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Alessio Ottaviani Federico Iacovelli Paola Fiorani Alessandro Desideri 《International journal of molecular sciences》2021,22(8)
Natural products are widely used as source for drugs development. An interesting example is represented by natural drugs developed against human topoisomerase IB, a ubiquitous enzyme involved in many cellular processes where several topological problems occur due the formation of supercoiled DNA. Human topoisomerase IB, involved in the solution of such problems relaxing the DNA cleaving and religating a single DNA strand, represents an important target in anticancer therapy. Several natural compounds inhibiting or poisoning this enzyme are under investigation as possible new drugs. This review summarizes the natural products that target human topoisomerase IB that may be used as the lead compounds to develop new anticancer drugs. Moreover, the natural compounds and their derivatives that are in clinical trial are also commented on. 相似文献
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Ashish Kumar Yadav Virendra Singh Rajesh Kushwaha Dr. Dependu Dolui Rohit Rai Dr. Prodyut Dhar Dr. Arnab Dutta Dr. Biplob Koch Dr. Samya Banerjee 《Chembiochem : a European journal of chemical biology》2023,24(10):e202300033
Four new CoII complexes, [Co(bpy)2(acac)]Cl ( 1 ), [Co(phen)2(acac)]Cl ( 2 ), [Co(bpy)2(cur)]Cl ( 3 ), [Co(phen)2(cur)]Cl ( 4 ), where bpy=2,2’-bipyridine ( 1 and 3 ), phen=1,10-phenanthroline ( 2 and 4 ), acac = acetylacetonate ( 1 and 2 ), cur=curcumin monoanion ( 3 and 4 ) have been designed, synthesized and fully characterized. The X-ray crystal structures of 1 and 2 indicated that the CoN4O2 core has a distorted octahedral geometry. The photoactivity of these complexes was tuned by varying the π conjugation in the ligands. Curcumin complexes 3 and 4 had an intense absorption band near 435 nm, which made them useful as visible-light photodynamic therapy agents; they also showed fluorescence with λem≈565 nm. This fluorescence was useful for studying their intracellular uptake and localization in MCF-7 breast cancer cells. The acetylacetonate complexes ( 1 and 2 ) were used as control complexes to understand the role of curcumin. The white-light-triggered anticancer profiles of the cytosol targeting complexes 3 and 4 were investigated in detail. These non-dark toxic complexes displayed significant apoptotic photo-cytotoxicity (under visible light) against MCF-7 cells through ROS generation. The control complexes 1 and 2 did not induce significant cell death in the light or dark. Interestingly, 1-4 produced a remarkable antibacterial response upon light exposure. Overall, the reported results here can increase the boundary of the CoII-based anticancer and antibacterial drug development. 相似文献
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Benzoxazines and benzoxazepines are nitrogen and oxygen-containing six and seven-membered benzo-fused heterocyclic scaffolds, respectively. Benzoxazepines and benzoxazines are well-known pharmacophores in pharmaceutical chemistry, which are of significant interest and have been extensively studied because of their promising activity against various diseases including their wide range of anticancer activity. Several reports are known for synthesizing benzoxazine and benzoxazepine-based compounds in the literature. Herein this review provides a critical analysis of synthetic strategies towards benzoxazines and benzoxazepines along with various ranges of anticancer activities based on these molecules that have been reported from 2010 onwards. This review also focuses on the structure-activity relationship of the benzoxazine and benzoxazepine scaffolds containing bioactive compounds and describes how the structural modification affects their anticancer activity. 相似文献
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Development of Novel Selective Peptidomimetics Containing a Boronic Acid Moiety,Targeting the 20S Proteasome as Anticancer Agents 下载免费PDF全文
Dr. Kety Scarbaci Dr. Valeria Troiano Dr. Roberta Ettari Dr. Andrea Pinto Dr. Nicola Micale Dr. Carmen Di Giovanni Dr. Carmen Cerchia Prof. Dr. Tanja Schirmeister Prof. Ettore Novellino Prof. Antonio Lavecchia Prof. Maria Zappalà Prof. Silvana Grasso 《ChemMedChem》2014,9(8):1801-1816
This paper describes the design, synthesis, and biological evaluation of peptidomimetic boronates as inhibitors of the 20S proteasome, a validated target in the treatment of multiple myeloma. The synthesized compounds showed a good inhibitory profile against the ChT‐L activity of 20S proteasome. Compounds bearing a β‐alanine residue at the P2 position were the most active, that is, 3‐ethylphenylamino and 4‐methoxyphenylamino (R)‐1‐{3‐[4‐(substituted)‐2‐oxopyridin‐1(2H)‐yl]propanamido}‐3‐methylbutylboronic acids ( 3 c and 3 d , respectively), and these derivatives showed inhibition constants (Ki) of 17 and 20 nM , respectively. In addition, they co‐inhibited post glutamyl peptide hydrolase activity ( 3 c , Ki=2.57 μM ; 3 d , Ki=3.81 μM ). No inhibition was recorded against the bovine pancreatic α‐chymotrypsin, which thus confirms the selectivity towards the target enzyme. Docking studies of 3 c and related inhibitors into the yeast proteasome revealed the structural basis for specificity. The evaluation of growth inhibitory effects against 60 human tumor cell lines was performed at the US National Cancer Institute. Among the selected compounds, 3 c showed 50 % growth inhibition (GI50) values at the sub‐micromolar level on all cell lines. 相似文献
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The treatment of cancer has been one of the most significant challenges for the medical field. Further research on the signal transduction pathway of tumor cells is driving the rapid development of antitumor agents targeting tyrosine kinases. However, most of the currently approved tyrosine kinase inhibitors based on the “single target/single drug” design are becoming less and less effective in the treatment of complex, heterogeneous, and multigenic cancers; this also results in resistance to chemotherapy. In contrast, multitargeted tyrosine kinase inhibitors (MT-TKIs) can effectively block multiple pathways of intracellular signal transduction. Therefore, they have therapeutic advantages over single-targeted inhibitors and have become a hotspot in antitumor drug research in recent years. This minireview summarizes recent advances in the discovery of MT-TKIs based on their chemical structures. In particular, we describe the kinase inhibitory and antitumor activity of promising compounds, as well as their structure – activity relationships (SARs). 相似文献
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Rania Hamdy Arwyn T. Jones Mohamed El-Sadek Alshaimaa M. Hamoda Sarra B. Shakartalla Zainab M. AL Shareef Sameh S. M. Soliman Andrew D. Westwell 《International journal of molecular sciences》2021,22(22)
A series of 3-(6-substituted phenyl-[1,2,4]-triazolo[3,4-b]-[1,3,4]-thiadiazol-3-yl)-1H-indoles (5a–l) were designed, synthesized and evaluated for anti-apoptotic Bcl-2-inhibitory activity. Synthesis of the target compounds was readily accomplished through a reaction of acyl hydrazide (1) with carbon disulfide in the presence of alcoholic potassium hydroxide to afford the corresponding intermediate potassium thiocarbamate salt (2), which underwent cyclization reaction in the presence of excess hydrazine hydrate to the corresponding triazole thiol (3). Further cyclisation reaction with substituted benzoyl chloride derivatives in the presence of phosphorous oxychloride afforded the final 6-phenyl-indol-3-yl [1,2,4]-triazolo[3,4-b]-[1,3,4]-thiadiazole compounds (5a–l). The novel series showed selective sub-micromolar IC50 growth-inhibitory activity against Bcl-2-expressing human cancer cell lines. The most potent 6-(2,4-dimethoxyphenyl) substituted analogue (5k) showed selective IC50 values of 0.31–0.7 µM against Bcl-2-expressing cell lines without inhibiting the Bcl-2-negative cell line (Jurkat). ELISA binding affinity assay (interruption of Bcl-2-Bim interaction) showed potent binding affinity for (5k) with an IC50 value of 0.32 µM. Moreover, it fulfils drug likeness criteria as a promising drug candidate. 相似文献
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Dr. Jinyun Dong Dr. Qijing Zhang Zengtao Wang Dr. Guang Huang Prof. Shaoshun Li 《ChemMedChem》2018,13(15):1490-1507
Cancer is one of the leading causes of human mortality globally; therefore, intensive efforts have been made to seek new active drugs with improved anticancer efficacy. Indazole‐containing derivatives are endowed with a broad range of biological properties, including anti‐inflammatory, antimicrobial, anti‐HIV, antihypertensive, and anticancer activities. In recent years, the development of anticancer drugs has given rise to a wide range of indazole derivatives, some of which exhibit outstanding activity against various tumor types. The aim of this review is to outline recent developments concerning the anticancer activity of indazole derivatives, as well as to summarize the design strategies and structure–activity relationships of these compounds. 相似文献
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Mohit K. Tiwari Dr. Paolo Coghi Prakhar Agrawal Bharti Rajesh K. Shyamlal Li Jun Yang Lalit Yadav Yuzhong Peng Richa Sharma Dr. Dharmendra K. Yadav Dr. Dinkar Sahal Dr. Vincent Kam Wai Wong Dr. Sandeep Chaudhary 《ChemMedChem》2020,15(13):1216-1228
A novel series of synthetic functionalized arylvinyl-1,2,4-trioxanes ( 8 a – p ) has been prepared and assessed for their in vitro antiplasmodial activity against the chloroquine-resistant Pf INDO strain of Plasmodium falciparum by using a SYBR green-I fluorescence assay. Compounds 8 g (IC50=0.051 μM; SI=589.41) and 8 m (IC50=0.059 μM; SI=55.93) showed 11-fold and >9-fold more potent antiplasmodial activity, respectively, as compared to chloroquine (IC50=0.546 μM; SI=36.63). Different in silico docking studies performed on many target proteins revealed that the most active arylvinyl-1,2,4-trioxanes ( 8 g and 8 m ) showed dihydrofolate reductase (DHFR) binding affinities on a par with those of chloroquine and artesunate. The in vitro cytotoxic potentials of 8 a – p were also evaluated against human lung (A549) and liver (HepG2) cancer cell lines along with immortalized normal lung (BEAS-2B) and liver (LO2) cell lines. Following screening, five derivatives viz. 8 a , 8 h , 8 l , 8 m and 8 o (IC50=1.65–31.7 μM; SI=1.08–10.96) were found to show potent cytotoxic activity against (A549) lung cancer cell lines, with selectivity superior to that of the reference compounds artemisinin (IC50=100 μM), chloroquine (IC50=100 μM) and artesunic acid (IC50=9.85 μM; SI=0.76). In fact, the most active 4-naphthyl-substituted analogue 8 l (IC50=1.65 μM; SI >10) exhibited >60 times more cytotoxicity than the standard reference, artemisinin, against A549 lung cancer cell lines. In silico docking studies of the most active anticancer compounds, 8 l and 8 m , against EGFR were found to validate the wet lab results. In summary, a new series of functionalized aryl-vinyl-1,2,4-trioxanes ( 8 a – p ) has been shown to display dual potency as promising antiplasmodial and anticancer agents. 相似文献
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Oxoisoaporphine alkaloids are a family of oxoisoquinoline‐derived alkaloids that were first isolated from the rhizome of Menispermum dauricum DC. (Menispermaceae). It has been demonstrated that oxoisoaporphine alkaloids possess various biological properties, such as cholinesterase and β‐amyloid inhibition, acting as a topoisomerase intercalator, monoamine oxidase A inhibition, and are expected to become anti‐Alzheimer's disease, anticancer, and antidepressant drugs. This review provides an overview of natural sources, synthetic routes, bioactivities, structure–function relationship, and modification investigations into oxoisoaporphine alkaloids, with the aim of providing references to the structure–activity relationships for the design and development of oxoisoaporphine derivatives with higher efficacy and therapeutic potential. 相似文献
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Prof. Guofan Jin Fuyan Xiao Zhenwang Li Dr. Xueyong Qi Dr. Lei Zhao Prof. Xianyu Sun 《ChemMedChem》2020,15(7):600-609
A series of novel quinoline and quinolinium iodide derivatives were designed and synthesized to discover potential anticancer and antibacterial agents. With regard to anticancer properties, in vitro cytotoxicities against three human cancer cell lines (A-549, HeLa and SGC-7901) were evaluated. The antibacterial properties against two strains, Escherichia coli (ATCC 29213) and Staphylococcus aureus (ATCC 8739), along with minimum inhibitory concentration (MIC) values were evaluated. The target alkyliodine substituted compounds exhibited significant antitumor and antibacterial activity, of which compound 8-((4-(benzyloxy)phenyl)amino)-7-(ethoxycarbonyl)-5-propyl-[1,3]dioxolo[4,5-g]quinolin-5-ium ( 12 ) was found to be the most potent derivative with IC50 values of 4.45±0.88, 4.74±0.42, 14.54±1.96, and 32.12±3.66 against A-549, HeLa, SGC-7901, and L-02 cells, respectively, stronger than the positive controls 5-FU and MTX. Furthermore, compound 12 had the most potent bacterial inhibitory activity. The MIC of this compound against both E. coli and S. aureus was 3.125 nmol ⋅ mL−1, which was smaller than that against the reference agents amoxicillin and ciprofloxacin. 相似文献
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Dahye Yun So Young Yoon Soo Jung Park Yoon Jung Park 《International journal of molecular sciences》2021,22(4)
Isoquinoline alkaloids-enriched herbal plants have been used as traditional folk medicine for their anti-inflammatory, antimicrobial, and analgesic effects. They induce cell cycle arrest, apoptosis, and autophagy, leading to cell death. While the molecular mechanisms of these effects are not fully understood, it has been suggested that binding to nucleic acids or proteins, enzyme inhibition, and epigenetic modulation by isoquinoline alkaloids may play a role in the effects. This review discusses recent evidence on the molecular mechanisms by which the isoquinoline alkaloids can be a therapeutic target of cancer treatment. 相似文献
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Taotao Zou Jing-Jing Zhang Bei Cao Ka-Chung Tong Chun-Nam Lok Chi-Ming Che 《Israel journal of chemistry》2016,56(9-10):825-833
Metal-based anticancer agents with non-DNA targets are anticipated for overcoming cisplatin resistance problems. Gold complexes are generally known to undergo ligand exchange or redox reactions with thiols, and hence, are potentially useful agents that could target thiol-containing enzymes, but not DNA. Recent studies have shown that deubiquitinases (DUBs), key enzymes regulating proteasome-related protein homeostasis, are potential anticancer targets of both gold(I) and gold(III) complexes. In this review, the current status of gold complexes as DUB inhibitors is discussed. In particular, auranofin and cyclometalated gold(III) complexes containing dithiocarbamate ligands (e.g., [(AuIII(C N)(DEDT)]+, HC N=2-phenylpyridine, DEDT=diethyldithiocarbamate) are highlighted as examples of DUB inhibitors. The mechanisms of their anticancer action, together with in vitro and/or in vivo antitumor potencies, are also explored. 相似文献
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Beata Tyliska Benita Wiatrak aneta Czynikowska Aneta Ciela-Niechwiadowicz Elbieta Gbarowska Anna Janicka-Kos 《International journal of molecular sciences》2021,22(8)
In the present paper, new pyrimidine derivatives were designed, synthesized and analyzed in terms of their anticancer properties. The tested compounds were evaluated in vitro for their antitumor activity. The cytotoxic effect on normal human dermal fibroblasts (NHDF) was also determined. According to the results, all the tested compounds exhibited inhibitory activity on the proliferation of all lines of cancer cells (colon adenocarcinoma (LoVo), resistant colon adenocarcinoma (LoVo/DX), breast cancer (MCF-7), lung cancer (A549), cervical cancer (HeLa), human leukemic lymphoblasts (CCRF-CEM) and human monocytic (THP-1)). In particular, their feature stronger influence on the activity of P-glycoprotein of cell cultures resistant to doxorubicin than doxorubicin. Tested compounds have more lipophilic character than doxorubicin, which determines their affinity for the molecular target and passive transport through biological membranes. Moreover, the inhibitory potential against topoisomerase II and DNA intercalating properties of synthesized compounds were analyzed via molecular docking. 相似文献
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Oxana Kazakova Codrua oica Marat Babaev Anastasiya Petrova Elmira Khusnutdinova Alexander Poptsov Ioana Macaoi George Drghici tefana Avram Lavinia Vlaia Alexandra Mioc Marius Mioc Cristina Dehelean Adrian Voicu 《International journal of molecular sciences》2021,22(19)
Cancer persists as a global challenge due to the extent to which conventional anticancer therapies pose high risks counterbalanced with their therapeutic benefit. Naturally occurring substances stand as an important safer alternative source for anticancer drug development. In the current study, a series of modified lupane and ursane derivatives was subjected to in vitro screening on the NCI-60 cancer cell line panel. Compounds 6 and 7 have been identified as highly active with GI50 values ranging from 0.03 µM to 5.9 µM (compound 6) and 0.18–1.53 µM (compound 7). Thus, these two compounds were further assessed in detail in order to identify a possible antiproliferative mechanism of action. DAPI (4′,6-diamidino-2-phenylindole) staining revealed that both compounds induced nuclei condensation and overall cell morphological changes consistent with apoptotic cell death. rtPCR analysis showed that both compounds induced upregulation of proapoptotic Bak and Bad genes while downregulating Bcl-XL and Bcl-2 antiapoptotic genes. Molecular docking analysis revealed that both compounds exhibited high scores for Bcl-XL inhibition, while compound 7 showed higher in silico Bcl-XL inhibition potential as compared to the native inhibitor ATB-737, suggesting that compounds may induce apoptotic cell death through targeted antiapoptotic protein inhibition, as well. 相似文献
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Francesca Persano Giuseppe Gigli Stefano Leporatti 《International journal of molecular sciences》2022,23(6)
In humans, glioblastoma is the most prevalent primary malignant brain tumor. Usually, glioblastoma has specific characteristics, such as aggressive cell proliferation and rapid invasion of surrounding brain tissue, leading to a poor patient prognosis. The current therapy—which provides a multidisciplinary approach with surgery followed by radiotherapy and chemotherapy with temozolomide—is not very efficient since it faces clinical challenges such as tumor heterogeneity, invasiveness, and chemoresistance. In this respect, natural substances in the diet, integral components in the lifestyle medicine approach, can be seen as potential chemotherapeutics. There are several epidemiological studies that have shown the chemopreventive role of natural dietary compounds in cancer progression and development. These heterogeneous compounds can produce anti-glioblastoma effects through upregulation of apoptosis and autophagy; allowing the promotion of cell cycle arrest; interfering with tumor metabolism; and permitting proliferation, neuroinflammation, chemoresistance, angiogenesis, and metastasis inhibition. Although these beneficial effects are promising, the efficacy of natural compounds in glioblastoma is limited due to their bioavailability and blood–brain barrier permeability. Thereby, further clinical trials are necessary to confirm the in vitro and in vivo anticancer properties of natural compounds. In this article, we overview the role of several natural substances in the treatment of glioblastoma by considering the challenges to be overcome and future prospects. 相似文献