellular signaling due to aberration of extracellular signaling pathways, namely PI3K/AKT cascade, by dysregulating erythropoiesis and myelopoiesis. Therefore, inhibition of PI3K/AKT, either individually, or by dual inhibitors, is shown to be effective in suppression of tumorigenesis. To increase the therapeutic viability and decrease adverse effects, including cytotoxicity due to off-target kinase inhibitions, customized targeted pharmacological agents are needed that would have greater treatment potential. In this work, using an interdisciplinary approach, we have identified dual inhibitors targeted to PI3K and AKT to significantly repress the cell proliferation in AML cancers. Diversity-based high-throughput virtual screening (D-HTVS) technique followed by conventional docking approach identified small molecules from ChemBridge library, having high binding affinity for PI3KCG subunit. Further computational screening of top identified PI3K-specific lead molecules predicts dual inhibitors with high binding affinity for AKT. To rule out the possibility for cross-reaction/off-target effects of identified small molecules, lead compounds having nil or negligible binding to PI3KCA- and PI3KCB subunits were chosen. Computational screening, enzyme inhibition and cell proliferation assays show compound C16,5-{[(1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)amino]methylene}-1-phenyl-2,4,6(1H,3H,5H)-pyrimidinetrione has better affinity for PI3KCG, delta, and AKT kinases compared to their respective known/established inhibitors, and has significant anti-cell proliferation activity in AML cells with a GI50 values of 77.25nM and 49.65nM in THP-1 and HL-60 cells, respectively. This work proposes a novel dual inhibitor that selectively targets PI3K/AKT and suppresses cell proliferation in AML cells as a potential lead molecule for treating AML cancers.

Insight into the physicochemical properties and bioactivities of therapeutic deep eutectic solvents based on matrine and fatty acids

• THEDESs based on matrine and fatty acids were developed. • Physicochemical properties of THEDESs were investigated. • Antibacterial and anti-cancer activities and cytotoxicity of THEDESs were studied. Deep eutectic solvents (DESs), as a new type of green solvent, have shown great advantages of easy preparation, no purification needed after synthesis and great potential for application in various fields. Recently, a new type of drug delivery system called therapeutic deep eutectic solvent (THEDES) was developed when combining active pharmaceutical ingredients (APIs) into DES. Herein, we have constructed a series of new THEDES based on matrine (API) and fatty acids. Their physicochemical properties and bioactivities were investigated. In a temperature range from 298.15 K to 338.15 K, both density and viscosity declined with the increasing temperature. Besides, the density of THEDES decreased with the increasing alkyl chain length of fatty acids due to the enhancement of free volume, while the alkyl chain length displayed no influence on the viscosity of THEDES. Moreover, THEDESs showed better antibacterial activity on S. aureus as compared with matrine and the mixture solution of matrine and fatty acids at the same concentration. THEDESs also displayed better cell antiproliferative activities and higher cytotoxicity than that of matrine. Therefore, the results presented herein provides important basis for the further applications of matrine in the form of THEDES.

Discovery of a novel ALK/ROS1/FAK inhibitor, APG-2449, in preclinical non-small cell lung cancer and ovarian cancer models

BackgroundTyrosine kinase inhibitors (TKIs) are mainstays of cancer treatment. However, their clinical benefits are often constrained by acquired resistance. To overcome such outcomes, we have rationally engineered APG-2449 as a novel multikinase inhibitor that is highly potent against oncogenic alterations of anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1 receptor tyrosine kinase (ROS1), and focal adhesion kinase (FAK). Here we present the preclinical evaluation of APG-2449, which exhibits antiproliferative activity in cells carrying ALK fusion or secondary mutations.MethodsKINOMEscan® and LANCE TR-FRET were used to characterize targets and selectivity of APG-2449. Water-soluble tetrazolium salt (WST-8) viability assay and xenograft tumorigenicity were employed to evaluate therapeutic efficacy of monotherapy or drug combination in preclinical models of solid tumors. Western blot, pharmacokinetic, and flow cytometry analyses, as well as RNA sequencing were used to explore pharmacokinetic–pharmacodynamic correlations and the mechanism of actions driving drug combination synergy.ResultsIn mice bearing wild-type or ALK/ROS1-mutant non-small-cell lung cancer (NSCLC), APG-2449 demonstrates potent antitumor activity, with correlations between pharmacokinetics and pharmacodynamics in vivo. Through FAK inhibition, APG-2449 sensitizes ovarian xenograft tumors to paclitaxel by reducing CD44+ and aldehyde dehydrogenase 1-positive (ALDH1+) cancer stem cell populations, including ovarian tumors insensitive to carboplatin. In epidermal growth factor receptor (EGFR)-mutated NSCLC xenograft models, APG-2449 enhances EGFR TKI-induced tumor growth inhibition, while the ternary combination of APG-2449 with EGFR (osimertinib) and mitogen-activated extracellular signal-regulated kinase (MEK; trametinib) inhibitors overcomes osimertinib resistance. Mechanistically, phosphorylation of ALK, ROS1, and FAK, as well as their downstream components, is effectively inhibited by APG-2449.ConclusionsTaken together, our studies demonstrate that APG-2449 exerts potent and durable antitumor activity in human NSCLC and ovarian tumor models when administered alone or in combination with other therapies. A phase 1 clinical trial has been initiated to evaluate the safety and preliminary efficacy of APG-2449 in patients with advanced solid tumors, including ALK+ NSCLC refractory to earlier-generation ALK inhibitors.Trial registrationClinicaltrial.gov registration: NCT03917043 (date of first registration, 16/04/2019) and Chinese clinical trial registration: CTR20190468 (date of first registration, 09/04/2019).

Structure-based virtual screening towards the discovery of novelFOXM1inhibitors.

Aim: Given the importance of FOXM1 in the treatment of ovarian cancer, we aimed to identify an excellent specific inhibitor and examined its underlying therapeutic effect. Materials & methods: The binding statistics for FDI-6 with FOXM1 were calculated through computer-aided drug design. We selected XST-119 through virtual screening, performed surface plasmon resonanceand invitro cell antiproliferative activity analysisand evaluated its antitumor efficacy in a mouse model. Results: XST-119 had significantly higher affinity for FOXM1 and antiproliferative activity than FDI-6. XST-119 had a definite inhibitory activity in a xenograft mousemodel. Conclusion: We identifiedXST-119, a FOXM1 inhibitor, with better efficacy for treatment of ovarian cancer. FOXM1 binding sites for small molecules are also highlighted, which may provide the foundation for further drug discovery.

Nonpeptidic, Polo-Box Domain-Targeted Inhibitors of PLK1 Block Kinase Activity, Induce Its Degradation and Target-Resistant Cells.

PLK1, polo-like kinase 1, is a central player regulating mitosis. Inhibition of the subcellular localization and kinase activity of PLK1 through the PBD, polo-box domain, is a viable alternative to ATP-competitive inhibitors, for which the development of resistance and inhibition of related PLK family members are concerns. We describe novel nonpeptidic PBD-binding inhibitors, termed abbapolins, identified through successful application of the REPLACE strategy and demonstrate their potent antiproliferative activity in prostate tumors and other cell lines. Furthermore, abbapolins show PLK1-specific binding and inhibitory activity, as measured by a cellular thermal shift assay and an ability to block phosphorylation of TCTP, a validated target of PLK1-mediated kinase activity. Additional evidence for engagement of PLK1 was obtained through the unique observation that abbapolins induce PLK1 degradation in a manner that closely matches antiproliferative activity. Moreover, abbapolins demonstrate antiproliferative activity in cells that are dramatically resistant to ATP-competitive PLK1 inhibitors.

In vitro performance of free and encapsulated bromelain

For centuries, bromelain has been used to treat a range of ailments, even though its mechanism of action is not fully understood. Its therapeutic benefits include enzymatic debridement of the necrotic tissues of ulcers and burn wounds, besides anti-inflammatory, anti-tumor, and antioxidant properties. However, the protease is unstable and susceptible to self-hydrolysis over time. To overcome the stability issues of bromelain, a previous study formulated chitosan-bromelain nanoparticles (C-B-NP). We evaluated the optimized nanoformulation for in vitro antioxidant, cell antiproliferative activities and cell migration/proliferation in the scratch assay, comparing it with free bromelain. The antioxidant activity of free bromelain was concentration and time-dependent; after encapsulation, the activity level dropped, probably due to the slow release of protein from the nanoparticles. In vitro antiproliferative activity was observed in six tumor cell lines for free protein after 48 h of treatment (glioma, breast, ovarian, prostate, colon adenocarcinoma and chronic myeloid leukemia), but not for keratinocyte cells, enabling its use as an active topical treatment. In turn, C-B-NP only inhibited one cell line (chronic myeloid leukemia) and required higher concentrations for inhibition. After 144 h treatment of glioma cells with C-B-NP, growth inhibition was equivalent to that promoted by the free protein. This last result confirmed the delayed-release kinetics of the optimized formulation and bromelain integrity. Finally, a scratch assay with keratinocyte cells showed that C-B-NP achieved more than 90% wound retraction after 24 h, compared to no retraction with the free bromelain. Therefore, nanoencapsulation of bromelain with chitosan conferred physical protection, delayed release, and wound retraction activity to the formulation, properties that favor topical formulations with a modified release. In addition, the promising results with the glioma cell line point to further studies of C-B-NP for anti-tumor treatments.

Mechanistic insight of cell anti-proliferative activity of fluoroquinolone drug-based Cu(II) complexes.

Pefloxacin-based mixed ligand Cu(II) complexes with substituted isatin of type [Cu(Isatin)(Pefloxacin)Cl] were synthesized, and characterized by EPR, mass, FT-IR, electronic spectrometry, metal content, magnetic moment, and conductance measurement. The g factors g [Formula: see text] > g [Formula: see text] > 2.0023 observed in EPR suggest a square-pyramidal environment of ligands around the copper metal. The compounds were screened for diverse biological activities. The compounds inhibit efficiently the cell proliferation of HCT 116 cancer cells. To take the insight of anticancer activity mechanism, we investigated compound-1 for further cellular assay-based biological activities like trypan blue assay, cell morphological alteration assay, colony formation assay, cell apoptosis, and cell necrosis assay. The compound-1 induced distinct morphological alteration in cells, inhibits cell viability, decreases % plating efficiency, and decreases the clonogenic ability of the HCT 116 cells. The cell death mechanism was confirmed by annexin V-FITC / PI assay and LDH release assay. The positive annexin V/PI stained cells in presence of compound-1 and the absence of a significant amount of lactate dehydrogenase suggest cell apoptosis mechanism for anticancer activity of compounds. We also screened compounds for in vitro antibacterial and cytotoxic activities. Synthesis, characterization, antibacterial, anticancer, and cytotoxicity activities of pefloxacin based Cu(II) complexes were studied. The compound -1 is more potent than standard anticancer drugs and it induced apoptosis to the HCT 116 cells.

Indolyl-α-keto-1,3,4-oxadiazoles: Synthesis, anti-cell proliferation activity, and inhibition of tubulin polymerization

A series of novel indolyl-α-keto-1,3,4-oxadiazole derivatives have been synthesized by employing molecular iodine-mediated oxidative cyclization of acylhydrazones. In vitro anti cell proliferation activity of these derivatives against various cancer cells lines such as human lymphoblast (U937), leukemia (Jurkat & SB) and human breast (BT474) was investigated. Among the synthesized indolyl-α-keto-1,3,4-oxadiazoles 19a-p, only one compound (19e) exhibited significant antiproliferative activity against a panel of cell lines. The compound 19e with 3,4,5-trimethoxyphenyl motif, endowed strong cytotoxicity against U937, Jurkat, BT474 and SB cancer cells with IC50 values of 7.1, 3.1, 4.1, and 0.8 µM, respectively. Molecular docking studies suggested a potential binding mode for 19e in the colchicine binding site of tubulin. When tested for in vitro tubulin polymerizaton, 19e inhibited tubulin polymezations (IC50 = 10.66 µM) and induced apoptosis through caspase 3/7 activation. Further, the derivative 19e did not cause necrosis when measured using lactate dehydrogenase assay.

In-vitro Chemopreventive Potential of a Chromone from Bomarea setacea (ALSTROEMERIACEAE) against Colorectal Cancer.

Chemoprevention with natural products may provide important alternatives in the search for new drugs to treat cancer. Thus, the ethanol extract of Bomarea setacea and its secondary metabolite (chromone) were evaluated in-vitro in SW480 and SW620 human adenocarcinoma colon cells to identify a possible effect on cell growth, antiproliferative and/or proapoptotic activity. The ethanol extract did not show growth inhibition of these cell lines 48 h after treatment; besides, it required higher concentration and time to have an antiproliferative effect. On the other hand, although the chromone was not as active as the reference drug (5-FU), it displayed a greater selectivity, being 156-fold more selective against SW480 cells (SI => 100) and 255-fold against SW620 cells (SI => 86,9). Additionally, the chromone caused an important arrest in G2/M (44.18%) with an important accumulation in subG0/G1 phase in SW620 cells, inducing loss in mitochondrial membrane potential and damage in the cell membrane of both cell lines, with activation of caspase 3, suggesting an apoptotic process independent of ROS production and p53 activation.

Rationally Designed Covalent BCL6 Inhibitor That Targets a Tyrosine Residue in the Homodimer Interface.

B-cell lymphoma 6 (BCL6) is a transcriptional repressor frequently deregulated in lymphoid malignancies. BCL6 engages with number of corepressors, and these protein-protein interactions are being explored as a strategy for drug development. Here, we report the development of an irreversible BCL6 inhibitor TMX-2164 that uses a sulfonyl fluoride to covalently react with the hydroxyl group of Tyrosine 58 located in the lateral groove. TMX-2164 exhibits significantly improved inhibitory activity compared to that of its reversible parental compound and displays sustained target engagement and antiproliferative activity in cells. TMX-2164 therefore represents an example of a tyrosine-directed covalent inhibitor of BCL6 which demonstrates advantages relative to reversible targeting.