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A series of novel selenourea derivatives and corresponding thiourea analogs were synthesized and tested against a panel of six human cancer cell lines: melanoma (1205Lu), lung carcinoma (A549), prostatic carcinoma (DU145), colorectal carcinoma (HCT116), pancreatic epithelioid carcinoma (PANC-1) and pancreatic adenocarcinoma (BxPC3). In general, we found that the selenium-containing derivatives were more potent than their isosteric sulfur analogs. Four selenourea derivatives (1e, 1f, 1g and 1i) showed IC50 values below 10 μM in all of tested cell lines at 72 h. On the basis of its potent activity, compound 1g was selected for further biological evaluation in different colon cancer cell lines. Our results indicated that compound 1g induced apoptosis by caspase activation, along with inhibition of anti-apoptotic proteins., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Patients affected by cutaneous leishmaniasis need a topical treatment which cures lesions without leaving scars. Lesions are produced not only by the parasite but also by an uncontrolled and persistent inflammatory immune response. In this study, we proposed the loading of β-lapachone (β-LP) in lecithin-chitosan nanoparticles (NP) for targeting the drug to the dermis, where infected macrophages reside, and promote wound healing. Although the loading of β-LP in NP did not influence the drug antileishmanial activity it was critical to achieve important drug accumulation in the dermis and permeation through the skin. When topically applied in Leishmania major infected BALB/c mice, β-LP NP achieved no parasite reduction but they stopped the lesion progression. Immuno-histopathological assays in CL lesions and quantitative mRNA studies in draining lymph nodes confirmed that β-LP exhibited anti-inflammatory activity leading to the down-regulation of IL-1β and COX-2 expression and a decrease of neutrophils infiltrate., From the Clinical Editor: Cutaneous leishmaniasis often leaves patients with unsightly scars due to the body's inflammatory response to the infection. The authors in this paper described topical treatment using β-lapachone (β- LP) loaded in lecithin-chitosan nanoparticles (NP) in an animal model. Results confirmed the reduction of inflammatory response without affecting the parasite killing efficacy. These findings would pave way for further clinical testing in the near future., (Copyright © 2015 Elsevier Inc. All rights reserved.)

A molecular modeling study has been carried out on two previously reported series of symmetric diselenide derivatives that show remarkable antileishmanial in vitro activity against Leishmania infantum intracellular amastigotes and in infected macrophages (THP-1 cells), in addition to showing favorable selectivity indices. Series 1 consists of compounds that can be considered as central scaffold constructed with a diaryl/dialkylaryl diselenide central nucleus, decorated with different substituents located on the aryl rings. Series 2 consists of compounds constructed over a diaryl diselenide central nucleus, decorated in 4 and 4' positions with an aryl or heteroaryl sulfonamide fragment, thus forming the diselenosulfonamide derivatives. With regard to the diselenosulfonamide derivatives (2 series), the activity can be related, as a first approximation, with (a) the ability to release bis(4-aminophenyl) diselenide, the common fragment which can be ultimately responsible for the activity of the compounds. (b) the anti-parasitic activity achieved by the sulfonamide pharmacophore present in the analyzed derivatives. The data that support this connection include the topography of the molecules, the conformational behavior of the compounds, which influences the bond order, as well as the accessibility of the hydrolysis point, and possibly the hydrophobicity and polarizability of the compounds., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Novel selenocyanate and diselenide derivatives containing a carbamate moiety were synthesised and evaluated in vitro to determine their cytotoxic and radical scavenging properties. Cytotoxic activity was tested against a panel of human cell lines including CCRF-CEM (lymphoblastic leukaemia), HT-29 (colon carcinoma), HTB-54 (lung carcinoma), PC-3 (prostate carcinoma), MCF-7 (breast adenocarcinoma), 184B5 (non-malignant, mammary gland derived) and BEAS-2B (non-malignant, derived from bronchial epithelium). Most of the compounds displayed high antiproliferative activity with GI50 values below 10μM in MCF-7, CCRF-CEM and PC-3 cells. Radical scavenging properties of the new selenocompounds were confirmed testing their ability to scavenge DPPH and ABTS radicals. Based on the activity of selenium-based glutathione peroxidases (GPxs), compounds 1a, 2e and 2h were further screened for their capacity to reduce hydrogen peroxide under thiol presence. Results suggest that compound 1a mimics GPxs activity. Cytotoxic parameters, radical scavenging activity and ADME profile point to 1a as promising drug candidate., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The PI3K/Akt/mTOR/S6 ribosomal protein signalling pathway is a key potential target in breast cancer therapy, playing a central role in proliferation and cell survival. In this study, we found that the seleno-compound 2,4-dihydroselenoquinazoline (3a) generally inhibited this signalling axis in MCF-7 breast cancer cells and caused downregulation of S6 ribosomal protein phosphorylation in a dose- and time-dependent manner. Furthermore, 3a caused a dose- and time-dependent decrease in MCF-7 cell viability as well as cell cycle arrest in G2/M. Interestingly 3a also induced apoptosis, as evidenced by cleavage of PARP and caspase-7, and inhibited autophagy, as demonstrated by accumulation of LC3-II and p62/SQSTM1. Given that induction of autophagy has been previously described as a mechanism by which some breast cancer cells counteract proapoptotic signalling and develop resistance to anti-hormone therapy, this suggests that this derivative, which both triggers apoptosis and inhibits autophagy, may be beneficial in preventing and overcoming resistance in breast cancer cells. The data also show the complexity of this signalling axis which is far from being understood., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Topical therapy is the ideal outpatient treatment of cutaneous leishmaniasis (CL) because of the ease of administration and lower cost. It could be suitable as monotherapy for localized cutaneous leishmaniasis (LCL) or in combination with systemic therapies for more severe forms of the disease. Although paromomycin (PM) ointment can be recommended for the treatment of LCL caused by Leishmaniamajor, a more effective topical treatment should be achieved regarding the physicochemical properties of this aminoglucoside and its rather poor intrinsic antileishmanial activity, that hampers the accumulation of enough amount of drug in the dermis (where the infected macrophages home) to exert its activity. In this work, we determined a 50% effective dose of 5.6 μM for a novel compound, bis-4-aminophenyldiselenide, against L. major intracellular amastigotes. This compound and PM were formulated in chitosan hydrogels and ex vivo permeation and retention studies in the different skin layers were performed with pig ear skin in Franz diffusion cells. The results showed that less than 2-4% of the diselenide drug penetrated and permeated through the skin. In contrast, the percentage of PM penetration was about 25-60% without important retention in the skin. When topically applied to lesions of L. major infected BALB/c mice, the novel diselenide chitosan formulation was unable to slow lesion progression and reduce parasite burden. Considerations during the process of novel drug development and formulation discovery algorithm for CL are discussed., (Copyright © 2014 Elsevier B.V. All rights reserved.)

A series of new aliphatic, aromatic and heteroaromatic carbamate derivatives containing a methylseleno moiety were synthesized and evaluated in vitro for their cytotoxic activity against a panel of human cell lines including CCRF-CEM (lymphoblastic leukaemia), K-562 (lymphocytic leukaemia), HT-29 (colon carcinoma), HTB-54 (lung carcinoma), PC-3 (prostate carcinoma), MCF-7 (breast adenocarcinoma), 184B5 (non-malignant, mammary gland derived) and BEAS-2B (non-malignant, derived from bronchial epithelium). Most of the compounds are highly cytotoxic with GI50 values below 10 μM in every tested tumour cell line. Based on its cytotoxic parameters, selectivity index and ADME profile, the biological activity of compound 2, the propyl derivative, was further analysed in CCRF-CEM and HTB-54 cells. Results showed that this compound is able to induce apoptosis in a time- and dose-dependent manner. Involvement of caspases in cell death induction by 2 was detected. Besides, compound 2 was also able to induce cell cycle arrest at G0/G1 in CCRF-CEM cells and at G2/M in HTB-54 cells., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Diselenide and sulfonamide derivatives have recently attracted considerable interest as leishmanicidal agents in drug discovery. In this study, a novel series of sixteen hybrid selenosulfonamides has been synthesized and screened for their in vitro activity against Leishmania infantum intracellular amastigotes and THP-1 cells. These assays revealed that most of the compounds exhibited antileishmanial activity in the low micromolar range and led us to identify three lead compounds (derivatives 2, 7 and 14) with IC50 values ranging from 0.83 to 1.47 μM and selectivity indexes (SI) over 17, much higher than those observed for the reference drugs miltefosine and edelfosine. When evaluated against intracellular amastigotes, hybrid compound 7 emerged as the most active compound (IC50 = 2.8 μM), showing higher activity and much less toxicity against THP-1 cells than edelfosine. These compounds could potentially serve as templates for future drug-optimization and drug-development efforts for their use as therapeutic agents in developing countries., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

A series of 31 new selenoesters were synthesized and their cytotoxic activity was evaluated against a prostate cancer cell line (PC-3). The most active compounds were also tested against three tumoural cell lines (MCF-7, A-549 and HT-29) and one non-tumour prostate cell line (RWPE-1). Thirteen compounds showed significant activity towards all tumour cells investigated, and some of them were even more potent than etoposide and cisplatin, which were used as reference drugs. Because of their pronounced potency and/or selectivity, four analogues (5, 21, 28 and 30), were selected in order to assess their redox properties related to a possible redox modulating activity. The glutathione peroxidase (GPx) assay showed slight activity for compound 30 and the 2,2-diphenyl-1-picrylhydrazyl-(DPPH) assay showed a weak activity for compounds 5 and 28. The present results revealed that analogues 5, 21, 28 and 30 might serve as a useful starting point for the design of improved anti-tumour agents., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Thermosensitive hydrogels are of a great interest due to their many biomedical and pharmaceutical applications. In this study, we synthesized a new series of random poly (methyl vinyl ether-co-maleic anhydride) (Gantrez(®) AN, GZ) and Pluronic(®) F127 (PF127) copolymers (GZ-PF127), that formed thermosensitive hydrogels whose gelation temperature and mechanical properties could be controlled by the molar ratio of GZ and PF127 polymers and the copolymer concentration in water. Gelation temperatures tended to decrease when the GZm/PF127 ratio increased. Thus, at a fixed GZm/PF127 value, sol-gel temperatures decreased at higher copolymer concentrations. Moreover, these hydrogels controlled the release of proteins such as bovine serum albumin (BSA) and recombinant recombinant kinetoplastid membrane protein of Leishmania (rKMP-11) more than the PF127 system. Toxicity studies carried out in J774.2 macrophages showed that cell viability was higher than 80%. Finally, histopathological analysis revealed that subcutaneous administration of low volumes of these hydrogels elicited a tolerable inflammatory response that could be useful to induce immune responses against the protein cargo in the development of vaccine adjuvants., (Copyright © 2013 Elsevier B.V. All rights reserved.)

A molecular modelling study has been carried out on a previously reported series of symmetrically substituted bisacylimidoselenocarbamate (BSeC) derivatives that show remarkable antitumour activity in vitro against a panel of human tumour cell lines. These derivatives can be considered as a central scaffold constructed around a methyl carbamimidoselenoate nucleus in which two heteroarylacyl fragments are located on the scaffold nitrogen atoms, thus forming the different BSeCs. The results reveal that the nature of the selected heteroaryl ring has a marked influence on the antiproliferative activity of the compounds and this can be related, as a first approximation, to the ability to release methylselenol (MeSeH), a compound that, according to our initial hypothesis, is ultimately responsible for the antitumour activity of the compounds under investigation. The release of MeSeH from the active BSeCs has been confirmed by means of Head Space Gas Chromatography Mass Spectrometry techniques. The data that support this connection include the topography of the molecules, the conformational behaviour of the compounds, which influences the accessibility of the hydrolysis point, the interaction map obtained for an O2H type probe, and the location and energy of the HOMO/LUMO orbitals., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Bisacylimidoselenocarbamate derivatives (BSC) are potent anticancer agents with a strong cytotoxic activity against different types of tumour cells. Based in phosphatidylserine exposure on the cell membranes we show that BSC treatment resulted in enhanced cell death in leukaemia CCRF-CEM cells. DNA fragmentation detection in breast adenocarcinoma MCF-7 cells showed that BSC triggered cell death is concentration and time dependent. We also show that two of these compounds, BSC 3g and 3n, cause cell-cycle arrest in the late G2/M in MCF-7 cells. Consistent with this, a reduction in CDK1 and CDK2 expression with no change in cyclin A an B1 was observed in this cell line. Activation of caspase-2 was also detected. However, the involvement of the caspase-dependent pathway in the process of cell death induced by either BSC 3g or 3n is discarded since cell death could not be prevented by pretreatment with the pancaspase inhibitor z-VAD-fmk. Moreover, since reduced levels of p21(CIP1) and Chk2 proteins but no change in p53 levels could be detected in MCF-7 cells after BSC 3g or 3n treatment our results suggest that BSC treated cells die from lethal mitosis.

In the search for molecules with potential antiangiogenic activity we found that several imidoselenocarbamate derivatives, which have pro-apoptotic and antiproliferative activities, under hypoxic conditions release methylselenol, a volatile and highly reactive gas that was considered to be responsible for the observed biological activity. The kinetic for the liberation of methylselenol is highly dependent on the nature of the overall structure and correlate with their proven pro-apoptotic activity in lung cancer cell line H157. The preliminary structure-activity relationships allow us to select as the basic structural element a scaffold constructed with an imidoselenocarbamate fragment decorated with a methyl residue on the Se central atom and two heteroaromatic lateral rings. These imidoselenocarbamate derivatives may be of interest both for their antitumoral activities and because they have a structure that can be considered as a template for the design of new derivatives with apoptotic activity. This activity is related to the controlled delivery of methylselenol and makes this an interesting approach to develop new antitumoral agents., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The synthesis, cytotoxic activities and selectivities of 35 derivatives related to quinazoline and pyrido[2,3-d]pyrimidine are described. The synthesized compounds were screened in vitro against four tumoral cell lines - leukemia (CCRF-CEM), colon (HT-29), lung (HTB-54) and breast (MCF-7) - and two cell lines derived from non-malignant cell lines, one mammary (184B5) and one from bronchial epithelium (BEAS-2B). MCF-7 and HTB-54 were the most sensitive cell lines with GI(50) values below 10μM for eleven and ten compounds, respectively. Two compounds (2o and 3a) were identified that evoked a marked cytotoxic effect in all cell lines tested and one compound, 7h, was potent and selective against MCF-7. A preliminary study into the mechanism of the potent derivatives 2o, 3a and 7h indicated that the cytotoxic activities of these compounds might be mediated by inducing cell death without affecting cell cycle phases., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

As a continuation of our work on new anti-tumoral derivatives with selective pro-apoptotic activity in cancer cells, we describe the synthesis and the preliminary evaluation of the cytotoxic and pro-apoptotic activities of a series of pyrimidin-2,4-diamine derivatives that are structurally related to quinazolin-2,4-diamine and pyrido[2,3-d]pyrimidin-2,4-diamine derivatives. We also describe the structure-activity relationship studies carried out on four series' of quinazolin-2,4-diamine, 2-(alkylsulfanyl)-N-alkyl- and 2-(alkylsulfanyl)-N-alkylarylpyrido[2,3-d]pyrimidine and pyrimidin-2,4-diamine derivatives. The proposed preliminary pharmacophore consists of a flat heterocyclic ring, preferably a pyrido[2,3-d]pyrimidine, with two equivalent alkylarylamine chains, preferably N-benzyl- or N-ethylphenylamine, located in positions 2 and 4 of the ring, and with a preferred ALogP in the range 4.5-5.5. The nitrogen present in the central ring can act as hydrogen bond acceptors (HBA) whereas the amino group in the 4-position can act as a donor (HBD) or an HBA and the amino group in the 2-position can act as an HBD. On the basis of the analyzed structural profiles, different mechanisms of action can be suggested for the quinazolin-2,4-diamine, the 2-(alkylsulfanyl)-N-alkylpyrido[2,3-d]pyrimidin-4-amine and the pyrido[2,3-d]pyrimidin-2,4-diamine derivatives., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

Thirty five selenocyanate and diselenide compounds were subjected to in vitro screening against Leishmania infantum promastigotes and the most active ones were also tested in an axenic amastigote model. In order to establish the selectivity indexes (SI) the cytotoxic effect of each compound was also assayed against Jurkat and THP-1 cell lines. Thirteen derivatives exhibit better IC(50) values than miltefosine and edelfosine. Bis(4-aminophenyl)diselenide exhibits the best activity when assayed in infected macrophages and one of the lowest cytotoxic activities against the human cell lines tested, with SI values of 32 and 24 against Jurkat and THP-1 cells, respectively. This compound thus represents a new lead for further studies aimed at establishing its mechanism of action., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

Kinases are enzymes that are involved in a wide-range of cellular targets such as cell proliferation, metabolism, survival and apoptosis. Aberrations in the activity of the kinases have been linked to many human diseases such as diabetes, inflammation and cancer. The discovery of more than 518 kinases encoded by the human genome has spurred the development of rapid screening techniques for potential drugs against these enzymes and these have been identified as interesting targets for medicinal chemistry programs, especially in cancer therapy. On the other hand, sulfur and selenium have been increasingly recognized as essential elements in biology and medicine. Converging data from epidemiological and clinical studies have highlighted these elements as effective chemopreventive agents, particularly against various types of cancer (prostate, lung, breast, leukemia, colon, skin, lymphome, thyroid, pancreas, liver). These elements act through a wide range of potential mechanisms where one identified signal pathway event is kinase modulation, which is common for the two elements and emerges as a valid target. The kinases modulated by sulfur and selenium derivatives include MAP, ERK, JNK, Akt, Cdc2, Cyclin B1 and Cdc25c amongst others. Although both of the elements in question are in the same group in the periodic table and have similar biochemistries, there are relevant differences related to redox potentials, stabilities, oxidation states and anticancer activity. Literature data suggest that the replacement of sulfur by selenium in established cancer chemopreventive agents results in more effective chemopreventive analogs. In view of the multi-target kinase mechanisms in preventing cellular transformation, as well as the differences and similarities between them, in this review we focus on the development of new structures that contain selenium and/or sulfur and discuss our understanding of the regulation of antitumoral effects with emphasis on kinase modulation activity and its implications in cancer.

Recent epidemiological studies have demonstrated that selenium may be an effective chemopreventive and anticancer agent with a broad spectrum against several human cancer cells (prostate, colon, bladder, lung, liver, ovarian, leukemia). A wide range of potential mechanisms have been proposed for the antitumorigenic effects of selenium and these include antiandrogen activity, growth inhibitory effects by regulation of p53 and antioxidant function, and through DNA damage. However, apoptosis is one of the most plausible mechanisms for the anticancer activity. The regulating mechanisms of apoptosis are extremely complex and for selenium compounds they mainly involve a mitochondrial pathway, protein kinases, tumor necrosis factor, activation of caspases and reactive oxygen species. The aim of this review is to summarize the current knowledge about more than twenty eight selenium-containing molecules and to discuss the implications for apoptosis and the impact in cancer therapy.

In the search for new derivatives with anticancer activity that are able to induce a selective pro-apoptotic mechanism in cancer cells, we have designed, synthesized, and evaluated a series of new 2-(alkylsulfanyl)-N-alkylpyrido[2,3-d]pyrimidine-4-amine derivatives as cytotoxic and apoptosis inducers. The potential antitumor activity of the compounds was evaluated in vitro by examining their cytotoxic effects against human breast, colon, and bladder cancer-cell lines. The IC(50)values of the compounds that showed cytotoxic activity were calculated. The cytotoxic compounds were then tested for their ability to induce caspase-3 activation and nuclear-chromatin degradation. Some compounds, such as 6c, 6d, 6e, 6j, 6o, and 6p, show significant in-vitro cytotoxicity in at least two of the three tested cell lines, induced apoptosis, and also produced a rapid dose-dependent increase in the caspase-3 level in some of the cell lines tested. In order to test the selectivity of the compounds, two non-tumoral human cell lines were used. Several compounds of the did not show cytotoxicity in these cell lines.

In recent years, a large number of new potent symmetrical cytotoxic agents that act through different mechanisms have been described. Apoptosis induction is one of the most representative of these mechanisms. Recent articles have revealed that the activation of apoptosis pathways is the key mechanism by which cytotoxic tumor cells are killed. The present review highlights the importance of the molecular symmetry of several chemical structures and their relation with cytotoxic and apoptotic activity.