Sulfur (Sâ ¥)-containing heterocyclic hybrids as antibacterial agents against methicillin-resistant Staphylococcus aureus (MRSA) and its SAR.

The discovery of new small molecule-based inhibitors is an attractive field in medicinal chemistry. Structurally diversified heterocyclic derivatives have been investigated to combat multi-drug resistant bacterial infections and they offers several mechanism of action. Methicillin-resistant Staphylococcus aureus (MRSA) is becoming more and more deadly to humans because of its simple method of transmission, quick development of antibiotic resistance, and ability to cause hard-to-treat skin and filmy diseases. The sulfur (SVI) particularly sulfonyl and sulfonamide based heterocyclic moieties, have found to be good anti-MRSA agents. The development of new nontoxic, economical and highly active sulfur (SVI) containing derivatives has become hot research topics in drug discovery research. Presently, more than 150 FDA approved Sulfur (SVI)-based drugs are available in the market, and they are widely used to treat various types of diseases with different therapeutic potential. The present collective data provides the latest advancements in Sulfur (SVI)-hybrid compounds as antibacterial agents against MRSA. It also examines the outcomes of in-vitro and in-vivo investigations, exploring potential mechanisms of action and offering alternative perspectives on the structure-activity relationship (SAR). Sulfur (SVI)-hybrids exhibits synergistic effects with existing drugs to provide antibacterial action against MRSA.

Synthesis of p-CuO/n-ZnO heterostructure by microwave hydrothermal method and evaluation of its photo and bio-catalytic performance.

The use of photocatalysts without noble metals is of great interest in the industrial field for the degradation of organic pollutants. In this study, a CuO/ZnO heterostructure was synthesized using the microwave hydrothermal method and characterized using various analytical techniques. The synthesized CuO/ZnO photocatalyst exhibited a low bandgap energy of 2.4 eV, enabling efficient visible light absorption. The photocatalytic activity of the CuO/ZnO heterostructure was evaluated for the degradation of Methyl Orange (MO) dye and showed a high degradation efficiency of 99 % due to its excellent electron-hole charge separation. The biological activity of the synthesized CuO/ZnO catalyst was further investigated through protein docking studies, which showed promising results. The CuO/ZnO was also evaluated for its anticancer and antibacterial properties. It exhibited effective anticancer activity against prostate cancer cells (PC-3) in a dose-dependent manner, with an IC50 value of 6.87 ± 8. In addition, it demonstrated potent antibacterial activity against Escherichia coli, Staphylococcus aureus, Bacillus cereous and Pseudomonas aeruginola. The results of this study demonstrate the potential of CuO/ZnO heterostructures as promising materials for various applications in the fields of photocatalysis, biomedicine and antimicrobial materials. Future research in this area will focus on further optimizing the properties of the CuO/ZnO heterostructure to enhance its performance in these applications.

Alternative Approach to Access 5-Hydroxy-1H-pyrrol-2-(5H)-ones from Base-Induced Tandem Intramolecular Cyclization of Sulfur Ylide with Ketones and 1,3-Hydroxy Rearrangement.

An easily adaptable protocol for the preparation of 5-hydroxy-1H-pyrrol-2(5H)-ones from readily available starting materials has been reported. The reaction of sulfur ylides with carbonyl compounds is a common approach to synthesizing epoxides. Alternatively, we have developed a method with mild reaction conditions wherein sulfur ylide underwent an intramolecular cyclization with a ketonic carbonyl group in a highly efficient way and was followed by 1,3-hydroxy rearrangement to produce 5-hydroxy-1H-pyrrol-2(5H)-ones in excellent yields. The present method offers a straightforward approach to synthesize 5-hydroxy-1H-pyrrol-2(5H)-ones from sulfur ylides without the aid of transition metal in one-pot operation, which involves sequential cyclization and rearrangement reaction. The formation of 5-hydroxy-1H-pyrrol-2(5H)-ones is supported by different spectroscopic techniques, including X-ray crystallographic data and 2D NMR studies (COSY, HSQC, HMBC, and DEPT).

Design and synthesis of 4-aminophenol-1,3,4-oxadiazole derivative potentiates apoptosis by targeting MAP kinase in triple negative breast cancer cells.

Women below 40 years greatly suffer from triple negative breast cancers (TNBCs). Compared to other breast cancer cases, the poor prognosis and lower survival rate of TNBC patients make it an alarming task to save the human era from this dreadful disease. Therefore, identifying potential novel leads is urgently required to combat the TNBC. To discover a novel anticancer agent, we synthesized a series of novel 4-aminophenolbenzamide-1,3,4 oxadiazole hybrid analogues (7a-l). The structure of the compounds was confirmed by spectral methods (1H & 13C NMR, IR and MS). All the compounds were subjected to their in-silico and in-vitro antiproliferative studies against the TNBC cell lines MDA-MB-468 and MDA-MB-231. The investigations revealed that 7i has significantly promoted apoptosis against MDA-MB-468 and MDA-MB-231 cells with IC50 values of 16.89 and 19.43 µM, respectively. Molecular docking of 7i, with MAPK has exhibited the highest binding score of -7.10 kcal/mol by interacting with crucial amino acids present at the active sites. Molecular docking is further validated with molecular dynamic studies with simulation for 100 ns, depicting various stable interactions with MAPK. Compound 7i, forms stable H-bonds and π-π stacking with amino acid residues. Molecular dynamic simulation (MDS) reveals that hydrophobic and water bridges were very prominent for 7i to bind, with the amino acid residues in close proximity to the active site of p38 MAPK. The investigations show that the In-vitro antiproliferative study of 7i agreed with the in-silico studies. Collectively, our investigations depict 7i as a potent novel lead for the inhibition of TNBCs by targeting p38 MAPK.Communicated by Ramaswamy H. Sarma.

A novel 4-aminophenolbenzamide-1,3,4 oxadiazole library of small molecules displayed potent antiproliferative activity.Compound 7i induces apoptosis significantly against triple-negative breast cancer cells.Compound 7i potentiates apoptosis by targeting p38 MAPK and altering mitochondrial membrane potential.Molecular docking and molecular dynamic simulation (MDSs) confirm the efficient binding of compound 7i with MAPK (Docking score of −7.10 kcal/mol).

Microwave assisted one-pot access to pyrazolo quinolinone and tetrahydroisoxazolo quinolinone derivatives via T3P®-DMSO catalysed tandem oxidative-condensation reaction.

A new approach for the synthesis of two important annulated pyrazolo quinolinone and tetrahydroisoxazolo quinolinone derivatives from multicomponent reactions was achieved by using T3P®-DMSO-catalysed reactions of stable alcohols, cyclic 1,3-dicarbonyl compounds and amino derivatives of phenyl pyrazoles and isoxazole and has been reported for the first time. This reaction occurred via a tandem oxidative-condensation reaction under microwave irradiation and notable characteristics of this protocol are MCR reactions, shorter reaction time, less waste creation, ease of workup, stable precursors, broad substrate scope and functional group tolerance.

Design, synthesis and docking studies of novel 4-aminophenol-1,2,4-oxadiazole hybrids as apoptosis inducers against triple negative breast cancer cells targeting MAP kinase.

In our study, a series of novel 4-aminophenol benzamide-1,2,4-oxadiazole hybrid analogues have been designed and synthesized by condensing 4-hydroxyphenyl arylamides (3a-c) and 5-chloromethyl-3-aryl-1,2,4-oxadiazoles (6a-d). The structure of the synthesised compounds was verified by various spectroscopic techniques (1H NMR, 13C NMR, IR and LC-MS). All the prepared compounds were subjected to in silico and in vitro antiproliferative study against TNBC cell lines MDA-MB-468 and MDA-MB-231. The investigations revealed that compound 7k significantly promoted apoptosis against MDA-MB-468 and MDA-MB-231 cells with IC50 values of 22.31 µM and 26.27 µM, respectively. Compound 7k interacted with crucial active sites of MAPK and exhibited the highest docking score of -7.06 kcal/mol. Docking was validated with molecular dynamic studies with simulation for 100 ns, depicting various stable interactions with MAPK. Consequently, 7k forms stable H-Bonds and π-π stacking with amino acid residues along with π-cation. Our investigations reveal that the in vitro antiproliferative study of 7k was in good correlation with the in silico studies. Hence, 7k serves as a potential novel lead for the inhibition of TNBCs by downregulating MAPK P38.Communicated by Ramaswamy H. Sarma.

Novel 4-aminophenol benzamide-1,2,4 oxadiazole library of small molecules displayed potent antiproliferative activity.Compound 7k induces apoptosis significantly against triple-negative breast cancer cells.Compound 7k potentiates apoptosis by targeting MAPK P38 and altering mitochondrial membrane potential.Molecular docking and molecular dynamic simulations confirm the efficient binding of compound 7k with MAPK (Docking score of ­7.06 kcal/mol).

Noncoding RNAs as regulators of STAT3 pathway in gastrointestinal cancers: Roles in cancer progression and therapeutic response.

Gastrointestinal (GI) tumors (cancers of the esophagus, gastric, liver, pancreas, colon, and rectum) contribute to a large number of deaths worldwide. STAT3 is an oncogenic transcription factor that promotes the transcription of genes associated with proliferation, antiapoptosis, survival, and metastasis. STAT3 is overactivated in many human malignancies including GI tumors which accelerates tumor progression, metastasis, and drug resistance. Research in recent years demonstrated that noncoding RNAs (ncRNAs) play a major role in the regulation of many signaling pathways including the STAT3 pathway. The major types of endogenous ncRNAs that are being extensively studied in oncology are microRNAs, long noncoding RNAs, and circular RNAs. These ncRNAs can either be tumor-promoters or tumor-suppressors and each one of them imparts their activity via different mechanisms. The STAT3 pathway is also tightly modulated by ncRNAs. In this article, we have elaborated on the tumor-promoting role of STAT3 signaling in GI tumors. Subsequently, we have comprehensively discussed the oncogenic as well as tumor suppressor functions and mechanism of action of ncRNAs that are known to modulate STAT3 signaling in GI cancers.

Coumarin derivative as a potent drug candidate against triple negative breast cancer targeting the frizzled receptor of wingless-related integration site signaling pathway.

Triple negative breast cancer constitutes to about 21.8 percent of the total breast cancer related cases. Its ability to affect young ladies and in pre-menstrual stage makes this a disease of concern worldwide. The current treatment regimens involve chemotherapy which are used for treatment of other cancer types. In this regard, there is a need for specific and targeted drug candidate for its effective treatment. In the current study, assessment of coumarin derivative 2-(2-(6- Methyl-2-Oxo-2H-chromen-4-yl) acetamido)-3-phenylpropanoic acid is carried out both In-silico and In-vitro methods. Frizzled transmembrane proteins of Wingless-related integration site signaling pathway was targeted in which Frizzled-7 proved to a prospective target and showed a binding energy of -6.78 kcal/mol. The complex was subjected to molecular dynamics simulation for 200 ns and showed stable interaction with cysteine rich domain of the receptor. Cell proliferation, viability and apoptosis assay were performed on MDA-MB-231 and MDA-MB-468 cell lines with an IC50 value of 81.23 and 84.68 µM, respectively. The results provide a drug candidate which is derivative of a natural compound with targeted TNBC inhibitory effect. Communicated by Ramaswamy H. Sarma.

Brucein D imparts a growth inhibitory effect in multiple myeloma cells by abrogating the Akt-driven signaling pathway.

The Akt signaling pathway is an oncogenic cascade activated in the bone marrow microenvironment of multiple myeloma (MM) cells and contributes to their uncontrolled proliferation. Abrogation of Akt signaling has been presented as one of the prime therapeutic targets in the treatment of MM. In the present report, we have investigated the effect of Brucein D (BD) on Akt-driven signaling events in MM cells. BD (300 nM) substantially inhibited cell viability and imparted growth-inhibitory effects in U266 cells as evidenced by cell viability assays and flow cytometric analysis. Effect of BD on cell viability was evaluated by MTT assay. Apoptotic cells and cell cycle arrest by BD were analyzed by flow cytometer. The results of the TUNEL assay and western blotting showed that BD induces apoptosis of MM cells by activating caspase-8 and 9 with subsequent reduction in the expression of antiapoptotic proteins (Bcl-2, Bcl-xl, survivin, cyclin D1, COX-2, VEGF, MMP-9). Analysis of activated kinases by Phospho-Kinase Array Kit revealed that Akt, p70S6K, HSP60, p53, and WNK1 were strongly expressed in untreated cells and BD treatment reversed this effect. Using transfection experiments, AKT depletion led to a decrease in phosphorylation of Akt, mTOR, p70S6K, and WNK. However, Akt overexpression led to increase in phosphorylation of these proteins. Depletion of Akt potentiated the apoptosis-inducing effect of BD whereas overexpression displayed resistance to BD-induced apoptosis suggesting the role of Akt in chemoresistance. Taken together, BD mitigates Akt-dependent signaling pathways in MM cells to impart its anticancer activity.

Novel 1,2,5-Trisubstituted Benzimidazoles Potentiate Apoptosis by Mitochondrial Dysfunction in Panel of Cancer Cells.

Synthetic small molecules have been very effective in decimating cancer cells by targeting various aberrantly overexpressed oncogenic proteins. These small molecules target proteins involved in cell cycle regulation, cell division, migration, invasion, angiogenesis, and other regulatory proteins to induce apoptosis in cancer cells. In this study, we have synthesized a novel 1,2,5-trisubstituted benzimidazole chemical library of small molecules and unveiled their anticancer potential against a panel of cancer cell lines such as Jurkat, K-562, MOLT-4, HeLa, HCT116, and MIA PaCa-2 cancer cells. The MTT assay and Trypan blue dye exclusion assay clearly unveiled the cytotoxic effect of methyl 1-benzyl-2-(4-fluoro-3-nitrophenyl)-1H-benzo[d]imidazole-5-carboxylate (TJ08) and its potential to induce apoptosis with effective IC50 of 1.88 ± 0.51, 1.89 ± 0.55, 2.05 ± 0.72, 2.11 ± 0.62, 3.04 ± 0.8, and 3.82 ± 0.25 µM against Jurkat, K562, MOLT-4, HeLa, HCT116, and MIA PaCa-2 cancer cell lines, respectively. Altered mitochondrial membrane potential was observed in HeLa, HCT116, and Jurkat cells due to TJ08 treatment, which was unveiled by JC10 staining. Induction of early and late apoptosis by TJ08 treatment was also unveiled by apoptotic analysis and immunofluorescence imaging. Cell cycle analysis distribution confirms the accumulation of cells in the S-phase in a dose-dependent manner.

Development of 1-(4-(Substituted)piperazin-1-yl)-2-((2-((4-methoxybenzyl)thio)pyrimidin-4-yl)oxy)ethanones That Target Poly (ADP-Ribose) Polymerase in Human Breast Cancer Cells.

A number of uracil amides cleave poly (ADP-ribose) polymerase and therefore novel thiouracil amide compounds were synthesized and screened for the loss of cell viability in a human-estrogen-receptor-positive breast cancer cell line. The synthesized compounds exhibited moderate to significant efficacy against human breast cancer cells, where the compound 5e IC50 value was found to be 18 µM. Thouracil amide compounds 5a and 5e inhibited the catalytical activity of PARP1, enhanced cleavage of PARP1, enhanced phosphorylation of H2AX, and increased CASPASE 3/7 activity. Finally, in silico analysis demonstrated that compound 5e interacted with PARP1. Hence, specific thiouracil amides may serve as new drug-seeds for the development of PARP inhibitors for use in oncology.

Leelamine Exerts Antineoplastic Effects in Association with Modulating Mitogen­Activated Protein Kinase Signaling Cascade.

Mitogen­activated protein kinase (MAPK) pathway is a prominent signaling cascade that modulates cell proliferation, apoptosis, stress response, drug resistance, immune response, and cell motility. Activation of MAPK by various small molecules/natural compounds has been demonstrated to induce apoptosis in cancer cells. Herein, the effect of leelamine (LEE, a triterpene derived from bark of pine trees) on the activation of MAPK in hepatocellular carcinoma (HCC) and breast cancer (BC) cells was investigated. LEE induced potent cytotoxicity of HCC (HepG2 and HCCLM3) and BC (MDA-MB-231 and MCF7) cells over normal counterparts (MCF10A). LEE significantly enhanced the phosphorylation of p38 and JNK MAPKs in a dose-dependent fashion and it did not affect the phosphorylation of ERK in HCC and BC cells. The apoptosis-driving effect of LEE was further demonstrated by cleavage of procaspase-3/Bid and suppression of prosurvival proteins (Bcl-xL and XIAP). Furthermore, LEE also reduced the SDF1-induced-migration and -invasion of HCC and BC cells. Taken together, the data demonstrated that LEE promotes apoptosis and induces an anti-motility effect by activating p38 and JNK MAPKs in HCC and BC cells.

Design and Activity of Novel Oxadiazole Based Compounds That Target Poly(ADP-ribose) Polymerase.

Novel PARP inhibitors with selective mode-of-action have been approved for clinical use. Herein, oxadiazole based ligands that are predicted to target PARP-1 have been synthesized and screened for the loss of cell viability in mammary carcinoma cells, wherein seven compounds were observed to possess significant IC50 values in the range of 1.4 to 25 µM. Furthermore, compound 5u, inhibited the viability of MCF-7 cells with an IC50 value of 1.4µM, when compared to Olaparib (IC50 = 3.2 µM). Compound 5s also decreased cell viability in MCF-7 and MDA-MB-231 cells with IC50 values of 15.3 and 19.2 µM, respectively. Treatment of MCF-7 cells with compounds 5u and 5s produced PARP cleavage, H2AX phosphorylation and CASPASE-3 activation comparable to that observed with Olaparib. Compounds 5u and 5s also decreased foci-formation and 3D Matrigel growth of MCF-7 cells equivalent to or greater than that observed with Olaparib. Finally, in silico analysis demonstrated binding of compound 5s towardsthe catalytic site of PARP-1, indicating that these novel oxadiazoles synthesized herein may serve as exemplars for the development of new therapeutics in cancer.

Identification of ß-aminopyrrolidine containing peptides as ß-amyloid aggregation inhibitors for Alzheimer's disease.

Alzheimer's disease (AD) is caused by a series of events initiated by the production and aggregation of the amyloid ß-protein (Aß). In the early stages of the disease, Aß is released in a soluble form then progressively forms oligomeric, multimeric, and fibrillar aggregates, triggering neurodegeneration. Thus, development of inhibitors that initiate reverse Aß aggregation is thought to be a logical approach in treating AD. In this context, we developed ß-aminopyrrolidine containing 12 mer peptide 3 which is very potent in inhibiting the Aß aggregation and also reducing Aß(42)-induced cytotoxicity.

Targeting STAT3 signaling pathway in cancer by agents derived from Mother Nature.

Signal transducer and activator of transcription (STAT) proteins are latent transcription factors that reside in the cytoplasm of several types of cells. In canonical signaling, upon stimulation by cytokines and growth factors, STATs get activated and translocate into the nucleus to transcribe target genes. Among STATs, the STAT3 variant has been studied extensively and implicated in diverse human malignancies. Transcriptionally, STAT3 can upregulate the expression of genes associated with cell proliferation, antiapoptosis, prosurvival, angiogenesis, metastasis, and immune evasion. STAT3 can be constitutively activated in a broad range of human cancers including solid as well as hematological tumors and overexpression of STAT3 has been observed in a wide-range of patient-derived tumor tissue samples that may contribute to dismal prognosis. In contrast, blockade of STAT3 activation using inhibitors or knockdown systems can markedly suppress tumor progression, thus highlighting the significance of abrogating STAT3 signaling cascade in cancer therapy. In this review, we have provided a comprehensive overview of mechanisms of STAT3 signal transduction and its endogenous negative modulators, the role of STAT3 in oncogenesis, the interplay of miRNAs in STAT3 signaling, and mechanisms involved in persistent activation of STAT3. Furthermore, the review also provides a detailed overview of STAT3 signaling inhibition by selected natural compounds, which have displayed potent activity in various preclinical cancer model.

Bacteria as a treasure house of secondary metabolites with anticancer potential.

Cancer stands in the frontline among leading killers worldwide and the annual mortality rate is expected to reach 16.4 million by 2040. Humans suffer from about 200 different types of cancers and many of them have a small number of approved therapeutic agents. Moreover, several types of major cancers are diagnosed at advanced stages as a result of which the existing therapies have limited efficacy against them and contribute to a dismal prognosis. Therefore, it is essential to develop novel potent anticancer agents to counteract cancer-driven lethality. Natural sources such as bacteria, plants, fungi, and marine microorganisms have been serving as an inexhaustible source of anticancer agents. Notably, over 13,000 natural compounds endowed with different pharmacological properties have been isolated from different bacterial sources. In the present article, we have discussed about the importance of natural products, with special emphasis on bacterial metabolites for cancer therapy. Subsequently, we have comprehensively discussed the various sources, mechanisms of action, toxicity issues, and off-target effects of clinically used anticancer drugs (such as actinomycin D, bleomycin, carfilzomib, doxorubicin, ixabepilone, mitomycin C, pentostatin, rapalogs, and romidepsin) that have been derived from different bacteria. Furthermore, we have also discussed some of the major secondary metabolites (antimycins, chartreusin, elsamicins, geldanamycin, monensin, plicamycin, prodigiosin, rebeccamycin, salinomycin, and salinosporamide) that are currently in the clinical trials or which have demonstrated potent anticancer activity in preclinical models. Besides, we have elaborated on the application of metagenomics in drug discovery and briefly described about anticancer agents (bryostatin 1 and ET-743) identified through the metagenomics approach.

Tris(dibenzylideneacetone)dipalladium(0) (Tris DBA) Abrogates Tumor Progression in Hepatocellular Carcinoma and Multiple Myeloma Preclinical Models by Regulating the STAT3 Signaling Pathway.

STAT3 is an oncogenic transcription factor that controls the expression of genes associated with oncogenesis and malignant progression. Persistent activation of STAT3 is observed in human malignancies, including hepatocellular carcinoma (HCC) and multiple myeloma (MM). Here, we have investigated the action of Tris(dibenzylideneacetone) dipalladium 0 (Tris DBA) on STAT3 signaling in HCC and MM cells. Tris DBA decreased cell viability, increased apoptosis, and inhibited IL-6 induced/constitutive activation of STAT3, JAK1, JAK2, and Src in HCC and MM cells. Tris DBA downmodulated the nuclear translocation of STAT3 and reduced its DNA binding ability. It upregulated the expression of SHP2 (protein and mRNA) to induce STAT3 dephosphorylation, and the inhibition of SHP2 reversed this effect. Tris DBA downregulated the expression of STAT3-driven genes, suppressed cell migration/invasion. Tris DBA significantly inhibited tumor growth in xenograft MM and orthotopic HCC preclinical mice models with a reduction in the expression of various prosurvival biomarkers in MM tumor tissues without displaying significant toxicity. Overall, Tris DBA functions as a good inhibitor of STAT3 signaling in preclinical HCC and MM models.

Crocetin imparts antiproliferative activity via inhibiting STAT3 signaling in hepatocellular carcinoma.

STAT3 is a key oncogenic transcription factor, often overactivated in several human cancers including hepatocellular carcinoma (HCC). STAT3 modulates the expression of genes that are connected with cell proliferation, antiapoptosis, metastasis, angiogenesis, and immune evasion in tumor cells. In this study, we investigated the effect of crocetin on the growth of HCC cells and dissected its underlying molecular mechanism in imparting a cytotoxic effect. Crocetin suppressed proliferation, promoted apoptosis, and counteracted the invasive capacity of HCC cells. Besides, crocetin downregulated the constitutive/inducible STAT3 activation (STAT3Y705 ), nuclear accumulation of STAT3 along with suppression of its DNA binding activity in HCC cells with no effect on STAT5 activation. Crocetin suppressed the activity of upstream kinases such as Src, JAK1, and JAK2. Sodium pervanadate treatment terminated the crocetin-propelled STAT3 inhibition suggesting the involvement of tyrosine phosphatases. Crocetin increased the expression of SHP-1 and siRNA-mediated SHP-1 silencing resulted in the negation of crocetin-driven STAT3 inhibition. Further investigation revealed that crocetin treatment inhibited the expression of STAT3 regulated genes (Bcl-2, Bcl-xL, cyclin D1, survivin, VEGF, COX-2, and MMP-9). Taken together, this report presents crocetin as a novel abrogator of the STAT3 pathway in HCC cell lines.

Pyrimidine-2,4-dione targets STAT3 signaling pathway to induce cytotoxicity in hepatocellular carcinoma cells.

Signal transducer and activator of transcription 3 (STAT3) is a tumorigenic transcription factor that is persistently activated in various human cancers including hepatocellular carcinoma (HCC). Therefore, STAT3 is considered as a prominent target to counteract the uncontrolled proliferation of cancer cells. In the present report, pyrimidine-2,4-diones (N-methyluracil derivatives) (MNK1-MNK14) were synthesized in an ionic liquid (BMIm PF6) medium employing a ligand-free Suzuki-Miyaura cross-coupling process. Among the 14 derivatives, compound MNK8 showed good cytotoxicity towards both the tested cell lines and did not display a toxic effect against normal hepatocytes (LO2). MNK8 significantly increased the Sub-G1 cell count in both cell lines and the cytotoxic effect of MNK8 was found to be mediated through the suppression of constitutive phosphorylation of STAT3Y705. It also decreased the DNA interaction ability of nuclear STAT3 in HCC cells. MNK8 downregulated the levels of apoptosis-related proteins (such as Bcl-2, cyclin D1, survivin) and increased cleaved caspase-3 inferring the apoptogenic effect of MNK8. It also reduced the CXCL12-triggered cell migration and invasion in in vitro assay systems. Overall, MNK8 has been demonstrated as a new inhibitor of STAT3 signaling cascade in HCC cells.

New Heparanase-Inhibiting Triazolo-Thiadiazoles Attenuate Primary Tumor Growth and Metastasis.

Compelling evidence ties heparanase, an endoglycosidase that cleaves heparan sulfate side (HS) chains of proteoglycans, with all steps of tumor development, including tumor initiation, angiogenesis, growth, metastasis, and chemoresistance. Moreover, heparanase levels correlate with shorter postoperative survival of cancer patients, encouraging the development of heparanase inhibitors as anti-cancer drugs. Heparanase-inhibiting heparin/heparan sulfate-mimicking compounds and neutralizing antibodies are highly effective in animal models of cancer progression, yet none of the compounds reached the stage of approval for clinical use. The present study focused on newly synthesized triazolo-thiadiazoles, of which compound 4-iodo-2-(3-(p-tolyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)phenol (4-MMI) was identified as a potent inhibitor of heparanase enzymatic activity, cell invasion, experimental metastasis, and tumor growth in mouse models. To the best of our knowledge, this is the first report showing a marked decrease in primary tumor growth in mice treated with small molecules that inhibit heparanase enzymatic activity. This result encourages the optimization of 4-MMI for preclinical and clinical studies primarily in cancer but also other indications (i.e., colitis, pancreatitis, diabetic nephropathy, tissue fibrosis) involving heparanase, including viral infection and COVID-19.