Lectins CGL and MTL, representatives of mytilectin family, exhibit different antiproliferative activity in Burkitt's lymphoma cells.

Lectins are carbohydrate-binding proteins, whose biological effects are exerted via binding to glycoconjugates expressed on the surface of cells. Exposure to lectins can lead not only to a change in the structure and properties of cells but also to their death. Here, we studied the biological activity of lectins from the mussels Crenomytilus graynus (CGL) and Mytilus trossulus (MTL) and showed that these proteins can affect the proliferation of human lymphoma cells. Both lectins suppressed the formation of colonies as well as cell cycle progression. The mechanism of action of these lectins was not mediated by reactive oxygen species but included damaging of mitochondria, inhibition of key cell cycle points, and activation of MAPK signaling pathway in tumor cells. Computer modeling suggested that various effects of CGL and MTL on lymphoma cells may be due to the difference in the energy of binding of these lectins to carbohydrate ligands on the cell surface. Thus, molecular recognition of residues of terminal carbohydrates on the surface of tumor cells is a key factor in the manifestation of the biological action of lectins.

Chalcones induce apoptosis, autophagy and reduce spreading in osteosarcoma 3D models.

Osteosarcoma is the most common primary bone malignancy with a challenging prognosis marked by a high rate of metastasis. The limited success of current treatments may be partially attributed to an incomplete understanding of osteosarcoma pathophysiology and to the absence of reliable in vitro models to select the best molecules for in vivo studies. Among the natural compounds relevant for osteosarcoma treatment, Licochalcone A (Lic-A) and chalcone derivatives are particularly interesting. Here, Lic-A and selected derivatives have been evaluated for their anticancer effect on multicellular tumor spheroids from MG63 and 143B osteosarcoma cell lines. A metabolic activity assay revealed Lic-A, 1i, and 1k derivatives as the most promising candidates. To delve into their mechanism of action, caspase activity assay was conducted in 2D and 3D in vitro models. Notably, apoptosis and autophagic induction was generally observed for Lic-A and 1k. The invasion assay demonstrated that Lic-A and 1k possess the ability to mitigate the spread of osteosarcoma cells within a matrix. The effectiveness of chalcone as a natural scaffold for generating potential antiproliferative agents against osteosarcoma has been demonstrated. In particular, chalcones exert their antiproliferative activity by inducing apoptosis and autophagy, and in addition they are capable of reducing cell invasion. These findings suggest Lic-A and 1k as promising antitumor agents against osteosarcoma cells.

Synthesis and antiproliferative evaluation of new hybrids of piperine and acylhydrazone.

Piperine, a natural amide isolated from the genus of Piper, serves as a pharmacophore in medicinal chemistry. In this study, we synthesised and evaluated 18 novel piperine-acylhydrazone hybrids (4a-4r) for their antiproliferative activities in vitro. The structures of these hybrids were validated using 1H,13C NMR, and HR-ESI-MS data. Furthermore, we screened all synthesised compounds for their antiproliferative activities against three human cancer cell lines: FaDu (laryngeal carcinoma cells), HepG2 (hepatoblastoma carcinoma cells), and MGC803 (gastric carcinoma cells). Among them, compound 4o exhibited significantly inhibitory activities against FaDu, HepG2, and MGC803 with IC50 values of 13.85 ± 0.19, 11.02 ± 1.45, and 13.47 ± 3.43 µM, respectively, which was approximately two-fold lower than the positive control cisplatin. These findings suggest that compound 4o has the potential to be promising leads for the design of anti-cancer drugs.

Growth inhibitory effect of Leptospermum scoparium (manuka) chloroform extract on breast and liver cancer cell lines.

Objective: Research has demonstrated that Leptospermum scoparium possesses various therapeutic benefits. This study set out to determine whether or not L. scoparium extracts had any effect on the ability of HepG2 and MCF-7 breast cancer cells to survive. Materials and Methods: The antiproliferative activity of L. scoparium extracts was explored using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and lactate dehydrogenase assays. The most active fraction was selected to investigate its effects on apoptosis induction using flow cytometry and quantitative real-time polymerase chain reaction. The constituents of this fraction were characterized using GC-MS analysis. Results: Research demonstrated that the chloroform fraction of L. scoparium (LSCF) significantly impacted the HepG2 and MCF-7 cancer cell lines. Treatment with LSCF led to a notable rise in both early and late apoptotic cells. Furthermore, there was an upregulation in the mRNA levels of P53, Bax, and caspases, while the expression of Bcl-2 mRNA saw a decrease. The analysis of LSCF revealed the primary components to be cis-calamenene, beta-eudesmol, cyclododecane, and alpha-muurolene. Conclusion: The study showed the promising antiproliferative activity of L. scoparium, suggesting its potential application for cancer treatment.

Novel tetrahydropyran-triazole hybrids with antiproliferative activity against human tumor cells.

A series of new hybrid compounds was prepared combining tetrahydropyran rings with different aromatic systems by means of a 1,2,3-triazole, using a building block strategy. The design of these structures was guided by Lead-Likeness and Molecular Analysis (LLAMA) software, adding modifications to our most potent scaffold (the tetrahydropyran ring) to generate promising "lead-like" candidates, which were subsequently compared against reported anticancer compounds. Our synthesized compounds demonstrated significant antiproliferative activity when compared with the standards cisplatin and 5-fluorouracil, across a panel of six different tumor cell lines. Moreover, compared with our group's previous hybrid compounds, these new structures exhibit similar activity while offering simpler synthesis and greater potential for structural diversification, a fact that was previously an issue. Further investigations on the most active compounds included assessments of reproductive cell survival, inhibition of cell migration, and effects on nuclear morphology, indicating potential diverse mechanisms of action for these compounds. Pharmacokinetic properties were also calculated for the whole series of compounds using the pkCSM online software.

Synthesis, biological evaluation, and molecular docking studies of novel N-substituted piperazine-tethered thiophene-3-carboxamide selenides as potent antiproliferative agents with EGFR kinase inhibitory activity.

In the context of structural investigation and optimization of various potential EGFR inhibitors, a novel series of asymmetrical piperazine-tethered trisubstituted thiophene-3-carboxamide selenide derivatives were synthesized and evaluated for their antiproliferative potential against selected human cancer cell lines. These derivatives, built based on a previously identified hit molecule, were synthesized via multiple-step reactions, including optimization of the C-Se cross-coupling reaction. Two compounds, 17i and 18i, displayed significant cytotoxicity (IC50 value: 4.82 ± 0.80 µM and 1.43 ± 0.08 µM) against HCT116 and A549 cancer cell lines, respectively. Quantitative analysis of apoptotic stages using Annexin V-FITC/PI double staining validated their apoptotic potential. Further, compound 18i demonstrated a remarkable inhibition of EGFR kinase, with an IC50 concentration of 42.3 nM. The lead compound 18i, with remarkable in vitro cytotoxicity, apoptosis induction capability, and EGFR inhibition, emerges as a promising candidate for anticancer therapy.

Chemical characterization and pharmacological properties of polysaccharides from Allium roseum leaves: In vitro and in vivo assays.

Allium roseum is amongst the most important wild medicinal plants. It is known for its diverse biological properties, including antioxidant, antibacterial and antidiabetic activities. In this work, the polysaccharides (PARLs) were ultrasonically extracted from Allium roesum leaves then purified and analyzed by several techniques. Chemical composition and GC-MS analysis showed that the obtained polysaccharides were composed mainly of glucose (40.20 %), mannose (25.30 %), fructose (10.60 %) and galacturonic acid (15.11 %). Moreover, PARLs exhibited a potent antioxidant effect with higher capacities up to 69.61 % and 71.72 % for DPPH and ABTS free radicals, respectively. Furthermore, PARLs significantly modulated inflammatory response by reducing TNF-α, IL-6, and IL-8 pro-inflammatory mediators and promoting the anti-inflammatory IL-10 mediator in LPS stimulated THP-1 derived macrophages. The in-vivo tests proved that the extract was able to decrease carrageenan-induced rat paw swelling by around 68.15 % after 4 h of treatment. PARLs, significantly reduced the growth of U87 (glioblastoma) and IGROV-1 cancer cells with IC50 values of about 4.27 and 7.89 mg/mL respectively. This research clearly shows that Allium roseum polysaccharides can be used as natural antioxidants with anti-inflammatory and anticancer properties.

Relationships of Prodiginins Mechanisms and Molecular Structures to their Antiproliferative Effects.

The Prodiginins (PGs) natural pigments are secondary metabolites produced by a broad spectrum of gram-negative and gram-positive bacteria, notably by species within the Serratia and Streptomyces genera. These compounds exhibit diverse and potent biological activities, including anticancer, immunosuppressive, antimicrobial, antimalarial, and antiviral effects. Structurally, PGs share a common tripyrrolic core but possess variable side chains and undergo cyclization, resulting in structural diversity. Studies have investigated their antiproliferative effects on various cancer cell lines, with some PGs advancing to clinical trials for cancer treatment. This review aims to illuminate the molecular mechanisms underlying PG-induced apoptosis in cancer cells and explore the structure-activity relationships pertinent to their anticancer properties. Such insights may serve as a foundation for further research in anticancer drug development, potentially leading to the creation of novel, targeted therapies based on PGs or their derivatives.

Molecular Hybrid Design, Synthesis, In Vitro Cytotoxicity, In Silico ADME and Molecular Docking Studies of New Benzoate Ester-Linked Arylsulfonyl Hydrazones.

In this paper, we present the synthesis and characterization of two known sulfonyl hydrazides (1 and 2) and their new sulfonyl hydrazone derivatives (9-20), as well as in vitro and in silico investigations of their cytotoxic properties against human lung (A549) and human breast (MCF-7) cancer cell lines. The target compounds (9-20) obtained in high yields were synthesized for the first time by a multi-step reaction, and their structures were confirmed by elemental analysis and various spectral techniques, including FT-IR, 1H-, and 13C-NMR. The antiproliferative profiles of these compounds (1, 2, and 9-20) in this study were determined at concentrations of 200, 100, 50, and 25 µM against selected cancer cell lines for 72 h using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) method. Except for compounds 1 and 2, other compounds (9-20) demonstrated cytotoxic activity at concentrations lower than 200 µM. The newly synthesized compounds (9-20) demonstrated antiproliferative activities at a micromolar level, with IC50 values in the range of 29.59-176.70 µM for the A549 cell line and 27.70-170.30 µM for the MCF-7 cell line. Among these compounds, compound 15 (IC50 = 29.59 µM against A549 cell line and IC50 = 27.70 µM against MCF-7 cell line) showed the highest cytotoxic activity against these two cancer cell lines compared to the reference drug cisplatin (IC50 = 22.42 µM against A549 cell line and IC50 = 18.01 µM against MCF-7 cell line). From docking simulations, to establish a plausible binding mode of compounds, we noticed that compound 15 demonstrated the highest affinity (-6.8508 kcal/mol) for estrogen receptor-beta (ERbeta) compared to others, suggesting promising ERbeta binding potential. Most compounds followed Lipinski's rule of five, with acceptable logP values. Additionally, all had mixed gastrointestinal absorption and limited blood-brain barrier permeability. Overall, our study proposed new sulfonyl hydrazones as a potential class of anticancer agents.

Health-Promoting Effects, Phytochemical Constituents and Molecular Genetic Profile of the Purple Carrot 'Purple Sun' (Daucus carota L.).

The purple carrot cultivar 'Purple Sun' (Daucus carota L.) is characterized by a relevant content of phenolic compounds and anthocyanins, which may play an important role in reducing the risk of chronic diseases and in the treatment of metabolic syndrome. In the present study, the genetic diversity, phytochemical composition, and bioactivities of this outstanding variety were studied for the first time. Genetic analysis by molecular markers estimated the level of genetic purity of this carrot cultivar, whose purple-pigmented roots were used for obtaining the purple carrot ethanol extract (PCE). With the aim to identify specialized metabolites potentially responsible for the bioactivities, the analysis of the metabolite profile of PCE by LC-ESI/LTQ Orbitrap/MS/MS was carried out. LC-ESI/HRMS analysis allowed the assignment of twenty-eight compounds, putatively identified as isocitric acid (1), phenolic acid derivatives (2 and 6), hydroxycinnamic acid derivatives (9, 10, 12-14, 16, 17, 19, 22, and 23), anthocyanins (3-5, 7, 8, 11, and 18), flavanonols (15 and 21), flavonols (20 and 24), oxylipins (25, 26, and 28), and the sesquiterpene 11-acetyloxytorilolone (27); compound 26, corresponding to the primary metabolite trihydroxyoctanoic acid (TriHOME), was the most abundant compound in the LC-ESI/HRMS analysis of the PCE, and hydroxycinnamic acid derivatives followed by anthocyanins were the two most represented groups. The antioxidant activity of PCE, expressed in terms of reactive oxygen species (ROS) level and antioxidant enzymes activity, and its pro-metabolic effect were evaluated. Moreover, the antibacterial activity on Gram (-) and (+) bacterial strains was investigated. An increase in the activity of antioxidant enzymes (SOD, CAT, and GPx), reaching a maximum at 0.5 mg/mL of PCE with a plateau at higher PCE concentrations (1.25, 2.5, and 5.0 mg/mL), was observed. PCE induced an initial decrease in ROS levels at 0.1 and 0.25 mg/mL concentrations, reaching the ROS levels of control at 0.5 mg/mL of PCE with a plateau at higher PCE concentrations (1.25, 2.5, and 5.0 mg/mL). Moreover, significant antioxidant and pro-metabolic effects of PCE on myoblasts were shown by a reduction in ROS content and an increase in ATP production linked to the promotion of mitochondrial respiration. Finally, the bacteriostatic activity of PCE was shown on the different bacterial strains tested, while the bactericidal action of PCE was exclusively observed against the Gram (+) Staphylococcus aureus. The bioactivities of PCE were also investigated from cellular and molecular points of view in colon and hematological cancer cells. The results showed that PCE induces proliferative arrest and modulates the expression of important cell-cycle regulators. For all these health-promoting effects, also supported by initial computational predictions, 'Purple Sun' is a promising functional food and an optimal candidate for pharmaceutical and/or nutraceutical preparations.

Antiproliferative metabolites against glioma cells from the marine-associated actinomycete Streptomyces sp. ZZ735.

Metabolites produced by the genus Streptomyces are the most important resource for discovering bioactive compounds. In this study, chemical investigation on the metabolites produced by the marine-derived Streptomyces sp. ZZ735 in rice solid medium led to the isolation of eighteen compounds (1-18). Chemical structures of the isolated compounds were determined based on their HRESIMS data and the extensive NMR spectral analyses. Streptonaphthothiazines A (1), B (2), 2-(2-hydroxy-2-methylpropanoylamino)-benzoic acid (7), and streptomycinoic acids A (17), B (18) are characterized as five previously undescribed compounds. The structural backbones of streptonaphthothiazines A (1), B (2) and streptomycinoic acids A (17), B (18) are found from a natural resource for the first time. It is also the first report of 2-(2-methylpropanoylamino)-benzoic acid (3), 2-(2-methylpropanoylamino)-benzamide (4), methyl 2-(3-hydroxypropanoylamino)-benzoate (5), 2-propionylaminobenzamide (6), and (2E)-3-(3-hydroxy-4,5-dimethoxyphenyl)-2-propenoic acid (15) as natural products. Streptonaphthothiazines A (1), B (2) and streptomycinoic acids A (17), B (18) have antiproliferative activity against human glioma U87MG or U251 cells with IC50 values ranging from 31.8 to 37.9 µM.

Synthesis of Isatin-derived Heterocycles with Promising Anticancer Activities.

Isatin or 1H-indole-2,3-dione skeleton has been playing a significant role in drug de-sign and development. Isatin itself and many of its derivatives are widely distributed in naturally occurring bioactive compounds. Various synthetic isatin derivatives were found to possess a broad range of significant pharmacological efficacies especially anti-cancer activity against a wide variety of cancer cell lines. Interestingly, on a few occasions, some isatin-derived scaffolds were reported as more potent than the tested reputed drug molecules. As a result, isatin-derived compounds have been gaining significant attention in cancer-based drug developments. In this re-view, we have summarized literature reported during the last two decades related to the synthesis of structurally diverse isatin-derived scaffolds with promising anti-cancer activities.

Design, synthesis, and bioevaluation of diarylpyrimidine derivatives as novel microtubule destabilizers.

In this work, a series of new diarylpyrimidine derivatives as microtubule destabilizers were designed, synthesized, and evaluated for anticancer activities. Based on restriction configuration strategy, we introduced the pyrimidine moiety containing the hydrogen-bond acceptors as cis-olefin bond of CA-4 analogs to improve structural stability. Compounds 11a-t exerted antiproliferative activities against three human cancer cell lines (SGC-7901, HeLa, and MCF-7), due to tubulin polymerization inhibition, showing high selectivity toward cancer cells in comparison with non-tumoral HSF cells, as evidenced by MTT assays. In mechanistic investigations, compound 11s remarkably inhibited tubulin polymerization and disorganized microtubule in SGC-7901 cells by binding to tubulin. Moreover, 11s caused G2/M phase cell cycle arrest in SGC-7901 cells in a concentration-dependent manner. Furthermore, molecular modeling analysis revealed that 11s interacts with tubulin through binding to the colchicine site. In addition, the prediction of physicochemical properties disclosed that 11s conformed well to the Lipinski's rule of five. This work offered a fresh viewpoint for the discovery of new tubulin-targeting anticancer drugs.

Fused in silico and bioactivity evaluation method for drug discovery: T001-10027877 was identified as an antiproliferative agent that targets EGFRT790M/C797S/L858R and EGFRT790M/L858R.

BACKGROUND: Facing the significant challenge of overcoming drug resistance in cancer treatment, particularly resistance caused by mutations in epidermal growth factor receptor (EGFR), the aim of our study was to identify potent EGFR inhibitors effective against the T790M/C797S/L858R mutant, a key player in resistance mechanisms. METHODS: Our integrated in silico approach harnessed machine learning, virtual screening, and activity evaluation techniques to screen 5105 compounds from three libraries, aiming to find candidates capable of overcoming the resistance conferred by the T790M and C797S mutations within EGFR. This methodical process narrowed the search down to six promising compounds for further examination. RESULTS: Kinase assays identified three compounds to which the T790M/C797S/L858R mutant exhibited increased sensitivity compared to the T790M/L858R mutant, highlighting the potential efficacy of these compounds against resistance mechanisms. Among them, T001-10027877 exhibited dual inhibitory effects, with IC50 values of 4.34 µM against EGFRT790M/C797S/L858R and 1.27 µM against EGFRT790M/L858R. Further investigations into the antiproliferative effects in H1975, A549, H460 and Ba/F3-EGFRL858/T790M/C797S cancer cells revealed that T001-10027877 was the most potent anticancer agent among the tested compounds. Additionally, the induction of H1975 cell apoptosis and cell cycle arrest by T001-10027877 were confirmed, elucidating its mechanism of action. CONCLUSIONS: This study highlights the efficacy of combining computational techniques with bioactivity assessments in the quest for novel antiproliferative agents targeting complex EGFR mutations. In particular, T001-10027877 has great potential for overcoming EGFR-mediated resistance and merits further in vivo exploration. Our findings contribute valuable insights into the development of next-generation anticancer therapies, demonstrating the power of an integrated drug discovery approach.

Suppressive Potential of Rosmarinus officinalis L. Extract against Triple-Negative and Luminal A Breast Cancer.

Rosemary is an aromatic plant with ancient and modern applications as a spice and herbal remedy. Due to the strong antioxidant potential of rosemary, the present study investigated the anti-proliferative and pro-apoptotic characteristics of rosemary on luminal A and triple-negative breast cancer cells. The effect of rosemary extract on the WNT10B and ß-Catenin genes was also evaluated. The WNT10B and ß-Catenin expression were measured by real-time PCR. The outcomes of the MTT assay and AnnexinV/PI flow cytometry assay showed that exposure of MCF-7 and MDA-MB-231 cells to rosemary reduced cell viability in a dose-time-dependent routine and promoted apoptosis in breast cancer cells. It was revealed that the extract could exert cytotoxic and apoptotic effects by downregulation of WNT10B and ß-Catenin. Our results suggest rosemary as a promising complementary herbal medicine for breast cancers, without the adverse effects of chemotherapy drugs.

Antimetastatic activity of (arene)ruthenium(II) complex of 4-aryl-4H-naphthopyran.

Metastatic cancer remains a formidable challenge in anticancer therapy. Despite efforts to develop effective antimetastasis drugs over the past half-century, currently approved treatments fall short of expectations. This report highlights the promising antiproliferative activity of a ruthenium-based therapeutic agent, namely dichlorido(p-cymene)[2-amino-4-(pyridin-3-yl)-4H-benzo[h]-chromene-3-carbonitrile]ruthenium(II) (complex 1) against metastatic cell lines. Complex 1 shows significant efficacy in metastatic LoVo and Du-145 cell lines at nanomolar concentrations, being markedly more active than clinically used anticancer cisplatin. Studies on the MDA-MB-231 cell line, which displays invasive characteristics, demonstrated that 1 significantly reduces cell invasion. This efficacy was confirmed by its impact on matrix metalloproteinase production in MDA-MB-231 cells. Given that cell migration drives cancer invasion and metastasis, complex 1's effect on MDA-MB-231 cell migration was evaluated via wound healing assay and vimentin network analysis. Results indicated a strong reduction in migration. A re-adhesion assay further demonstrated that 1 significantly lowers the re-adhesion ability of MDA-MB-231 cells compared to cisplatin. To better simulate the human body environment, a 3D spheroid invasion assay was used. This method showed that 1 effectively inhibits tumor spheroids from infiltrating the surrounding extracellular matrix. This study underscores the potential of (arene)ruthenium(II) complexes with naphthopyran ligands as potent antimetastatic agents for chemotherapy.

Melanin Synthesized by the Endophytic Aureobasidium Pullulans AKW: A Multifaceted Biomolecule with Antioxidant, Wound Healing, and Selective Anti-Cancer Activity.

INTRODUCTION: This study explores the potential of the endophytic fungus Aureobasidium pullulans AKW for melanin production and its anticancer activity. METHOD: We report a significant achievement: A. pullulans AKW synthesized 4.89 g/l of melanin in a simple fermentation medium devoid of tyrosine, a precursor typically required for melanin biosynthesis. This suggests a potentially novel pathway for melanin production compared to previous studies relying on complex media and tyrosine. Furthermore, the isolated and characterized melanin exhibited promising selectivity as an anti-cancer agent. It triggered apoptosis in A431 cancer cells, demonstrating some selectivity compared to normal cells. This selectivity was confirmed by IC50 values and further supported by gene expression changes in A431 cells. Melanin treatment downregulated the anti-apoptotic Bcl2 gene while upregulating pro-apoptotic Bax and p53 genes, indicating its ability to induce programmed cell death in cancer cells. RESULT: Our results demonstrate that A. pullulans AKW-derived melanin exhibits cytotoxic effects against A431, HEPG2, and MCF7 cell lines. Interestingly, the present fungal strain synthesized melanin in a simple medium without requiring precursors. CONCLUSION: The selective activity of the current melanin towards cancer cells, its ability to induce apoptosis, and its relatively low toxicity towards normal cells warrant further investigation for its development as a novel therapeutic option.

Novel Coumarin-steroid/terpenoid Hybrids: In vitro and in silico Anticancer Studies.

We have synthesized a series of novel coumarin-steroid and triterpenoid hybrids and evaluated their potential anticancer activity through molecular docking calculations and in vitro antiproliferative assays. These hybrids, derived from estrone and oleanolic acid, were linked via hydrocarbon spacers of varying lengths. Molecular docking studies against human aromatase revealed strong interactions, particularly for compound 11d, which exhibited significant binding affinity (-12.6308 kcal/mol). In vitro assays demonstrated that compounds 6b and 11d had notable antiproliferative effects, with GI50 values of 5.4 and 7.0 µM against WiDr (colon) and HeLa (cervix) cancer cells, respectively. These findings highlight the potential of these hybrids as novel anticancer agents targeting aromatase, warranting further investigation and optimization.

Discovery and prospects of new heterocyclic Isatin-hydrazide derivative with a novel role as estrogen receptor α degrader in breast cancer cells.

Introduction: Isatin, a heterocycle scaffold, is the backbone of many anticancer drugs and has previously been reported to engage multiple cellular targets and mechanisms, including angiogenesis, cell cycle, checkpoint pathways and multiple kinases. Here, we report that a novel isatin derivative, 5i, degrades estrogen receptor alpha (ERα) in estrogen-dependent breast cancer cells. This effect of the isatin nucleus has not been previously reported. Tamoxifen and fulvestrant represent standard therapy options in estrogen-mediated disease but have their own limitations. Isatin-based triple angiokinase inhibitor BIBF1120 (Nintedanib) and multikinase inhibitor Sunitinib (Sutent) have been approved by the FDA. Methods: Keeping this in view, we synthesized a series of N'-(1-benzyl-2-oxo-1, 2-dihydro-3H-indol-3-ylidene) hydrazide derivatives and evaluated them in vitro for antiproliferative activities in MCF-7 (ER+) cell line. We further investigated the effect of the most potent compound (5i) on the Erα through Western Blot Analysis. We used in silico pharmacokinetics prediction tools, particularly pkCSM tool, to assess the activity profiles of the compounds. Results and discussion: Compound 5i showed the best antiproliferative activity (IC50 value; 9.29 ± 0.97 µM) in these cells. Furthermore, 5i downregulated ERα protein levels in a dose-dependent manner in MCF-7. A multifaceted analysis of physicochemical properties through Data Warrior software revealed some prominent drug-like features of the synthesized compounds. The docking studies predicted the binding of ligands (compounds) with the target protein (ERα). Finally, molecular dynamics (MD) simulations indicated stable behavior of the protein-ligand complex between ERα and its ligand 5i. Overall, these results suggest that the new isatin derivative 5i holds promise as a new ERα degrader.

GQIcombi application to subdue glioma via differentiation therapy.

Current therapy protocols fail to cure high-grade gliomas and prevent recurrence. Therefore, novel approaches need to be developed. A re-programing of glioma cell fate is an alternative attractive way to stop tumor growth. The two-step protocol applies the antiproliferative GQ bi-(AID-1-T) and small molecule inducers with BDNF to trigger neural differentiation into terminally differentiated cells, and it is very effective on GB cell cultures. This original approach is a successful example of the "differentiation therapy". To demonstrate a versatility of this approach, in this publication we have extended a palette of cell cultures to gliomas of II, III and IV Grades, and proved an applicability of that version of differential therapy for a variety of tumor cells. We have justified a sequential mode of adding of GQIcombi components to the glioma cells. We have shown a significant retardation of tumor growth after a direct injection of GQIcombi into the tumor in rat brain, model 101/8. Thus, the proposed strategy of influencing on cancer cell growth is applicable to be further translated for therapy use.