A new group of potent histone deacetylase inhibitors (HDACis) capable of inhibiting cell growth and affecting cell-cycle progression in Tohoku Hospital Pediatrics-1 (THP-1) monocytic leukaemia cells was synthesized. The inhibitors belong to a series of hydroxamic acid derivatives. We designed and synthesized a series of 22 N-hydroxycinnamamide derivatives, out of which 20 are new compounds. These compounds contain various substituted anilides as the surface recognition moiety (SRM), a p-hydroxycinnamate linker, and hydroxamic acids as the zinc-binding group (ZBG). The whole series of synthesized hydroxamic acids inhibited THP-1 cell proliferation. Compounds 7d and 7p, which belong to the category of derivatives with the most potent antiproliferative properties, exert a similar effect on cell-cycle progression as vorinostat and induce apoptosis in THP-1 cells. Furthermore, compounds 7d and 7p were demonstrated to inhibit HDAC class I and II in THP-1 cells with comparable potency to vorinostat and increase acetylation of histones H2a, H2b, H3, and H4. Molecular modelling was used to predict the probable binding mode of the studied HDACis in class I and II histone deacetylases in terms of Zn2+ ion chelation by the hydroxamate group.

• Keywords
• HDACi, anticancer agents, haematological malignancies, hydroxamic acid, inhibitors of histone deacetylases,
• MeSH
• Apoptosis * drug effects   MeSH
• Cell Cycle drug effects   MeSH
• Histone Deacetylases metabolism   MeSH
• Histone Deacetylase Inhibitors * pharmacology   chemical synthesis   chemistry   MeSH
• Hydroxamic Acids * pharmacology   chemical synthesis   chemistry   MeSH
• Coumaric Acids * pharmacology   chemistry   chemical synthesis   MeSH
• Humans MeSH
• Molecular Structure MeSH
• Cell Line, Tumor MeSH
• Cell Proliferation drug effects   MeSH
• Antineoplastic Agents * pharmacology   chemical synthesis   chemistry   MeSH
• Drug Screening Assays, Antitumor MeSH
• Molecular Docking Simulation MeSH
• THP-1 Cells MeSH
• Dose-Response Relationship, Drug MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Histone Deacetylases MeSH
• Histone Deacetylase Inhibitors * MeSH
• Hydroxamic Acids * MeSH
• Coumaric Acids * MeSH
• Antineoplastic Agents * MeSH

Aminopeptidase N (APN), also known as CD13 antigen or membrane alanyl aminopeptidase, belongs to the M1 family of the MA clan of zinc metallopeptidases. In cancer cells, the inhibition of aminopeptidases including APN causes the phenomenon termed the amino acid deprivation response (AADR), a stress response characterized by the upregulation of amino acid transporters and synthetic enzymes and activation of stress-related pathways such as nuclear factor kB (NFkB) and other pro-apoptotic regulators, which leads to cancer cell death by apoptosis. Recently, APN inhibition has been shown to augment DR4-induced tumor cell death and thus overcome resistance to cancer treatment with DR4-ligand TRAIL, which is available as a recombinant soluble form dulanermin. This implies that APN inhibitors could serve as potential weapons for overcoming cancer treatment resistance. In this study, a series of basically substituted acetamidophenones and the semicarbazones and thiosemicarbazones derived from them were prepared, for which APN inhibitory activity was determined. In addition, a selective anti-proliferative activity against cancer cells expressing APN was demonstrated. Our semicarbazones and thiosemicarbazones are the first compounds of these structural types of Schiff bases that were reported to inhibit not only a zinc-dependent aminopeptidase of the M1 family but also a metalloenzyme.

• Keywords
• Schiff bases, acetamidophenones, aminopeptidase N, inhibition of proliferation, semicarbazones, thiosemicarbazones,
• MeSH
• Aminopeptidases MeSH
• CD13 Antigens metabolism   MeSH
• Humans MeSH
• Neoplasms * drug therapy   MeSH
• Semicarbazones * MeSH
• Thiosemicarbazones * MeSH
• Zinc pharmacology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Aminopeptidases MeSH
• CD13 Antigens MeSH
• Semicarbazones * MeSH
• Thiosemicarbazones * MeSH
• Zinc MeSH

The superimposition of the X-ray complexes of cyclohexanediones (i.e., TUB015), described by our research group, and nocodazole, within the colchicine binding site of tubulin provided an almost perfect overlap of both ligands. This structural information led us to propose hybrids of TUB015 and nocodazole using a salicylanilide core structure. Interestingly, salicylanilides, such as niclosamide, are well-established signal transducers and activators of transcription (STAT3) inhibitors with anticancer properties. Thus, different compounds with this new scaffold have been synthesized with the aim to identify compounds inhibiting tubulin polymerization and/or STAT3 signaling. As a result, we have identified new salicylanilides (6 and 16) that showed significant antiproliferative activity against a panel of cancer cells. Both compounds were able to reduce the levels of p-STAT3Tyr705 without affecting the total expression of STAT3. While compound 6 inhibited tubulin polymerization and arrested the cell cycle of DU145 cells at G2/M, similar to TUB015, compound 16 showed a more potent effect on inhibiting STAT3 phosphorylation and arrested the cell cycle at G1/G0, similar to niclosamide. In both cases, no toxicity towards PBMC cells was detected. Thus, the salicylanilides described here represent a new class of antiproliferative agents affecting tubulin polymerization and/or STAT3 phosphorylation.

• Keywords
• colchicine site, niclosamide, salicylanilides, signal transducer and activator of transcription (STAT3) inhibitors, tubulin polymerization inhibitors,
• Publication type
• Journal Article MeSH

Ring-substituted 1-hydroxynaphthalene-2-carboxanilides were previously investigated for their antimycobacterial properties. In our study, we have shown their antiproliferative and cell death-inducing effects in cancer cell lines. Cell proliferation and viability were assessed by WST-1 assay and a dye exclusion test, respectively. Cell cycle distribution, phosphatidylserine externalization, levels of reactive oxygen or nitrogen species (RONS), mitochondrial membrane depolarization, and release of cytochrome c were estimated by flow cytometry. Levels of regulatory proteins were determined by Western blotting. Our data suggest that the ability to inhibit the proliferation of THP-1 or MCF-7 cells might be referred to meta- or para-substituted derivatives with electron-withdrawing groups -F, -Br, or -CF3 at anilide moiety. This effect was accompanied by accumulation of cells in G1 phase. Compound 10 also induced apoptosis in THP-1 cells in association with a loss of mitochondrial membrane potential and production of mitochondrial superoxide. Our study provides a new insight into the action of salicylanilide derivatives, hydroxynaphthalene carboxamides, in cancer cells. Thus, their structure merits further investigation as a model moiety of new small-molecule compounds with potential anticancer properties.

• Keywords
• antiproliferative effect, apoptosis, cell cycle, hydroxynaphthalene carboxamides, salicylanilides,
• MeSH
• Anilides chemistry   pharmacology   MeSH
• Apoptosis drug effects   MeSH
• Cell Cycle drug effects   MeSH
• Humans MeSH
• Membrane Potential, Mitochondrial drug effects   MeSH
• MCF-7 Cells MeSH
• Mitochondria drug effects   metabolism   MeSH
• Molecular Structure MeSH
• Naphthols chemistry   MeSH
• Cell Proliferation drug effects   MeSH
• Antineoplastic Agents chemistry   pharmacology   MeSH
• Reactive Oxygen Species metabolism   MeSH
• Salicylanilides chemistry   pharmacology   MeSH
• Superoxides metabolism   MeSH
• THP-1 Cells MeSH
• Cell Survival drug effects   MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Anilides MeSH
• Naphthols MeSH
• Antineoplastic Agents MeSH
• Reactive Oxygen Species MeSH
• salicylanilide MeSH Browser
• Salicylanilides MeSH
• Superoxides MeSH

Ring-substituted hydroxynaphthanilides are considered as cyclic analogues of salicylanilides, compounds possessing a wide range of pharmacological activities, including promising anticancer properties. The aim of this study was to evaluate the potential anticancer effect of novel nitro-substituted hydroxynaphthanilides with a special focus on structure-activity relationships. The antiproliferative effect was assessed by Water Soluble Tetrazolium Salts-1 (WST-1) assay, and cytotoxicity was evaluated via dye exclusion test. Flow cytometry was used for cell cycle analysis and detection of apoptosis using Annexin V-FITC/PI assay. Protein expression was estimated by Western blotting. Our data indicate that the potential to cause the antiproliferative effect increases with the shift of the nitro substituent from the ortho- to the para-position. The most potent compounds, 3-hydroxy-N-(3-nitrophenyl)naphthalene-2-carboxamide (2), and 2-hydroxy-N-(4-nitrophenyl)-naphthalene-1-carboxamide (6) showed antiproliferative activity against THP-1 and MCF-7 cancer cells without affecting the proliferation of 3T3-L1 non-tumour cells. Compounds 2 and 6 induced the accumulation of THP-1 and MCF-7 cells in G1 phase associated with the downregulation of cyclin E1 protein levels, while the levels of cyclin B1 were not affected. Moreover, compound 2 was found to exert the pro-apoptotic effect on the THP-1 cells. These results suggest that hydroxynaphthanilides might represent a potential model structure for the development of novel anticancer agents.

• Keywords
• anticancer effect, apoptosis, cell proliferation, hydroxynaphthanilides, salicylanilides,
• MeSH
• Anilides pharmacology   MeSH
• Apoptosis drug effects   MeSH
• Cell Cycle drug effects   MeSH
• Humans MeSH
• MCF-7 Cells MeSH
• Molecular Structure MeSH
• Naphthalenes chemistry   pharmacology   MeSH
• Naphthols pharmacology   MeSH
• Cell Proliferation drug effects   MeSH
• Antineoplastic Agents pharmacology   MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• 2-hydroxy-N-(4-nitrophenyl)naphthalene-1-carboxamide MeSH Browser
• 3-hydroxy-N-(3-nitrophenyl)naphthalene-2-carboxamide MeSH Browser
• Anilides MeSH
• Naphthalenes MeSH
• Naphthols MeSH
• Antineoplastic Agents MeSH

Paulownia tomentosa, a member of the plant family Paulowniaceae and a rich source of biologically active secondary metabolites, is traditionally used in Chinese herbal medicine. Flavonoids, lignans, phenolic glycosides, quinones, terpenoids, glycerides, phenolic acids, and miscellaneous other compounds have been isolated from different parts of P. tomentosa plant. Recent interest in this species has focused on isolating and identifying of prenylated flavonoids, that exhibit potent antioxidant, antibacterial, and antiphlogistic activities and inhibit severe acute respiratory syndrome coronavirus papain-like protease. They show cytotoxic activity against various human cancer cell lines and inhibit the effects of human cholinesterase, butyrylcholinesterase, and bacterial neuraminidases. Most of the compounds considered here have never been isolated from any other species of plant. This review summarizes the information about the isolated compounds that are active, their bioactivities, and the structure-activity relationships that have been worked out for them.

• Keywords
• Bignonia tomentosa, Flavonoid, Lignan, Paulownia tomentosa, Paulowniaceae, Phenolic glycosides,
• Publication type
• Journal Article MeSH
• Review MeSH

Aims. In this work we studied cytodifferentiation effects of newly characterized prenyl flavonoid 4'-O-methylkuwanon E (4ME) isolated from white mulberry (Morus alba L.). Main Methods. Cell growth and viability were measured by dye exclusion assay; cell cycle and surface antigen CD11b were monitored by flow cytometry. For the cytodifferentiation of cells the NBT reduction assay was employed. Regulatory proteins were assessed by western blotting. Key Findings. 4ME induced dose-dependent growth inhibition of THP-1 cells, which was not accompanied by toxic effect. Inhibition of cells proliferation caused by 4ME was associated with the accumulation in G1 phase and with downregulation of hyperphosphorylated pRb. Treatment with 4ME led to significant induction of NBT-reducing activity of PMA stimulated THP-1 cells and upregulation expression of differentiation-associated surface antigen CD11b. Our results suggest that monocytic differentiation induced by 4ME is connected with up-regulation of p38 kinase activity. Significance. Our study provides the first evidence that 4ME induces the differentiation of THP-1 human monocytic leukemia cells and thus is a potential cytodifferentiating anticancer agent.

• Publication type
• Journal Article MeSH

A series of twenty substituted 2-hydroxy-3-[(2-aryloxyethyl)amino]propyl 4-[(alkoxycarbonyl)amino]benzoates were prepared and characterized. As similar compounds have been described as potential antimycobacterials, primary in vitro screening of the synthesized carbamates was also performed against two mycobacterial species. 2-Hydroxy-3-[2-(2,6-dimethoxyphenoxy)ethylamino]-propyl 4-(butoxycarbonylamino)benzoate hydrochloride, 2-hydroxy-3-[2-(4-methoxyphenoxy)ethylamino]-propyl 4-(butoxycarbonylamino)benzoate hydrochloride, and 2-hydroxy-3-[2-(2-methoxyphenoxy)ethylamino]-propyl 4-(butoxycarbonylamino)benzoate hydrochloride showed higher activity against M. avium subsp. paratuberculosis and M. intracellulare than the standards ciprofloxacin, isoniazid, or pyrazinamide. Cytotoxicity assay of effective compounds was performed using the human monocytic leukaemia THP-1 cell line. Compounds with predicted amphiphilic properties were also tested for their effects on the rate of photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. All butyl derivatives significantly stimulated the rate of PET, indicating that the compounds can induce conformational changes in thylakoid membranes resulting in an increase of their permeability and so causing uncoupling of phosphorylation from electron transport.

• MeSH
• Anti-Bacterial Agents chemical synthesis   pharmacology   MeSH
• Benzoates chemical synthesis   pharmacology   MeSH
• Carbamates chemical synthesis   pharmacology   MeSH
• Mycobacterium avium subsp. paratuberculosis drug effects   MeSH
• Uncoupling Agents chemical synthesis   pharmacology   MeSH
• Spinacia oleracea drug effects   MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Anti-Bacterial Agents MeSH
• Benzoates MeSH
• Carbamates MeSH
• Uncoupling Agents MeSH

In this study, a series of twenty-two ring-substituted 3-hydroxy-N-phenylnaphthalene-2-carboxanilides were prepared and characterized. The compounds were tested for their activity related to inhibition of photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. Primary in vitro screening of the synthesized compounds was also performed against four Staphylococcus strains and against two mycobacterial species. 3-Hydroxy-N-(2-methoxyphenyl)naphthalene-2-carboxamide showed high biological activity (MIC = 55.0 µmol/L) against S. aureus as well as methicillin-resistant strains. N-(2-Fluorophenyl)-3-hydroxynaphthalene-2-carboxamide showed higher activity (MIC = 28.4 µmol/L) against M. marinum than the standard isoniazid and 3-hydroxy-N-(4-nitrophenyl)naphthalene-2-carboxamide expressed higher activity (MIC = 13.0 µmol/L) against M. kansasii than the standard isoniazid. Cytotoxicity assay of effective antimicrobial compounds was performed using the human monocytic leukemia THP-1 cell line. The PET-inhibiting activity expressed by IC50 value of the most active compound 3-hydroxy-N-(3-nitrophenyl)naphthalene-2-carboxamide was 16.9 μmol/L. The structure-activity relationships of all compounds are discussed.

• MeSH
• Anti-Bacterial Agents chemical synthesis   pharmacology   MeSH
• Chloroplasts drug effects   MeSH
• Photosynthesis drug effects   MeSH
• Herbicides chemical synthesis   pharmacology   MeSH
• Hydrazines chemical synthesis   chemistry   pharmacology   MeSH
• Humans MeSH
• Microbial Sensitivity Tests MeSH
• Spinacia oleracea drug effects   MeSH
• Staphylococcus aureus drug effects   MeSH
• Electron Transport drug effects   MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Anti-Bacterial Agents MeSH
• Herbicides MeSH
• Hydrazines MeSH

Morus alba L. (MA) is a natural source of many compounds with different biological effects. It has been described to possess anti-inflammatory, antioxidant, and hepatoprotective activities. The aim of this study was to evaluate cytotoxicity of three flavonoids isolated from MA (kuwanon E, cudraflavone B, and 4'-O-methylkuwanon E) and to determine their effects on proliferation of THP-1 cells, and on cell cycle progression of cancer cells. Anti-inflammatory effects were also determined for all three given flavonoids. Methods used in the study included quantification of cells by hemocytometer and WST-1 assays, flow cytometry, western blotting, ELISA, and zymography. From the three compounds tested, cudraflavone B showed the strongest effects on cell cycle progression and viability of tumor and/or immortalized cells and also on inflammatory response of macrophage-like cells. Kuwanon E and 4'-O-methylkuwanon E exerted more sophisticated rather than direct toxic effect on used cell types. Our data indicate that mechanisms different from stress-related or apoptotic signaling pathways are involved in the action of these compounds. Although further studies are required to precisely define the mechanisms of MA flavonoid action in human cancer and macrophage-like cells, here we demonstrate their effects combining antiproliferative and anti-inflammatory activities, respectively.

• Publication type
• Journal Article MeSH