Histone Deacetylase Inhibitory Activity and Antiproliferative Potential of New [6]-Shogaol Derivatives

Twenty newly synthesized derivatives of [6]-shogaol (4) were tested for inhibitory activity against histone deacetylases. All derivatives showed moderate to good histone deacetylase inhibition at 100 µM with a slightly lower potency than the lead compound. Most potent inhibitors among the derivatives were the pyrazole products, 5j and 5k, and the Michael adduct with pyridine 4c and benzothiazole 4d, with IC₅₀ values of 51, 65, 61 and 60 µM, respectively. They were further evaluated for isoform selectivity via a molecular docking study. Compound 4d showed the best selectivity towards HDAC3, whereas compound 5k showed the best selectivity towards HDAC2. The potential derivatives were tested on five cancer cell lines, including human cervical cancer (HeLa), human colon cancer (HCT116), human breast adenocarcinoma cancer (MCF-7), and cholangiocarcinoma (KKU100 and KKU-M213B) cells with MTT-based assay. The most active histone deacetylase inhibitor 5j exhibited the best antiproliferative activity against HeLa, HCT116, and MCF-7, with IC₅₀ values of 8.09, 9.65 and 11.57 µM, respectively, and a selective binding to HDAC1 based on molecular docking experiments. The results suggest that these compounds can be putative candidates for the development of anticancer drugs via inhibiting HDACs.     

Design,Synthesis, and In Vitro Evaluation of Novel Indolyl DiHydropyrazole Derivatives as Potential Anticancer Agents

Indoles derived from both natural sources or artificial synthetic methods have been known to interact with aryl hydrocarbon receptors (AhR), and exhibit anticancer activity. In light of these attractive properties, a series of hybrid molecules with structural features of indoles, i.e., those bearing a pyrazoline nucleus, were evaluated for their enhanced anticancer activity. The designed molecules were subjected to molecular docking in order to screen for potential AhR interacting compounds, and the identified indolyl dihydropyrazole derivatives were synthesized. The synthesized compounds were characterized, and their cytotoxicity was evaluated against four human cancer cell lines using the MTT assay. Based on the Glide g-score, H-bonding interactions and bonding energy of 20 candidate molecules were selected for further analysis from the 64 initially designed molecules. These candidate molecules have shown promising anti-proliferative activity against the cell lines tested. Among these candidate molecules, the compounds with hydroxy phenyl substitution on the pyrazoline ring have shown potent activity across all the tested cell lines. The designed scaffold was proven effective for screening potential candidate molecules with anticancer properties, and may be further optimized structurally for yielding the ideal anti-tumorigenic compound for the treatment of various cancers.     

Novel Perbutyrylated Glucose Derivatives of (–)-Epigallocatechin-3-Gallate Inhibit Cancer Cells Proliferation by Decreasing Phosphorylation of the EGFR: Synthesis,Cytotoxicity, and Molecular Docking

Lung cancer is one of the most commonly occurring cancer mortality worldwide. The epidermal growth factor receptor (EGFR) plays an important role in cellular functions and has become the new promising target. Natural products and their derivatives with various structures, unique biological activities, and specific selectivity have served as lead compounds for EGFR. D-glucose and EGCG were used as starting materials. A series of glucoside derivatives of EGCG (7–12) were synthesized and evaluated for their in vitro anticancer activity against five human cancer cell lines, including HL-60, SMMC-7721, A-549, MCF-7, and SW480. In addition, we investigated the structure-activity relationship and physicochemical property–activity relationship of EGCG derivatives. Compounds 11 and 12 showed better growth inhibition than others in four cancer cell lines (HL-60, SMMC-7721, A-549, and MCF), with IC₅₀ values in the range of 22.90–37.87 μM. Compounds 11 and 12 decreased phosphorylation of EGFR and downstream signaling protein, which also have more hydrophobic interactions than EGCG by docking study. The most active compounds 11 and 12, both having perbutyrylated glucose residue, we found that perbutyrylation of the glucose residue leads to increased cytotoxic activity and suggested that their potential as anticancer agents for further development.     

Synthesis and Biological Evaluation of Amino Chalcone Derivatives as Antiproliferative Agents

Chalcone is a common scaffold found in many biologically active compounds. The chalcone scaffold was also frequently utilized to design novel anticancer agents with potent biological efficacy. Aiming to continue the research of effective chalcone derivatives to treat cancers with potent anticancer activity, fourteen amino chalcone derivatives were designed and synthesized. The antiproliferative activity of amino chalcone derivatives was studied in vitro and 5-Fu as a control group. Some of the compounds showed moderate to good activity against three human cancer cells (MGC-803, HCT-116 and MCF-7 cells) and compound 13e displayed the best antiproliferative activity against MGC-803 cells, HCT-116 cells and MCF-7 cells with IC₅₀ values of 1.52 μM (MGC-803), 1.83 μM (HCT-116) and 2.54 μM (MCF-7), respectively which was more potent than the positive control (5-Fu). Further mechanism studies were explored. The results of cell colony formatting assay suggested compound 10e inhibited the colony formation of MGC-803 cells. DAPI fluorescent staining and flow cytometry assay showed compound 13e induced MGC-803 cells apoptosis. Western blotting experiment indicated compound 13e induced cell apoptosis via the extrinsic/intrinsic apoptosis pathway in MGC-803 cells. Therefore, compound 13e might be a valuable lead compound as antiproliferative agents and amino chalcone derivatives worth further effort to improve amino chalcone derivatives’ potency.     

Design,Synthesis and Anticancer Activity of a New Series of N-aryl-N′-[4-(pyridin-2-ylmethoxy)benzyl]urea Derivatives

The development of cancer treatments requires continuous exploration and improvement, in which the discovery of new drugs for the treatment of cancer is still an important pathway. In this study, based on the molecular hybridization strategy, a new structural framework with an N-aryl-N’-arylmethylurea scaffold was designed, and 16 new target compounds were synthesized and evaluated for their antiproliferative activities against four different cancer cell lines A549, MCF7, HCT116, PC3, and human liver normal cell line HL7702. The results have shown seven compounds with 1-methylpiperidin-4-yl groups having excellent activities against all four cancer cell lines, and they exhibited scarcely any activities against HL7702. Among them, compound 9b and 9d showed greatly excellent activity against the four kinds of cells, and the IC₅₀ for MCF7 and PC3 cell lines were even less than 3 μM.     

Synthesis of Carvacrol Derivatives as Potential New Anticancer Agent against Lung Cancer

Lung cancer remains a major public health concern among all cancer diseases due to the toxicity and side-effects of the available commercially synthesized drugs. Natural product-derived synthesized anticancer drugs are now of promising interest to fight against cancer death. Carvacrol is a major component of most essential oil-bearing plants with potential pharmacological activity, especially against various cancer cell lines. Among the other organometallic compounds, copper complexes have been reported to be effective anticancer agents against various cancer cell lines, especially lung and leukemia cancers, due to the nontoxic nature of copper in normal cells since it is an endogenic metal. In this study, we synthesized three carvacrol derivatives, i.e., carvacrol aldehyde, Schiff base, and copper–Schiff base complex, through an established synthesis protocol and characterized the synthesized product using various spectroscopic techniques. The synthesized derivatives were evaluated for in vitro cytotoxic activity against different cancer cell lines, including human lung cancer (A549) and human fibroblast (BALB-3T3). Our findings showed that the copper–Schiff base complex derived from carvacrol inhibited the proliferation and migration of the A549 cell lines in a dose-dependent manner. This activity might be due to the inhibition of cell proliferation and migration at the G₂/M cell-cycle phase, as well as apoptosis, possibly through the activation of the mitochondrial apoptotic pathway. To our knowledge, this is the first report on the activity of the copper–Schiff base complex of carvacrol against A549 cell lines. Our result highlights that a new synthesized copper complex from carvacrol could be a novel potential drug in the treatment of lung cancer.     

Multifunctional Small Molecules as Potential Anti-Alzheimer’s Disease Agents

Alzheimer’s disease (AD) is a severe multifactorial neurodegenerative disorder characterized by a progressive loss of neurons in the brain. Despite research efforts, the pathogenesis and mechanism of AD progression are not yet completely understood. There are only a few symptomatic drugs approved for the treatment of AD. The multifactorial character of AD suggests that it is important to develop molecules able to target the numerous pathological mechanisms associated with the disease. Thus, in the context of the worldwide recognized interest of multifunctional ligand therapy, we report herein the synthesis, characterization, physicochemical and biological evaluation of a set of five (1a–e) new ferulic acid-based hybrid compounds, namely feroyl-benzyloxyamidic derivatives enclosing different substituent groups, as potential anti-Alzheimer’s disease agents. These hybrids can keep both the radical scavenging activity and metal chelation capacity of the naturally occurring ferulic acid scaffold, presenting also good/mild capacity for inhibition of self-Aβ aggregation and fairly good inhibition of Cu-induced Aβ aggregation. The predicted pharmacokinetic properties point towards good absorption, comparable to known oral drugs.     

Curcumin Scaffold as a Multifunctional Tool for Alzheimer’s Disease Research

Alzheimer’s disease (AD) is one of the most common neurodegenerative disorders, which is caused by multi-factors and characterized by two histopathological hallmarks: amyloid-β (Aβ) plaques and neurofibrillary tangles of Tau proteins. Thus, researchers have been devoting tremendous efforts to developing and designing new molecules for the early diagnosis of AD and curative purposes. Curcumin and its scaffold have fluorescent and photochemical properties. Mounting evidence showed that curcumin scaffold had neuroprotective effects on AD such as anti-amyloidogenic, anti-inflammatory, anti-oxidative and metal chelating. In this review, we summarized different curcumin derivatives and analyzed the in vitro and in vivo results in order to exhibit the applications in AD diagnosis, therapeutic monitoring and therapy. The analysis results showed that, although curcumin and its analogues have some disadvantages such as short wavelength and low bioavailability, these shortcomings can be conquered by modifying the structures. Curcumin scaffold still has the potential to be a multifunctional tool for AD research, including AD diagnosis and therapy.     

Nifuroxazide Mitigates Angiogenesis in Ehlrich’s Solid Carcinoma: Molecular Docking,Bioinformatic and Experimental Studies on Inhibition of Il-6/Jak2/Stat3 Signaling

Nifuroxazide is an antidiarrheal medication that has promising anticancer activity against diverse types of tumors. The present study tested the anticancer activity of nifuroxazide against Ehrlich’s mammary carcinoma grown in vivo. Furthermore, we investigated the effect of nifuroxazide on IL-6/jak2/STAT3 signaling and the possible impact on tumor angiogenesis. The biological study was supported by molecular docking and bioinformatic predictions for the possible effect of nifuroxazide on this signaling pathway. Female albino mice were injected with Ehrlich carcinoma cells to produce Ehrlich’s solid tumors (ESTs). The experimental groups were as follows: EST control, EST + nifuroxazide (5 mg/kg), and EST + nifuroxazide (10 mg/kg). Nifuroxazide was found to reduce tumor masses (730.83 ± 73.19 and 381.42 ± 109.69 mg vs. 1099.5 ± 310.83) and lessen tumor pathologies. Furthermore, nifuroxazide downregulated IL-6, TNF-α, NFk-β, angiostatin, and Jak2 proteins, and it also reduced tumoral VEGF, as indicated by ELISA and immunohistochemical analysis. Furthermore, nifuroxazide dose-dependently downregulated STAT3 phosphorylation (60% and 30% reductions, respectively). Collectively, the current experiment shed light on the antitumor activity of nifuroxazide against mammary solid carcinoma grown in vivo. The antitumor activity was at least partly mediated by inhibition of IL-6/Jak2/STAT3 signaling that affected angiogenesis (low VEGF and high angiostatin) in the EST. Therefore, nifuroxazide might be a promising antitumor medication if appropriate human studies will be conducted.     

Synthesis and biological evaluation of novel sulfonanilide compounds as antiproliferative agents for breast cancer

Combinatorial chemistry approaches facilitate drug discovery processes and result in structural modifications of lead compounds that enhance pharmacological activity, improve pharmacokinetic properties, or reduce unwanted side effects. Epidemiological and animal model studies have suggested that nonsteroidal anti-inflammatory drugs (NSAIDs) can act as chemopreventive agents. The cyclooxygenase-2 (COX-2) inhibitor nimesulide shows anticancer effects in several cancer cell lines via COX-2-dependent and -independent mechanisms. The molecular structure of nimesulide was used as a starting scaffold to design novel sulfonanilide analogs and examine the structural features that contribute to this anticancer effect. A systematic combinatorial chemical approach was used to generate diversely substituted sulfonanilide derivatives that were tested for their effects on the proliferation of human breast cancer cells. Structure-function analysis indicated that the inhibition of cell growth by compounds derived from the novel sulfonanilides required a bulky terminal phenyl ring, a methanesulfonamide, and a hydrophobic carboxamide moiety.     

Evaluation of Antiproliferative Palladium(II) Complexes of Synthetic Bisdemethoxycurcumin towards In Vitro Cytotoxicity and Molecular Docking on DNA Sequence

Metallodrugs form a large family of therapeutic agents against cancer, among which is cisplatin, a paradigmatic member. Therapeutic resistance and undesired side effects to Pt(II) related drugs, prompts research on different metal–ligand combinations with potentially enhanced biological activity. We present the synthesis and biological tests of novel palladium(II) complexes containing bisdemethoxycurcumin (BDMC) 1 and 2. Complexes were fully characterized and their structures were determined by X-ray diffraction. Their biological activity was assessed for several selected human tumor cell lines: Jurkat (human leukaemic T-cell lymphoma), HCT-116 (human colorectal carcinoma), HeLa (human cervix epitheloid carcinoma), MCF-7 (human breast adenocarcinoma), MDA-MB-231 (human mammary gland adenocarcinoma), A549 (human alveolar adenocarcinoma), Caco-2 (human colorectal carcinoma), and for non-cancerous 3T3 cells (murine fibroblasts). The cytotoxicity of 1 is comparable to that of cisplatin, and superior to that of 2 in all cell lines. It is a correlation between IC₅₀ values of 1 and 2 in the eight studied cell types, promising a potential use as anti-proliferative drugs. Moreover, for Jurkat cell line, complexes 1 and 2, show an enhanced activity. DFT and docking calculations on the NF-κB protein, Human Serum Albumin (HSA), and DNA were performed for 1 and 2 to correlate with their biological activities.     

Synthetic Strategies of Pyrimidine-Based Scaffolds as Aurora Kinase and Polo-like Kinase Inhibitors

The past few decades have witnessed significant progress in anticancer drug discovery. Small molecules containing heterocyclic moieties have attracted considerable interest for designing new antitumor agents. Of these, the pyrimidine ring system is found in multitude of drug structures, and being the building unit of DNA and RNA makes it an attractive scaffold for the design and development of anticancer drugs. Currently, 22 pyrimidine-containing entities are approved for clinical use as anticancer drugs by the FDA. An exhaustive literature search indicates several publications and more than 59 patents from the year 2009 onwards on pyrimidine derivatives exhibiting potent antiproliferative activity. These pyrimidine derivatives exert their activity via diverse mechanisms, one of them being inhibition of protein kinases. Aurora kinase (AURK) and polo-like kinase (PLK) are protein kinases involved in the regulation of the cell cycle. Within the numerous pyrimidine-based small molecules developed as anticancer agents, this review focuses on the pyrimidine fused heterocyclic compounds modulating the AURK and PLK proteins in different phases of clinical trials as anticancer agents. This article aims to provide a comprehensive overview of synthetic strategies for the preparation of pyrimidine derivatives and their associated biological activity on AURK/PLK. It will also present an overview of the synthesis of the heterocyclic-2-aminopyrimidine, 4-aminopyrimidine and 2,4-diaminopyrimidine scaffolds, and one of the pharmacophores in AURK/PLK inhibitors is described systematically.     

Review on recent development of quinoline for anticancer activities

Quinoline is an efficient scaffold for anticancer drug development as its derivatives have shown potent results through several mechanisms like growth regulators through “apoptosis, disruption of cell migration, inhibition of angiogenesis, modulation of nuclear receptor responsiveness and cell cycle arrest, etc.,” The potential of quinoline derivatives has been proved in several cancer cell lines like breast cancer, colon cancer, lung cancer, colorectal cancer, renal cancer, etc. This review article aims to provide information about the synthesis, potential of the anticancer property, cytotoxicity, and level of clinical treatments, which could lay out the research to develop more effective quinoline-derived anticancer drugs.     

Recent Applications of the Multicomponent Synthesis for Bioactive Pyrazole Derivatives

Pyrazole and its derivatives are considered a privileged N-heterocycle with immense therapeutic potential. Over the last few decades, the pot, atom, and step economy (PASE) synthesis of pyrazole derivatives by multicomponent reactions (MCRs) has gained increasing popularity in pharmaceutical and medicinal chemistry. The present review summarizes the recent developments of multicomponent reactions for the synthesis of biologically active molecules containing the pyrazole moiety. Particularly, it covers the articles published from 2015 to date related to antibacterial, anticancer, antifungal, antioxidant, α-glucosidase and α-amylase inhibitory, anti-inflammatory, antimycobacterial, antimalarial, and miscellaneous activities of pyrazole derivatives obtained exclusively via an MCR. The reported analytical and activity data, plausible synthetic mechanisms, and molecular docking simulations are organized in concise tables, schemes, and figures to facilitate comparison and underscore the key points of this review. We hope that this review will be helpful in the quest for developing more biologically active molecules and marketed drugs containing the pyrazole moiety.     

取代噻吩双酰胺类化合物的设计、 合成及生物活性

利用中间体衍生化方法, 将噻吩环引入到双酰胺类化合物中, 合成了一系列取代噻吩双酰胺类化合物1~3; 目标化合物的结构经核磁共振波谱、 红外光谱及元素分析确认. 生物活性测试结果表明, 化合物1在600 mg/L剂量下对小菜蛾具有良好的杀虫效果, 致死率均为100%, 其中化合物1a和1e在20 mg/L剂量下对小菜蛾的致死率仍达到60%以上; 改变双酰胺结构中的吡唑环得到化合物2和3, 其杀虫活性消失, 说明该类化合物中吡唑环结构对杀虫活性具有关键作用.     

Synthesis and Biological Evaluation of a Novel Series of Chalcones Incorporated Pyrazole Moiety as Anticancer and Antimicrobial Agents

A newly synthesized series of chalcone derivatives containing pyrazole rings were synthesized and evaluated for their cytotoxic activities in vitro against several human cancer cell lines. Most of the prepared compounds showed potential cytotoxicity against human breast cancer cell lines MCF-7, HEPG-2, and HCT-116. Also the compounds were evaluated as antimicrobial agents. The three compounds 3, 4, and 5 were proved to be better anticancer agents than the positive standard doxorubicin with IC50 values (4.7, 4.4, and 3.9???g/ml) against the same human cancer cell lines, whereas compounds 5 and 6 showed the most active antimicrobial compounds in comparison to the other chalcones.     

Synthesis of Anti-Inflammatory Spirostene-Pyrazole Conjugates by a Consecutive Multicomponent Reaction of Diosgenin with Oxalyl Chloride,Arylalkynes and Hydrazines or Hydrazones

Steroid sapogenin diosgenin is of significant interest due to its biological activity and synthetic application. A consecutive one-pot reaction of diosgenin, oxalyl chloride, arylacetylenes, and phenylhydrazine give rise to steroidal 1,3,5-trisubstituted pyrazoles (isolated yield 46–60%) when the Stephens–Castro reaction and heterocyclization steps were carried out by heating in benzene. When the cyclization step of alkyndione with phenylhydrazine was performed in 2-methoxyethanol at room temperature, steroidal α,β-alkynyl (E)- and (Z)-hydrazones were isolated along with 1,3,5-trisubstituted pyrazole and the isomeric 2,3,5-trisubstituted pyrazole. The consecutive reaction of diosgenin, oxalyl chloride, phenylacetylene and benzoic acid hydrazides efficiently forms steroidal 1-benzoyl-5-hydroxy-3-phenylpyrazolines. The structure of new compounds was unambiguously corroborated by comprehensive NMR spectroscopy, mass-spectrometry, and X-ray structure analyses. Performing the heterocyclization step of ynedione with hydrazine monohydrate in 2-methoxyethanol allowed the synthesis of 5-phenyl substituted steroidal pyrazole, which was found to exhibit high anti-inflammatory activity, comparable to that of diclofenac sodium, a commercial pain reliever. It was shown by molecular docking that the new derivatives are incorporated into the binding site of the protein Keap1 Kelch-domain by their alkynylhydrazone or pyrazole substituent with the formation of more non-covalent bonds and have higher affinity than the initial spirostene core.     

Design,Synthesis, In Silico and In Vitro Studies of New Immunomodulatory Anticancer Nicotinamide Derivatives Targeting VEGFR-2

VEGFR-2, the subtype receptor tyrosine kinase (RTK) responsible for angiogenesis, is expressed in various cancer cells. Thus, VEGFER-2 inhibition is an efficient approach for the discovery of new anticancer agents. Accordingly, a new set of nicotinamide derivatives were designed and synthesized to be VEGFR-2 inhibitors. The chemical structures were confirmed using IR, ¹H-NMR, and ¹³C-NMR spectroscopy. The obtained compounds were examined for their anti-proliferative activities against the human cancer cell lines (HCT-116 and HepG2). VEGFR-2 inhibitory activities were determined for the titled compounds. Compound 8 exhibited the strongest anti-proliferative activities with IC₅₀ values of 5.4 and 7.1 µM against HCT-116 and HepG2, respectively. Interestingly, compound 8 was the most potent VEGFR-2 inhibitor with an IC₅₀ value of 77.02 nM (compare to sorafenib: IC₅₀ = 53.65 nM). Treatment of HCT-116 cells with compound 8 produced arrest of the cell cycle at the G0–G1 phase and a total apoptosis increase from 3.05 to 19.82%—6.5-fold in comparison to the negative control. In addition, compound 8 caused significant increases in the expression levels of caspase-8 (9.4-fold) and Bax (9.2-fold), and a significant decrease in the Bcl-2 expression level (3-fold). The effects of compound 8 on the levels of the immunomodulatory proteins (TNF-α and IL-6) were examined. There was a marked decrease in the level of TNF-α (92.37%) compared to the control (82.47%) and a non-significant reduction in the level of IL-6. In silico docking, molecular dynamics simulations, and MM-PBSA studies revealed the high affinity, the correct binding, and the optimum dynamics of compound 8 inside the active site of VEGFR-2. Finally, in silico ADMET and toxicity studies indicated acceptable values of drug-likeness. In conclusion, compound 8 has emerged as a promising anti-proliferative agent targeting VEGFR-2 with significant apoptotic and immunomodulatory effects.     

Oxazinethione Derivatives as a Precursor to Pyrazolone and Pyrimidine Derivatives: Synthesis,Biological Activities,Molecular Modeling,ADME, and Molecular Dynamics Studies

In this study, we used oxazinethione as a perfect precursor to synthesize new pyrimidine and pyrazole derivatives with potent biological activities. Biological activities were determined for all compounds against A. flavus, E. coli, S. aureus, and F. moniliform. Compounds 3, 4a-b, and 5 exhibited higher activities toward A. flavus, E. coli, S. aureus, and F. moniliform; this was indicated through the MIC (minimum inhibitory concentration). At the same time, anticancer activities were determined through four cell lines, Ovcar-3, Hela, MCF-7, and LCC-MMk. The results obtained indicated that compound 5 was the most potent compound for both cell lines. Molecular docking was studied by the MOE (molecular operating environment). The in silico ADME of compounds 2 and 5 showed good pharmacokinetic properties. The present research strengthens the applicability of these compounds as encouraging anticancer and antibacterial drugs. Moreover, JAGUAR module MD simulations were carried out at about 100 ns. In addition, spectroscopic studies were carried out to establish the reactions of the synthesized structure derivatives.