Molecular Targets of Plant-based Alkaloids and Polyphenolics in Liver and Breast Cancer- An Insight into Anticancer Drug Development.

Liver and Breast cancer are ranked as the most prevailing cancers that cause high cancer-related mortality. As cancer is a life-threatening disease that affects the human population globally, there is a need to develop novel therapies. Among the available treatment options include radiotherapy, chemotherapy, surgery, and immunotherapy. The most superlative modern method is the use of plant-derived anticancer drugs that target the cancerous cells and inhibit their proliferation. Plant-derived compounds are generally considered safer than synthetic drugs/traditional therapies and could serve as potential novel targets to treat liver and breast cancer to revolutionize cancer treatment. Alkaloids and Polyphenols have been shown to act as anticancer agents through molecular approaches. They disrupt various cellular mechanisms, inhibit the production of cyclins and CDKs to arrest the cell cycle, and activate the DNA repairing mechanism by upregulating p53, p21, and p38 expression. In severe cases, when no repair is possible, they induce apoptosis in liver and breast cancer cells by activating caspase-3, 8, and 9 and increasing the Bax/Bcl-2 ratio. They also deactivate several signaling pathways, such as PI3K/AKT/mTOR, STAT3, NF-kB, Shh, MAPK/ERK, and Wnt/ß-catenin pathways, to control cancer cell progression and metastasis. The highlights of this review are the regulation of specific protein expressions that are crucial in cancer, such as in HER2 over-expressing breast cancer cells; alkaloids and polyphenols have been reported to reduce HER2 as well as MMP expression. This study reviewed more than 40 of the plant-based alkaloids and polyphenols with specific molecular targets against liver and breast cancer. Among them, Oxymatrine, Hirsutine, Piperine, Solamargine, and Brucine are currently under clinical trials by qualifying as potent anticancer agents due to lesser side effects. As a lot of research is there on anticancer compounds, there is a desideratum to compile data to move towards clinical trials phase 4 and control the prevalence of liver and breast cancer.

Synthesis and characterization of bis-amide SSE1917 as a microtubule-stabilizing anticancer agent.

Microtubule dynamics are critical for spindle assembly and chromosome segregation during cell division. Pharmacological inhibition of microtubule dynamics in cells causes prolonged mitotic arrest, resulting in apoptosis, an approach extensively employed in treating different types of cancers. The present study reports the synthesis of thirty-two novel bis-amides (SSE1901-SSE1932) and the evaluation of their antiproliferative activities. N-(1-oxo-3-phenyl-1-(phenylamino)propan-2-yl)benzamide (SSE1917) exhibited the most potent activity with GI50 values of 0.331 ± 0.01 µM in HCT116 colorectal and 0.48 ± 0.27 µM in BT-549 breast cancer cells. SSE1917 stabilized microtubules in biochemical and cellular assays, bound to taxol site in docking studies, and caused aberrant mitosis and G2/M arrest in cells. Prolonged treatment of cells with the compound increased p53 expression and triggered apoptotic cell death. Furthermore, SSE1917 suppressed the growth of both mouse and patient-derived human colon cancer organoids, highlighting its potential therapeutic value as an anticancer agent.

Design, Synthesis, and Biological Evaluation of SSE1806, a Microtubule Destabilizer That Overcomes Multidrug Resistance.

Microtubules are dynamic structures that form spindle fibers during cell division; pharmacological inhibition of microtubule dynamics arrests cells in mitosis, leading to apoptosis, and they have been extensively used to treat various cancers. However, the efficacy of such drugs is often limited by multidrug resistance. This study synthesized and evaluated 30 novel derivatives of podophyllotoxin, a natural antimitotic compound, for their antiproliferative activities. Compound SSE1806 exhibited the most potent antiproliferative activity with GI50 values ranging from 1.29 ± 0.01 to 21.15 ± 2.1 µM in cancer cell lines of different origins; it directly inhibited microtubule polymerization, causing aberrant mitosis and G2/M arrest. Prolonged treatment with SSE1806 increased p53 expression, induced cell death in monolayer cultures, and reduced the growth of mouse- and patient-derived human colon cancer organoids. Importantly, SSE1806 overcame multidrug resistance in a cell line overexpressing MDR-1. Thus, SSE1806 represents a potential anticancer agent that can overcome multidrug resistance.

Selenoneine-inspired selenohydantoins with glutathione peroxidase-like activity.

Chronic diseases such as cystic fibrosis, inflammatory bowel diseases, rheumatoid arthritis, and cardiovascular illness have been linked to a decrease in selenium levels and an increase in oxidative stress. Selenium is an essential trace element that exhibits antioxidant properties, with selenocysteine enzymes like glutathione peroxidase being particularly effective at reducing peroxides. In this study, a series of synthetic organoselenium compounds were synthesized and evaluated for their potential antioxidant activities. The new selenohydantoin molecules were inspired by selenoneine and synthesized using straightforward methods. Their antioxidant potential was evaluated and proven using classical radical scavenging and metal-reducing methods. The selenohydantoin derivatives exhibited glutathione peroxidase-like activity, reducing hydroperoxides. Theoretical calculations using Density Functional Theory (DFT) revealed the selenone isomer to be the only one occurring in solution, with selenolate as a possible tautomeric form in the presence of a basic species. Cytocompatibility assays indicated that the selenohydantoin derivatives were non-toxic to primary human aortic smooth muscle cells, paving the way for further biological evaluations of their antioxidant activity. The results suggest that selenohydantoin derivatives with trifluoro-methyl (-CF3) and chlorine (-Cl) substituents have significant activities and could be potential candidates for further biological trials. These compounds may contribute to the development of effective therapies for chronic diseases such cardiovascular diseases.

Perplexing Polyphenolics: The Isolations, Syntheses, Reappraisals, and Bioactivities of Flavonoids, Isoflavonoids, and Neoflavonoids from 2016 to 2022.

Flavonoids, isoflavonoids, neoflavonoids, and their various subcategories are polyphenolics-an extensive class of natural products. These compounds are bioactive and display multiple activities, including anticancer, antibacterial, antiviral, antioxidant, and neuroprotective activities. Thus, these compounds can serve as leads for therapeutic agents or targets for complex synthesis; they are coveted and routinely isolated, characterized, biologically evaluated, and synthesized. However, data regarding the compounds' sources, isolation procedures, structural novelties, bioactivities, and synthetic schemes are often dispersed and complex, a dilemma this review aims to address. To serve as an easily accessible guide for researchers wanting to apprise themselves of the latest advancements in this subfield, this review summarizes seventy-six (76) articles published between 2016 and 2022 that detail the isolation and characterization of two hundred and forty-nine (249) novel compounds, the total and semisyntheses of thirteen (13) compounds, and reappraisals of the structures of twenty (20) previously reported compounds and their bioactivities. This article also discusses new synthetic methods and enzymes capable of producing or modifying flavonoids, isoflavonoids, or neoflavonoids.

Centrosome Clustering & Chemotherapy.

Centrosome abnormalities are the hallmark of cancer. How it affects tumorigenesis is still a mystery. However, the presence of more than two centrosomes at the onset of mitosis often leads to chromosomal instability and subsequent tumorigenesis. Unlike normal cells that undergo repair or apoptosis in response to this instability, cancer cells learn to cope with supernumerary centrosomes through various mechanisms and survive. Centrosome clustering is the most prevalent mechanism, allowing the cancer cells to form two daughter cells through a pseudo-bipolar spindle. Since healthy cells are devoid of the mechanisms involved in clustering, the de-clustering of centrosomes can be considered a promising approach to selectively eliminate cells with extra centrosomes. Several proteins such as PARP, KIFC1, Hsp70, Cortical actin, APC/C-CDH1 complex and Eg5 have been discussed in this review which participate in centrosome clustering, and the inhibition of these proteins can facilitate in impeding tumor growth specifically by declustering centrosomes. In this review, we also present the role of the centrosome in the cell cycle, centrosome amplification, clustering mechanism and reported centrosome de-clustering agents to present the current state of work in the field.

Indole-Containing Natural Products 2019-2022: Isolations, Reappraisals, Syntheses, and Biological Activities.

Indole alkaloids represent a large subset of natural products, with more than 4100 known compounds. The majority of these alkaloids are biologically active, with some exhibiting excellent antitumor, antibacterial, antiviral, antifungal, and antiplasmodial activities. Consequently, the natural products of this class have attracted considerable attention as potential leads for novel therapeutics and are routinely isolated, characterized, and profiled to gauge their biological potential. However, data on indole alkaloids, their various structures, and bioactivities are complex due to their diverse sources, such as plants, fungi, bacteria, sponges, tunicates, and bryozoans; thus, isolation methods produce an incredible trove of information. The situation is exacerbated when synthetic derivatives, as well as their structures, bioactivities, and synthetic schemes, are considered. Thus, to make such data comprehensive and inform researchers about the current field's state, this review summarizes recent reports on novel indole alkaloids. It deals with the isolation and characterization of 250 novel indole alkaloids, a reappraisal of previously reported compounds, and total syntheses of indole alkaloids. In addition, several syntheses and semi-syntheses of indole-containing derivatives and their bioactivities are reported between January 2019 and July 2022.

Identification and Characterization of Natural and Semisynthetic Quinones as Aurora Kinase Inhibitors.

Aurora kinases (Aurora A, B, and C) are a family of serine/threonine kinases that play critical roles during mitotic initiation and progression. Aurora A and B kinases are ubiquitously expressed, and their overexpression and/or amplification in many cancers have been associated with poor prognosis. Several inhibitors that target Aurora kinases A, B, or both have been developed during the past decade with efficacy in different in vitro and in vivo models for a variety of cancers. Recent studies have also identified Aurora A as a synthetic lethal target for different tumor suppressors, including RB1, SMARCA4, and ARID1A, which signifies the need for Aurora-A-selective inhibitors. Here, we report the screening of a small library of quinones (nine naphthoquinones, one orthoquinone, and one anthraquinone) in a biochemical assay for Aurora A kinase that resulted in the identification of several quinones as inhibitors. IC50 determination against Aurora A and B kinases revealed the inhibition of both kinases with selectivity toward Aurora A. Two of the compounds, natural quinone naphthazarin (1) and a pseudo anthraquinone, 2-(chloromethyl)quinizarin (11), potently inhibited the proliferation of various cancer cell lines with IC50 values ranging from 0.16 ± 0.15 to 1.7 ± 0.06 and 0.15 ± 0.04 to 6.3 ± 1.8 µM, respectively. Treatment of cancer cells with these compounds for 24 h resulted in abrogated mitosis and apoptotic cell death. Direct binding of both the compounds with Aurora A kinase was also confirmed through STD NMR analysis. Docking studies predicted the binding of both compounds to the ATP binding pocket of Aurora A kinase. We have, therefore, identified quinones as Aurora kinase inhibitors that can serve as a lead for future drug discovery endeavors.

Synthesis and evaluation of novel 1, 2, 4-substituted triazoles for urease and anti-proliferative activity.

1,2,4-triazoles are a major group of heterocyclic compounds. In the current work, a concise library of such triazoles synthesized through a multistep protocol. The synthesis involved hydrazinolysis of ethyl-2-(p-Cl-phenoxy) acetate followed by reflux with phenyl isothiocyanate to yield the intermediate 2-[2-(p-Cl-phenoxy)acetyl)-N-phenyl-hydrazinecarbothioamide. This intermediate was then cyclized to form 5-[p-(Cl-phenoxy)-methyl]-4-phenyl-4H-1,2,4-triazole-3-thiol (the parent moiety) at alkaline pH. In parallel, 3-bromopropionyl bromide was reacted with a series of phenylamines to yield N-(substituted-phenyl)bromopropanamides. In the final step, N-substitution of 5-[p-(Cl-phenoxy)-methyl]-4- phenyl-4H-1,2,4-triazole-3-thiol was carried out with N-(substituted-phenyl)bromopropanamides to give desired library of 3-[5-[(p-Cl-phenoxy)-methyl]-4- phenyl-4H-1,2,4-triazole-3-ylthio]-N-(substituted-phenyl) propan-amides (8a-l). The prepared moieties were identified via IR, NMR, & EIMS and evaluated for urease and anti-proliferative activities. 3-[5-[(p-Cl-phenoxy)-methyl]-4- phenyl-4H-1,2,4-triazole-3-ylthio]-N-(3-methyl-phenyl)propanamide 8k, was found to be most prominent hit as urease inhibitor (IC50= 42.57± 0.13 µM) using thiourea as standard (IC50= 21.25±0.15µM). The interaction of 8k with urease were studied using docking studies. Anti-proliferative activity results showed 8k as promising candidates and rest of the synthesized derivatives were found to be moderately anti-proliferative. Molecular docking results also displayed 8k, 8h, and 8c as potential hits for further study.

Selenium-containing Peptides and their Biological Applications.

Selenium (Se) has been known for its beneficial biological roles for several years, but interest in this trace element has seen a significant increase in the past couple of decades. It has been reported to be a part of important bioactive organic compounds, such as selenoproteins and amino acids, including selenocysteine (SeCys), selenomethionine (SeMet), selenazolidine (SeAzo), and selenoneine. The traditional Se supplementations (primarily as selenite and selenomethionine), though have been shown to carry some benefits, also have associated toxicities, thereby paving the way for the organoselenium compounds, especially the selenoproteins and peptides (SePs/SePPs) that offer several health benefits beyond fulfilling the elementary nutritional Se needs. This review aims to showcase the applications of selenium-containing peptides that have been reported in recent decades. This article summarizes their bioactivities, including neuroprotective, antiinflammatory, anticancer, antioxidant, hepatoprotective, and immunomodulatory roles. This will offer the readers a sneak peek into the current advancements to invoke further developments in this emerging research area.

Structure Dependent Differential Modulation of Aß Fibrillization by Selenadiazole-Based Inhibitors.

Misfolding and fibrillar aggregation of Aß is a characteristic hallmark of Alzheimer's disease and primarily participates in neurodegenerative pathologies. There has been no breakthrough made in the therapeutic regime of Alzheimer's disease while the pharmacological interventions against Aß are designed to sequester and clear Aß burden from the neurological tissues. Based on the physiological relevance of Aß, therapeutic approaches are required to inhibit and stabilize Aß fibrillization, instead of cleaning it from the neurological system. In this context, we have designed a selenadiazole-based library of compounds against the fibrillization paradigm of Aß. Compounds that completely inhibited the Aß fibrillization appeared to stabilize Aß at the monomeric stage as indicated by ThT assay, CD spectrophotometry, and TEM imaging. Partial inhibitors elongated the nucleation phase and allowed limited fibrillization of Aß into smaller fragments with slightly higher ß-sheets contents, while noninhibitors did not interfere in Aß aggregation and resulted in mature fibrils with fibrillization kinetics similar to Aß control. Molecular docking revealed the different binding positions of the compounds for three classes. Complete inhibitors alleviated Aß toxicity to SH-SY5Y neuroblastoma cells and permeated across the blood-brain barrier in zebrafish larvae. The amino acid residues from Aß peptide that interacted with the compounds from all three classes were overlapping and majorly lying in the amyloidogenic regions. However, compounds that stabilize Aß monomers displayed higher association constants (Ka) and lower dissociation constants (Kd) in comparison to partial and noninhibitors, as corroborated by ITC. These results support further structure activity-based preclinical development of these selenadiazole compounds for potential anti-Alzheimer's therapy.

CCT245718, a dual FLT3/Aurora A inhibitor overcomes D835Y-mediated resistance to FLT3 inhibitors in acute myeloid leukaemia cells.

BACKGROUND: Activating mutations in the Fms-like tyrosine kinase 3 (FLT3) are among the most prevalent oncogenic mutations in acute myeloid leukaemia. Inhibitors selectively targeting FLT3 kinase have shown promising clinical activity; their success in the clinic, however, has been limited due to the emergence of acquired resistance. METHODS: CCT245718 was identified and characterised as a dual Aurora A/FLT3 inhibitor through cell-based and biochemical assays. The ability of CCT245718 to overcome TKD-mediated resistance was evaluated in a cell line-based model of drug resistance to FLT3 inhibitors. RESULTS: CCT245718 exhibits potent antiproliferative activity towards FLT3-ITD + AML cell lines and strongly binds to FLT3-ITD and TKD (D835Y) mutants in vitro. Activities of both FLT3-ITD and Aurora A are also inhibited in cells. Inhibition of FLT3 results in reduced phosphorylation of STAT5, downregulation of survivin and induction of apoptotic cell death. Moreover, CCT245718 overcomes TKD-mediated resistance in a MOLM-13-derived cell line containing FLT3 with both ITD and D835Y mutations. It also inhibits FLT3 signalling in both parental and resistant cell lines compared to FLT3-specific inhibitor MLN518, which is only active in the parental cell line. CONCLUSIONS: Our results demonstrate that CCT245718 is a potent dual FLT3/Aurora A inhibitor that can overcome TKD-mediated acquired resistance.

In Silico Validation, Fabrication and Evaluation of Nano-Liposomes of Bistorta amplexicaulis Extract for Improved Anticancer Activity Against Hepatoma Cell Line (HepG2).

BACKGROUND: Bistorta amplexicaulis of the genus Polygonum (Polygonaceae) has been reported for its antioxidant and anticancer activities. However, the low cellular uptake of the compounds in its extract limits its therapeutic application. OBJECTIVES: The present study aimed at developing a nanoliposomal carrier system for B. amplexicaulis extracts for improved cellular uptake, thus resulting in enhanced anticancer activity. METHODS: Ultra Pressure Liquid Chromatography (UPLC) was used to identify major compounds in the plant extract. Nanoliposomes (NLs) were prepared by employing a thin-film rehydration method using DPPC, PEG2000DSPE and cholesterol, followed by characterization through several parameters. In vitro screening was performed against breast cancer cell line (MCF-7) and Hepatocellular carcinoma cell line (HepG-2) using MTT-assay. Raw extract and nanoliposomes were tested on Human Umbilical Vein Endothelial Cells (HUVEC). Moreover, molecular docking was performed to validate the data obtained through wet lab. RESULTS: The UHPLC method identified gallic acid, caffeic acid, chlorogenic acid and catechin as the major compounds in the extract. The NLs with a size ranging between 140-155 nm, zeta potential -16.9 to -19.8 mV and good polydispersity index of < 0.1 were prepared, with a high encapsulation efficiency of 81%. The MTT assay showed significantly (p > 0.05) high uptake and cytotoxicity of NLs as compared to the plant extract. Moreover, reduced toxicity against HUVEC cells was observed as compared to the extract. Also, the docking of identified compounds suggested a favorable interaction with the SH2 domain of both STAT3 and STAT5. CONCLUSION: Overall, the results suggest NLs as a potential platform that could be developed for the improved intracellular delivery of plant extract, thus increasing the therapeutic outcomes.

Detection of aflatoxin M1 by fiber cavity attenuated phase shift spectroscopy.

Aflatoxin M1 (AFM1) is a carcinogenic compound commonly found in milk in excess of the WHO permissible limit, especially in developing countries. Currently, state-of-the-art tests for detecting AFM1 in milk include chromatographic systems and enzyme-linked-immunosorbent assays. Although these tests provide fair accuracy and sensitivity, they require trained laboratory personnel, expensive infrastructure, and many hours to produce final results. Optical sensors leveraging spectroscopy have a tremendous potential of providing an accurate, real-time, and specialist-free AFM1 detector. Despite this, AFM1 sensing demonstrations using optical spectroscopy are still immature. Here, we demonstrate an optical sensor that employs the principle of cavity attenuated phase shift spectroscopy in optical fiber cavities for rapid AFM1 detection in aqueous solutions at 1550 nm. The sensor constitutes a cavity built by two fiber Bragg gratings. We splice a tapered fiber of < 10 µm waist inside the cavity as a sensing head. For ensuring specific binding of AFM1 in a solution, the tapered fiber is functionalized with DNA aptamers followed by validation of the conjugation via FTIR, TGA, and EDX analyses. We then detect AFM1 in a solution by measuring the phase shift between a sinusoidally modulated laser input and the sensor output at resonant frequencies of the cavity. Our results show that the sensor has the detection limit of 20 ng/L (20 ppt), which is well below both the U.S. and the European safety regulations. We anticipate that the present work will lead towards a rapid and accurate AFM1 sensor, especially for low-resource settings.

A Comprehensive Review of Aminochalcones.

Chalcones, members of the flavonoid family, display a plethora of interesting biological activities including but not limited to antioxidant, anticancer, antimicrobial, anti-inflammatory, and antiprotozoal activities. The literature cites the synthesis and activity of a range of natural, semisynthetic, and synthetic chalcones. The current review comprehensively covers the literature on amino-substituted chalcones and includes chalcones with amino-groups at various positions on the aromatic rings as well as those with amino-groups containing mono alkylation, dialkylation, alkenylation, acylation, and sulfonylation. The aminochalcones are categorized according to their structure, and the corresponding biological activities are discussed as well. Some compounds showed high potency against cancer cells, microbes, and malaria, whereas others did not. The purpose of this review is to serve as a one-stop location for information on the aminochalcones reported in the literature in recent years.

Natural and Semisynthetic Chalcones as Dual FLT3 and Microtubule Polymerization Inhibitors.

Activating mutations in FLT3 receptor tyrosine kinase are found in a third of acute myeloid leukemia (AML) patients and are associated with disease relapse and a poor prognosis. The majority of these mutations are internal tandem duplications (ITDs) in the juxtamembrane domain of FLT3, which have been validated as a therapeutic target. The clinical success of selective inhibitors targeting oncogenic FLT3, however, has been limited due to the acquisition of drug resistance. Herein the identification of a dual FLT3/microtubule polymerization inhibitor, chalcone 4 (2'-allyloxy-4,4'-dimethoxychalcone), is reported through screening of 15 related chalcones for differential antiproliferative activity in leukemia cell lines dependent on FLT3-ITD (MV-4-11) or BCR-ABL (K562) oncogenes and by subsequent screening for mitotic inducers in the HCT116 cell line. Three natural chalcones (1-3) were found to be differentially more potent toward the MV-4-11 (FLT3-ITD) cell line compared to the K562 (BCR-ABL) cell line. Notably, the new semisynthetic chalcone 4, which is a 2'-O-allyl analogue of the natural chalcone 3, was found to be more potent toward the FLT3-ITD+ cell line and inhibited FLT3 signaling in FLT3-dependent cells. An in vitro kinase assay confirmed that chalcone 4 directly inhibited FLT3. Moreover, chalcone 4 induced mitotic arrest in these cells and inhibited tubulin polymerization in both cellular and biochemical assays. Treatment of MV-4-11 cells with this inhibitor for 24 and 48 h resulted in apoptotic cell death. Finally, chalcone 4 was able to overcome TKD mutation-mediated acquired resistance to FLT3 inhibitors in a MOLM-13 cell line expressing FLT3-ITD with the D835Y mutation. Chalcone 4 is, therefore, a promising lead for the discovery of dual-target FLT3 inhibitors.

A cell-based high-throughput screen identifies inhibitors that overcome P-glycoprotein (Pgp)-mediated multidrug resistance.

Multidrug resistance (MDR) to chemotherapeutic drugs remains one of the major impediments to the treatment of cancer. Discovery and development of drugs that can prevent and reverse the acquisition of multidrug resistance constitute a foremost challenge in cancer therapeutics. In this work, we screened a library of 1,127 compounds with known targets for their ability to overcome Pgp-mediated multidrug resistance in cancer cell lines. We identified four compounds (CHIR-124, Elesclomol, Tyrphostin-9 and Brefeldin A) that inhibited the growth of two pairs of parental and Pgp-overexpressing multidrug-resistant cell lines with similar potency irrespective of their Pgp status. Mechanistically, CHIR-124 (a potent inhibitor of Chk1 kinase) inhibited Pgp activity in both multidrug-resistant cell lines (KB-V1 and A2780-Pac-Res) as determined through cell-based Pgp-efflux assays. Other three inhibitors on the contrary, were effective in Pgp-overexpressing resistant cells without increasing the cellular accumulation of a Pgp substrate, indicating that they overcome resistance by avoiding efflux through Pgp. None of these compounds modulated the expression of Pgp in resistant cell lines. PIK-75, a PI3 Kinase inhibitor, was also determined to inhibit Pgp activity, despite being equally potent in only one of the two pairs of resistant and parental cell lines. Strong binding of both CHIR-124 and PIK-75 to Pgp was predicted through docking studies and both compounds inhibited Pgp in a biochemical assay. The inhibition of Pgp causes accumulation of these compounds in the cells where they can modulate the function of their target proteins and thereby inhibit cell proliferation. In conclusion, we have identified compounds with various cellular targets that overcome multidrug resistance in Pgp-overexpressing cell lines through mechanisms that include Pgp inhibition and efflux evasion. These compounds, therefore, can avoid challenges associated with the co-administration of Pgp inhibitors with chemotherapeutic or targeted drugs such as additive toxicities and differing pharmacokinetic properties.

Synthesis and evaluation of novel α-substituted chalcones with potent anti-cancer activities and ability to overcome multidrug resistance.

A series of forty α-substituted chalcones were synthesized and screened for their antiproliferative activities against HCT116 (colorectal) and HCC1954 (breast) cancer cell lines. Compounds 5a and 5e were found to be the most potent compounds with GI50 values of 0.63 µM and 0.725 µM in HCC1954 cell line and 0.69 µM and 1.59 µM in HCT116 cell line, respectively. Both compounds induced a G2/M cell cycle arrest and caused apoptotic cell death in HCT116 cells as shown by the induction of PARP cleavage. The compounds also stabilized p53 in a dose-dependent manner in HCT116 cells following 24-hour treatment. Furthermore, both 5a and 5e were able to overcome multidrug resistance in two MDR-1 overexpressing multidrug resistant cell lines.

Synthesis and identification of novel pyridazinylpyrazolone based diazo compounds as inhibitors of human islet amyloid polypeptide aggregation.

We have carried out a docking inspired synthesis and screening of a library of diazenyl-derivatives of pyridazinylpyrazolone molecules for their ability to modulate the amyloidogenic self-assembly of human islet amyloid polypeptide (hIAPP). hIAPP is a 37-residue peptide which is involved in glycemic control along with insulin. Its extracellular fibrillar assemblies in pancreatic ß-cells are responsible for type 2 diabetes. A three-step synthetic scheme was used to prepare these novel compounds using 2-(6-chloropyridazin-3-yl)-5-methyl-2,4-dihydro-3H-pyrazol-3-one as a key intermediate that was reacted with various diazo electrophiles to generate a library of compounds with yields ranging from 64 to 85%. The effect of the compounds on hIAPP amyloid fibril formation was evaluated with a thioflavin T (ThT) fluorescence-based kinetic assay. Furthermore, TEM imaging was carried out to corroborate the interactions of the compounds with hIAPP and subsequent hIAPP inhibition at the different level of fibrillization. The CD spectroscopy showed that upon incubation with SSE15314 for 12 h, the percentage of α-helices was maintained to a level of hIAPP at 0 h. The current study presents identification and characterization of SSE15314 as the hit, which completely inhibited the fibril formation and can be further optimized into a lead compound.

Identification and characterization of SSE15206, a microtubule depolymerizing agent that overcomes multidrug resistance.

Microtubules are highly dynamic structures that form spindle fibres during mitosis and are one of the most validated cancer targets. The success of drugs targeting microtubules, however, is often limited by the development of multidrug resistance. Here we describe the discovery and characterization of SSE15206, a pyrazolinethioamide derivative [3-phenyl-5-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1H-pyrazole-1-carbothioamide] that has potent antiproliferative activities in cancer cell lines of different origins and overcomes resistance to microtubule-targeting agents. Treatment of cells with SSE15206 causes aberrant mitosis resulting in G2/M arrest due to incomplete spindle formation, a phenotype often associated with drugs that interfere with microtubule dynamics. SSE15206 inhibits microtubule polymerization both in biochemical and cellular assays by binding to colchicine site in tubulin as shown by docking and competition studies. Prolonged treatment of cells with the compound results in apoptotic cell death [increased Poly (ADP-ribose) polymerase cleavage and Annexin V/PI staining] accompanied by p53 induction. More importantly, we demonstrate that SSE15206 is able to overcome resistance to chemotherapeutic drugs in different cancer cell lines including multidrug-resistant KB-V1 and A2780-Pac-Res cell lines overexpressing MDR-1, making it a promising hit for the lead optimization studies to target multidrug resistance.