Strong Antiproliferative Agents Research Articles

Biotinylated selenocyanates: Potent and selective cytostatic agents

Most of the currently available cytotoxic agents for tackling cancer are devoid of selectivity, thus causing severe side-effects. This situation stimulated us to develop new antiproliferative agents with enhanced affinity towards tumour cells. We focused our attention on novel chalcogen-containing compounds (thiosemicarbazones, disulfides, selenoureas, thio- and selenocyanates), and particularly on selenium derivatives, as it has been documented that this kind of compounds might act as prodrugs releasing selenium-based reactive species on tumour cells. Particularly interesting in terms of potency and selectivity was a pharmacophore comprised by a selenocyanato-alkyl fragment connected to a p-phenylenediamine residue, where the nature of the second amino moiety (free, Boc-protected, enamine-protected) provided a wide variety of antiproliferative activities, ranging from the low micromolar to the nanomolar values. The optimized structure was in turn conjugated through a peptide linkage with biotin (vitamin B7), a cellular growth promoter, whose receptor is overexpressed in numerous cancer cells; the purpose was to develop a selective vector towards malignant cells. Such biotinylated derivative behaved as a very strong antiproliferative agent, achieving GI50 values in the low nM range for most of the tested cancer cells; moreover, it was featured with an outstanding selectivity, with GI50 > 100 µM against human fibroblasts.Mechanistic studies on the mode of inhibition of the biotinylated selenocyanate revealed (Annexin-V assay) a remarkable increase in the number of apoptotic cells compared to the control experiment; moreover, depolarization of the mitochondrial membrane was detected by flow cytometry analysis, and with fluorescent microscopy, what supports the apoptotic cell death. Prior to the apoptotic events, cytostatic effects were observed against SW1573 cells using label-free cell-living imaging; therefore, tumour cell division was prevented.Multidrug resistant cell lines exhibited a reduced sensitivity towards the biotinylated selenocyanate, probably due to its P-gp-mediated efflux. Remarkably, antiproliferative levels could be restored by co-administration with tariquidar, a P-gp inhibitor; this approach can, therefore, overcome multidrug resistance mediated by the P-gp efflux system.

Synthesis and anticancer activity of oxazolo and oxazinoquinolinone derivatives

A convenient and efficient reduction of 3-nitro-4-hydroxy-1-methylquinolin-2(1H)-one using tin and hydrochloric acid produced the novel 3-amino-4-hydroxyquinolinone derivative. The aminoquinoline was reacted with various electrophilic reagents such as acid anhydrides, acyl chlorides and esters to give a tricyclic system namely; oxazoloquinolinone and oxazinoquinolinone. Diazotization and alkylation of aminoquinoline were carried out affording the interesting N-alkylated quinoline and azodye derivatives. Selected products were screened for their anticancer activity against HepG-2 and MCF-7 cell lines. Among the various synthesized derivatives, the aminoquinoline compound is the strong antiproliferative agent and may consider a specific therapeutic index.

Selenocoumarins as new multitarget antiproliferative agents: Synthesis, biological evaluation and in silico calculations

Herein we report a straightforward preparation of new antiproliferative agents based on the hybridization of a coumarin skeleton and an organoselenium motif. Three families were obtained: isoselenocyanate, selenocarbamates and selenoureas. The main purpose of these hybrid structures is the development of new antiproliferative agents with a multitarget mode of action.A strong correlation between the nature of the organosenium scaffold and the antiproliferative activity was observed. Thus, whereas selenocarbamates proved to be inactive, or moderate antiproliferative agents, isoselenocyanate and most of the selenoureas behaved as strong antiproliferative agents, with GI50 values within the low micromolar range. Interestingly, a good selectivity toward tumor cell lines was found for some of the compounds. Moreover, an increase in the ROS level was observed for tumor cells, and accordingly, these pro-oxidant species might be involved in their mode of action. Overall, title compounds were found not to be substrates for P-glycoprotein, which is overexpressed in many cancer cells as a way of detoxification, and thus, to develop drug resistance.In silico calculations revealed that the selenoderivatives prepared herein might undergo a strong interaction with the active site of HDAC8, and therefore, be potential inhibitors of histone deacetylase 8. In vitro assessment against HDAC8 revealed a strong inhibition of such enzyme exerted by selenoureas, particularly by symmetrical coumarin-containing selenourea.Two compounds showed good antiproliferative data and appear as plausible leads for further testings. The symmetrical coumarin 6 displays the best in vitro inhibition of HDAC8, but is affected by P-gp. In contrast, the N-butyl selenourea coumarin derivative 5a escapes P-gp resistance but has lower HDAC8 inhibition activity.

Chalcogen-containing phenolics as antiproliferative agents.

The increasing number of cancer cases has stimulated researchers to seek for novel approaches. We have combined two bioactive moieties: a polyphenolic scaffold and an organoselenium motif. Four different families (isothiocyanates/thioureas, and their selenium isosters) derived from dopamine, (±)-norepinephrine and R-epinephrine were accessed. Heterocumulenes derived from dopamine and β-O-methylnoradrenaline were strong antiproliferative agents (GI50<10μM). Selenoureas derived from β-O-methylnoradrenaline bearing electron-withdrawing groups (halogen, -NO2, -Ph) on the phenyl ring, were also strong antiproliferative agents, besides exhibiting good antiradical and glutathione peroxidase-like activities. Up to a 14-fold increased activity was achieved compared with classical chemotherapeutic agents, exhibiting also different mechanisms of action (cell cycle assays). Redox analysis on HeLa cells suggested an increase of ROS levels after the incubation period. the combination of organoselenium and phenolic moieties might provide valuable lead compounds with relevant antiproliferative properties.

Pro-Apoptotic Activity of 4-Isopropyl-2-(1-Phenylethyl) Aniline Isolated from Cordyceps bassiana

Cordyceps species including Cordyceps bassiana are a notable anti-cancer dietary supplement. Previously, we identified several compounds with anti-cancer activity from the butanol fraction (Cb-BF) of Cordyceps bassiana. To expand the structural value of Cb-BF-derived anti-cancer drugs, we employed various chemical moieties to produce a novel Cb-BF-derived chemical derivative, KTH-13-amine-monophenyl [4-isopropyl-2-(1-phenylethyl) aniline (KTH-13-AMP)], which we tested for anti-cancer activity. KTH-13-AMP suppressed the proliferation of MDA-MB-231, HeLa, and C6 glioma cells. KTH-13-AMP also dose-dependently induced morphological changes in C6 glioma cells and time-dependently increased the level of early apoptotic cells stained with annexin V-FITC. Furthermore, the levels of the active full-length forms of caspase-3 and caspase-9 were increased. In contrast, the levels of total forms of caspases-3, caspase-8, caspase-9, and Bcl-2 were decreased in KTH-13-AMP treated-cells. We also confirmed that the phosphorylation of STAT3, Src, and PI3K/p85, which is linked to cell survival, was diminished by treatment with KTH-13-AMP. Therefore, these results strongly suggest that this compound can be used to guide the development of an anti-cancer drug or serve as a lead compound in forming another strong anti-proliferative agent.

Diosgenin-based thio(seleno)ureas and triazolyl glycoconjugates as hybrid drugs. Antioxidant and antiproliferative profile

The stereoselective preparation of diosgenin-derived thio(seleno)ureas and glycomimetics bearing a 1,2,3-triazolyl tether on C-3 has been accomplished. The key steps in the synthetic pathway are the incorporation of an amino moiety and its further transformation into thio- and selenoureas, and also a click chemistry reaction involving a propargyl residue and an azido moiety to afford carbohydrate-derived 1,2,3-triazoles; subsequent BF3-promoted acetolysis of the spiranic moiety afforded the corresponding 22-oxocholestanic structure.The N-phenyl selenourea, an hitherto unknown steroidal derivative, turned out to be a potent ROS scavenger, in particular against free radicals (EC50 = 29.47 ± 2.33 μM, DPPH method), and as a glutathione peroxidase mimic in the elimination of H2O2 (t1/2 = 4.8 min, 1% molar ratio). 22-Oxocholestane structures bearing a C-3 azido, propargyl, thioureido, and particularly selenoureido moiety behaved as strong antiproliferative agents against HeLa cells (IC50 1.87–11.80 μM). N-phenyl selenourea also exhibited IC50 values lower than 6.50 μM for MDA-MB-231, MCF-7 and HepG2 cancer cells; apoptosis was found to be involved in its mode of action. Such compound was also capable of efficiently eliminating ROS endogenously produced by HeLa cells. Antiproliferative properties of thioxo and selenoxo derivatives were stronger than diosgenin.

Anti-Infective and Antiproliferative Potential of African Medicinal Plants

The importance of traditional medicine as a source of primary health care was first officially recognized by the World Health Organization (WHO) in the primary Health Care Declaration of Alma Ata (1978) and has been globally addressed since 1976 by the Traditional Medicine Programme of the WHO. In Africa, traditional healers and remedies made from plants play an important role in the health of millions of people. Scientific evidence of their pharmacological potential is being provided continuously. For this special issue, we have invited investigators to contribute original research articles as well as review articles that will provide evidences on the basis of traditional knowledge of the use of African medicinal plants used in the treatment of ailments. Six papers of this special issue focused on antimicrobial and two on antiproliferative properties of African medicinal plants. One paper of the issue reports the antibacterial properties of the methanol extracts of some Cameroonian medicinal plants and the effect of their associations with currently used antibiotics on multidrug-resistant (MDR) Gram-negative bacteria overexpressing active efflux pumps. Three extracts Garcinia lucida, Garcinia kola, and Picralima nitida showed significant activities against such bacteria and are suggested as possible alternative in chemotherapy involving MDR bacterial species. Another paper highlights the importance of Annona senegalensis and it active constituent, kaurenoic acid as a potential antibacterial drugs against Bacillus subtilis, Pseudomonas aeruginosa, and Staphylococcus aureus. Another paper provides evidence on the inhibitory potential of the acetone and aqueous extracts of mature stem bark of Sclerocarya birrea on a panel of bacteria and fungi such Streptococcus pyogenes, Plesiomonas shigelloides, Aeromonas hydrophila, Salmonella typhimurium, Cryptococcus neoformans, Candida glabrata, Trichosporon mucoides, and Candida krusei. There is also a paper which demonstrates that extracts from South African medicinal plants Euclea natalensis A.DC., Knowltonia vesicatoria (L.f) Sims and Pelargonium sidoides DC can successfully be combined with isoniazid (INH) to improve it antimycobacterial activity. This paper also demonstrates that stigmasta-5,23-dien-3-ol isolated from K. vesicatoria is a bioactive compound against M. tuberculosis. Another paper reports the antimicrobial activity of the ethanol extract of Artemisia afra and identified some of its components acacetin, scopoletin and betulinic acid as bioactive compounds against Gram-positive bacteria (Actinomyces naeslundii, Actinomyces israelii and Streptococcus mutans), Gram-negative bacteria (Prevotella intermedia, Porphyromonas gingivalis, and Aggregatibacter actinomycetemcomitans) and a yeast, Candida albicans. One of these six papers provides information on the possible use of Pterygota macrocarpa and Cola gigantean in the fight of microbial infections involving E. coli, P. aeruginosa,S. aureus,B. subtilis, and C. albicans. Two papers of this special issue were related to cancer. Paper one provides information on the ethanol leaf extracts of Harpephyllum caffrum as an antityrosinase agent for dermatological disorders such as age spots and melasoma. The other paper reports the anticancer activities of African spices,Origanum vulgare, Rosmarinus officinalis, Lavandula spica, Laurus nobilis, Thymus vulgaris, Lavandula-x-intermedia, Petroselinum crispum, Foeniculum vulgare, and Capsicum annuum L. (Paprika). It identifies L. nobilis and R. officinalis as strong antiproliferative agents against the human cervical cancer cell line, HeLa. Victor Kuete Namrita Lall Thomas Efferth

Guanosine supplementation reduces the antiproliferative and apoptotic effects of the IMPDH inhibitor gnidilatimonoein in K562 cells

IMPDH (inosine 5'-monophosphate dehydrogenase) is the rate-limiting enzyme in the de novo biosynthetic pathway of guanine nucleotides, which is usually up-regulated in human leukaemia cell lines. Our previous studies have classified gnidilatimonoein, isolated from Daphne mucronata, as an IMPDH inhibitor and a strong antiproliferative agent among several types of leukaemia cells. In the present study, we investigated the effects of gnidilatimonoein on intracellular GTP pool size and its link to differentiation and apoptosis of K562 cells. It was found that gnidilatimonoein inhibited cell proliferation and induced G0/G1 cell cycle arrest in K562 cells after 24 h exposure to a single dose of gnidilatimonoein (1.5 μM), while no significant effects were observed on unstimulated and phytohaemagglutinin-stimulated peripheral blood lymphocyte cells at the gnidilatimonoein dose (1.5 μM) used. Based on the morphological changes, Wright-Giemsa staining, benzidine assay and the expression of cell surface markers [GPIIb (glycoprotein IIb) and glycophorin A], as analysed by flow cytometry, we found that K562 cells had differentiated towards megakaryocytic lineage. In addition, gnidilatimonoein induced apoptosis among K562 cells based on Acridine Orange/ethidium bromide and annexin V/propidium iodide double-staining observations. These changes, which were abrogated by the addition of guanosine, became evident when the intracellular GTP level decreased to approx. 20-35% of the untreated control level. Based on these findings, it can be concluded that gnidilatimonoein induces differentiation and apoptosis in K562 cells through perturbation of GTP metabolism, as one of its routes of action.

Perlecan domain V modulates astrogliosis In vitro and after focal cerebral ischemia through multiple receptors and increased nerve growth factor release

Astrogliosis constitutes part of the central nervous system's physiological response to injury. Considered for decades to be a major challenge for brain repair, recent studies have highlighted it as a promoter of such repair mechanisms. Recently, our group demonstrated the ability of perlecan domain V (DV) to be a novel potential stroke therapy by its neuroprotective effects. However, the potential for DV to modulate astrogliosis has not been investigated. The aim of this study is to better understand the relevance of DV to astrogliosis using both in vitro and in vivo rodent models. Notably, under basal conditions, astrocytes express all three DV receptors described in the literature: integrin α2β1, α5β1, and α-dystroglycan (αDG). DV promoted astrocyte cell adhesion, cell migration as well as astrocyte stellation. Moreover, DV induced nerve growth factor (NGF) secretion through a αDG- and ERK-dependent pathway. In contrast, α2β1 or α5β1 mediated DV antiproliferative effects in astrocytes. NGF production after DV treatment acted as a strong anti-proliferative agent. Another remarkable effect of DV was that it decreased several markers of astrogliosis such as glial fibrillary acidic protein (GFAP), neurocan and phosphacan both in vitro and in vivo, suggesting the role of DV as a potential modulator of postinjury during late astrogliosis, and eventually the onset of glial scarring. Taken together, our study demonstrates the ability of DV to modulate key events of astrogliosis by promoting early astrogliosis and inhibiting glial scar formation, suggesting an additional therapeutic benefit of DV for recovery from stroke. © 2011 Wiley-Liss, Inc.

Effects of 3-Hydrogenkwadaphnin on intracellular purine nucleotide contents and their link to K562 cell death

Our previous studies have classified 3-Hydrogenkwadaphnin (3-HK), isolated from Dendrostellera lessertii (Thymelaeaceae), as a strong anti-proliferative agent that induces apoptosis among the treated leukemia cells mainly through IMP dehydrogenase inhibition. To disclose this point, we measured the intracellular ATP and GTP levels among K562 cells exposed to a single dose of 3-HK (7, 12 and 25nM). The HPLC analyses of the 3-HK-treated cell lysates indicated a dose-dependent reduction in both GTP and ATP levels. The reduction of purine nucleotide levels was also associated with decreased activity of adenylosuccinate synthetase (AdSS) and enhanced level of cell death through apoptosis. However, the inhibitory effect of 3-HK was reversed by exogenous addition of guanosine with respect to GTP and partially with respect to ATP level. These data suggest that 3-HK targets a delicate regulatory system which governs the life/death fate of the cells partially through modulation of the GTP/ATP pool sizes.

Ferrocenyl Quinone Methides as Strong Antiproliferative Agents: Formation by Metabolic and Chemical Oxidation of Ferrocenyl Phenols

Schwer verdaulich für Krebszellen: Potenziell zytotoxische Ferrocenylchinonmethide entstehen durch metabolische oder chemische Oxidation von Ferrocenylphenolen. Die Spezies wirken stark proliferationshemmend.

Ferrocenyl Quinone Methides as Strong Antiproliferative Agents: Formation by Metabolic and Chemical Oxidation of Ferrocenyl Phenols

Hard on cancer cells: Ferrocenyl quinone methides, potentially cytotoxic species, are formed by metabolic and chemical oxidation of ferrocenyl phenols (see scheme). These species display strong antiproliferative properties.

Anti-endothelial properties of 1,25-dihydroxy-3-epi-vitamin D 3, a natural metabolite of calcitriol

Background: Calcitriol [1,25-(OH) 2D 3] is a strong anti-proliferative agent both in vitro and in vivo. Earlier studies have established that calcitriol inhibits the growth factor-stimulated proliferation of endothelial cells (EC) and angiogenesis. However, the lethal calcemic side effects of calcitriol prohibit its use as a therapeutic agent. Several analogs of vitamin D have been developed to minimize these calcemic side effects. 1,25-dihydroxy–3–epi–vitamin D 3 (3-epiD 3), a naturally formed vitamin D metabolite is one such analog. Objective: To demonstrate that 3-epiD 3, a calcitriol analog, inhibits endothelial cell proliferation and induces apoptosis. Results: Treatment of EC with 3-epiD 3 showed 60% inhibition ( P<0.006) of proliferation. Cell viability assays corroborated these results. Pro-apoptotic caspase-3 activity was increased fourfold ( P<0.01) in 3-epiD 3-treated cells over controls. 3-epiD 3 induced apoptosis in EC as shown by genomic DNA fragmentation. Cell cycle analysis of 3-epiD 3-treated EC revealed a G0/G1 arrest. Conclusions: 3-epiD 3, a low-calcemic, natural analog of calcitriol, inhibits EC proliferation by causing a G0/G1 arrest and induces apoptosis more effectively than 1,25-(OH) 2D 3. These results suggest that 3-epiD 3 is a potent inhibitor of EC growth.

Anti-endothelial properties of 1,25-dihydroxy-3-epi-vitamin D3, a natural metabolite of calcitriol*1

Background: Calcitriol [1,25-(OH) 2 D 3 ] is a strong anti-proliferative agent both in vitro and in vivo. Earlier studies have established that calcitriol inhibits the growth factor-stimulated proliferation of endothelial cells (EC) and angiogenesis. However, the lethal calcemic side effects of calcitriol prohibit its use as a therapeutic agent. Several analogs of vitamin D have been developed to minimize these calcemic side effects. 1,25-dihydroxy–3–epi–vitamin D 3 (3-epiD 3 ), a naturally formed vitamin D metabolite is one such analog. Objective: To demonstrate that 3-epiD 3 , a calcitriol analog, inhibits endothelial cell proliferation and induces apoptosis. Results: Treatment of EC with 3-epiD 3 showed 60% inhibition ( P <0.006) of proliferation. Cell viability assays corroborated these results. Pro-apoptotic caspase-3 activity was increased fourfold ( P <0.01) in 3-epiD 3 -treated cells over controls. 3-epiD 3 induced apoptosis in EC as shown by genomic DNA fragmentation. Cell cycle analysis of 3-epiD 3 -treated EC revealed a G0/G1 arrest. Conclusions: 3-epiD 3 , a low-calcemic, natural analog of calcitriol, inhibits EC proliferation by causing a G0/G1 arrest and induces apoptosis more effectively than 1,25-(OH) 2 D 3 . These results suggest that 3-epiD 3 is a potent inhibitor of EC growth.

Prostaglandin D 2 strongly inhibits growth of murine mastocytoma cells

The effects of prostaglandins D 2, E 2 and F 2α on the growth of murine mastocytoma cells were investigated by adding them to cultures at concentrations of 0.1 – 50 μg/ml. At the same time, their effects on DNA synthesis were investigated. Of these prostaglandins, prostaglandin D 2 was the strongest inhibitor of mastocytoma cell growth and at 10 μg/ml of medium it also caused cell death within 24 h. Prostaglandin E 2 at this concentration only inhibited cell growth. Prostaglandin F 2α had no effect on cell growth at concentrations of. up to 50 μg/ml. These findings show that prostaglandin D 2 is a strong anti-proliferative agent.