Sphingosine kinase (SphK) is an oncogenic lipid kinase that regulates the sphingolipid metabolic ... more Sphingosine kinase (SphK) is an oncogenic lipid kinase that regulates the sphingolipid metabolic pathway that has been shown to play a role in numerous hyperproliferative/inflammatory diseases. The SphK isoforms (SphK1 and SphK2) catalyze the conversion of the proapoptotic substrate d-erythrosphingosine to the promitogenic/migratory product sphingosine 1-phosphate (S1P). Accumulation of S1P has been linked to the development/progression of cancer and various other diseases including, but not limited to, asthma, inflammatory bowel disease, rheumatoid arthritis, and diabetic nephropathy. SphK therefore represents a potential new target for developing novel therapeutics for cancer and other diseases. This finding has stimulated the development and evaluation of numerous SphK inhibitors over the past decade or so. In this review, we highlight the recent advancement in the field of SphK inhibitors including SphK1 and SphK2 specific inhibitors. Both sphingolipid based and nolipidic small molecule inhibitors and their importance in treatment of cancer and other diseases are discussed.
Bisacylimidoselenocarbamate derivatives (BSC) are potent anticancer agents with a strong cytotoxi... more 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.
Arkivoc Archive For Organic Chemistry, Aug 23, 2013
A series of 22 quinazolines, pyrido [2,3-d]pyrimidines and their hydroselenite salts were synthes... more A series of 22 quinazolines, pyrido [2,3-d]pyrimidines and their hydroselenite salts were synthesized with the aim of evaluating in vitro their cytotoxicity against PC-3 cell line and their antioxidant properties related to DPPH (1,1-diphenyl-2-picrylhydrazylradical) activity, showing some of them better profile than the respective controls. Three of these derivatives (5d, 6d and 7f) were selected in order to gain preliminary insights to establish the mechanism of action. Caspase-3 activity and cell cycle regulation studies revealed that compound 6d provoked an increase in caspase-3 level accompanied by cell cycle perturbation in a time-dependent manner. a: POCl 3 /DMF; b: The corresponding amine, TEA, EtOH; c: SeO 2 , EtOH:H 2 O (1:1).
In the search for new molecules with potential antiangiogenic activity, we found that several imi... more In the search for new molecules with potential antiangiogenic activity, we found that several imidoselenocarbamate derivatives effectively suppressed the expression of vascular endothelial growth factor (VEGF) induced by hypoxia in NCI-H157 tumor cells. Mechanistic studies indicated that these compounds inhibited STAT3 phosphorylation triggered by hypoxia, suggesting that inhibition of STAT3 function may play a role in VEGF inhibition. Moreover, these molecules showed interesting proapoptotic and antiproliferative effects. Both the presence of selenium, but not sulfur, and the nature of the radical substituents were important for activity. Interestingly, under hypoxic conditions, several methyl imidoselenocarbamate derivatives released methylselenol, a highly reactive and cytotoxic gas, which was responsible for their biological activities. The kinetics of the release of methylselenol by these molecules was highly dependent on the nature of the substituent radicals and correlated with their early proapoptotic activity. Our results support the notion that pharmacological activities reported for methyl imidoselenocarbamate derivatives are dependent on the release of methylselenol. Given the wellknown antitumor activities of this compound, imidoselenocarbamate derivatives represent a promising approach to develop new drugs that release methylselenol in a controlled way.
Selenium is a trace element whose derivatives fulfil important biological functions and have bein... more Selenium is a trace element whose derivatives fulfil important biological functions and have being widely studied in cancer prevention and chemotherapy due to their roles as antioxidant and antiproliferative agents(1). Hence, our group has explored recently the anticancer properties of different selenoderivatives. In this research, twenty-six carboxymethylselenoesters were synthesized and biologically evaluated(2), and, although most active ones had noteworthy antiproliferative values in the cancer cell line (PC-3), overall activity was below the expectatives. In order to improve the biological activity fifteen methyl, tert-butyl and phenyl carboxylic esters of the most active carboxymethylselenoesters were synthesized. As preliminary results in prostate cancer cells (PC-3) showed that methyl esterification enhances the biological effect(3), nine selected derivatives were more-in-depth studied in the Université Paris Descartes against a panel of eight cell lines using the Crystal Vi...
Selenium is a trace element with several biological functions. It has been reported to be an anti... more Selenium is a trace element with several biological functions. It has been reported to be an antioxidant and low serum levels of selenium raise the risk of suffer common diseases such as viral infections, cardiovascular diseases or cancer. Some compounds with selenium, like methylseleninic acid and diphenyldiselenide, are being investigated due to their antiproliferative, chemopreventive and anticarcinogenic properties. In order to broaden the knowledge about the relationship between organoselenium compounds and cancer we planned the synthesis and biological evaluation of twenty-six novel selenylacetic acids derivatives according to the general structure shown below. Novel selenocompounds were tested against a prostate cell line (PC-3), and five of them resulted to be more cytotoxic than etoposide, a drug commonly employed in cancer theraphy. These more active compounds were tested against and one mammary gland-derived non-malignant cell line 184B5 and four tumoral cell lines: CCRF-...
Selenium and its organic and inorganic derivatives fullfil a lot of biological functions and have... more Selenium and its organic and inorganic derivatives fullfil a lot of biological functions and have been used in cancer prevention and chemotherapy(1). Several selenocompounds, like diphenyldiselenide(2) and Se-methylselenocysteine(3), are under investigation because of their cytotoxic and anticarcinogenic properties. Due to these antecedents, our research group designed, synthesized and determined biological activity parameters of twenty-six novel selenocompounds with the general formula Ar/Het-CO-Se-CH2-COOH(4). The five most active selenylacetic acids obtained had a good cytotoxicity activity in prostate cancer cell line (PC-3), but activity of the remaining ones was below our expectatives. Consequently, we decided to study esterification, a logical structural modification of the previous compounds, and planned the chemical synthesis of carboxylic esters of selected selenylacetic acids. Methyl, tert-butyl and phenyl esters had been isolated and the compounds evaluated in PC-3 cance...
The understanding of the essential role of selenium (Se) in human health has increased substantia... more The understanding of the essential role of selenium (Se) in human health has increased substantially in recent decades. Micronutrient deficiencies are very common in the general population and may be even more common in patients with different pathologies due to genetic or environmental causes and prescription drug use.
Several selenoxo (C=Se) derivatives, including selenoureas, have shown potent cytotoxic activitie... more Several selenoxo (C=Se) derivatives, including selenoureas, have shown potent cytotoxic activities in various cancer models acting through different mechanisms of action, such as superoxide anion scavenging and iNOS inhibition. We have now designed a series of seleno- and corresponding thio-urea derivatives of several biologically active heterocyclic scaffolds such as acridine, anthracene-9,10- dione, benzo[d][1,3]dioxole, 5-nitrofuran, 2H-chromen-2-one, quinaxoline, pyrrole benzyl, isoxazol and 1,3-dioxoindoline. The in vitro effects on cell viability was assessed using a colorimetric MTT assay at 24, 48 and 72 h in several cancer cell lines, including pancreatic (Panc-1 and BxPC-3), melanoma (1205Lu) and colon (HCT116) cancer cell lines. Most of these derivatives reduced cell viability in a dose dependent manner; derivatives of 2H-chromen-2-one and anthracene-9,10-dione moieties were more effective, with EC50 values ranging from 5 to 25 μM in all of the cell lines tested at 72 h. ...
The generation of new antileishmanial drugs has become a priority. Selenium and its derivatives a... more The generation of new antileishmanial drugs has become a priority. Selenium and its derivatives are standing out as having promising leishmanicidal activity. In fact, some parasites express selenoproteins, and metabolize selenium. Recently, selenium derivatives have shown the potential to reduce parasitemia, clinical manifestations and mortality in parasite-infected mice. In this paper, after selecting four candidates according to drug-likeness parameters, we observed that two of them, called 2B: (Methyl N,N' -di(thien-2-ylcarbonyl)-imidoselenocarbamate) and 4B: (Methyl N,N' -di(5-nitrothien-3-ylcarbonyl)-imidoselenocarbamate), exhibit in Leishmania major promastigotes low IC50s (<3μM), good selectivity index (SI>5) and lack toxicity on macrophages. In addition, analyzing their therapeutic potential against L. major in vitro infection, both compounds display a dramatic reduction of amastigote burden (∼ 80%) with sub-lethal concentrations. Furthermore, in macrophages, these selenocompounds induce nitric oxide production, which has been described to be critical for the defence against intracellular pathogens. 2B: and 4B: demonstrated to cause cell cycle arrest in G1. Interestingly, evaluation of gene expression related to proliferation (PCNA), treatment resistance (ABC-transporter and α-tubulin) and virulence (QDPR) showed several alterations in gene expression profiling. All these aforementioned results prompt us to propose both compounds as candidates to treat leishmanial infections.
A molecular modeling study has been carried out on two previously reported series of symmetric di... more 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.
Dietary intake of selenium was suggested to reduce methylmercury (MeHg) toxicity in the 1970s. He... more Dietary intake of selenium was suggested to reduce methylmercury (MeHg) toxicity in the 1970s. Here, we report the molecular mechanisms of MeHg detoxification by the novel selenium-containing imidazole compound, 2-selenyl-trimethyl-histidine, selenoneine. (Yamashita and Yamashita, JBC, 285, 18134-18138, 2010). This compound has a strong radical scavenging activity, and is incorporated by a specific transporter, organic cations/carnitine transporter-1 (OCTN1). We characterized that both selenoneine and OCTN1 mediated MeHg detoxification by the exosomal secretory pathway in zebrafish embryos. The embryos at 8 h post fertilization were microinjected with MeHg-Cys (0.2 ng Hg/embryo) into yolk sac, and cultured in embryonic water for 24 h. The secreted exosomes released into rearing water from the embryos were collected by ultracentrifugation at 100,000 x g for 3 h, and their mercury and selenium contents and protein components were examined. The exosomes released in rearing water contained exosomal marker CD63, endosome marker rab5, lysosomal and autophagic proteins (MAP1-LC3B, cathepsin L, exosomal serine protease), molecular chaperones (HSC70, CDC48), OCTN1 transporter, and ceramide, and the exosomal formation was enhanced by MeHg exposure, and such cellular function was accelerated in the presence of selenoneine. In addition, the treatment of embryos with H + -ATPase inhibitor, bafilomycin A1, and the knockdown of ATG7, CDC48 or OCTN1 genes enhanced MeHg toxicity and caused severe apoptosis in central nervous system in the MeHg-injected embryos. Therefore, the exosomal secretory pathway triggered by endosomal sorting complexes required for transport (ESCRT) might involve in MeHg detoxification.
Our recent reports have demonstrated potent antitumor activity for several classes of organo-Se c... more Our recent reports have demonstrated potent antitumor activity for several classes of organo-Se compounds, particularly where Se atom is present in functional groups such as selenomethyl, selenocyanate, isoselenocyanate, diselenide, selenol or selenourea. We have now designed a series of seleno-and corresponding thio-urea derivatives of several biologically active heterocyclic scaffolds such as acridine, anthracene-9,10-dione, benzo[d][1,3]dioxole, 5-nitrofuran, 2H-chromen-2-one and quinaxoline. The in vitro effects on cell viability was assessed using a colorimetric MTT assay at 24, 48 and 72 h in several cancer cell lines, including pancreatic (Panc-1 and BxPC-3), melanoma (1205Lu) and colon (HCT116) cancer cell lines. Most of these derivatives reduced cell viability in a dose dependent manner; derivatives of 2H-chromen-2-one and anthracene-9,10-dione moieties were more effective, with EC 50 values ranging from 5 to 25 µM in all of the cell lines tested at 72 h. Interestingly, while in most cases Se compounds were more effective than the corresponding sulfur analogs, in the case of anthracene-9,10-dione scaffold, thiourea analog (VA8G) was more cytotoxic, particularly in pancreatic cancer cell lines tested (EC 50 values of 6.6 and 7.6 µM versus 43.3 and 14.2 µM for the sulfur and Se analogs in BxPC3 and Panc-1 cell lines, respectively, at 72 h treatment). Notably, this analog was very effective in BxPC-3 cells, which are resistant to current chemotherapy compounds and to other derivatives prepared here. Based on these studies we identified two selenourea derivatives (VA7G and VA7I) and a thiourea derivative (VA8G) as the most potent compounds. These agents effectively induced PARP cleavage. Detailed results of these investigations will be presented.
Metallomics : integrated biometal science, Jan 11, 2015
The biological activity of thyroid hormones (TH) is regulated by selenoenzymes of the iodothyroni... more The biological activity of thyroid hormones (TH) is regulated by selenoenzymes of the iodothyronine deiodinase (DIO) family catalysing TH activating and inactivating reactions. Besides TH metabolism, several studies indicate an important role of DIO isoenzymes in tumorigenesis and cancer growth. It is therefore of therapeutic importance to identify modulators of DIO expression. We have synthesized and studied a series of selenocompounds containing a methyl- or benzyl-imidoselenocarbamate backbone. One of these novel compounds had chemotherapeutic activities in a murine xenograft tumour model by an unknown mechanism. Therefore, we tested their effects on DIO expression in vitro. In HepG2 hepatocarcinoma cells, DIO1 activity was strongly (up to 10-fold) increased by the methyl- but not by the corresponding benzyl-imidoselenocarbamates. Steady-state mRNA levels remained unaltered under these conditions indicating a post-transcriptional mode of action. The effects were further character...
Sphingosine kinase (SphK) is an oncogenic lipid kinase that regulates the sphingolipid metabolic ... more Sphingosine kinase (SphK) is an oncogenic lipid kinase that regulates the sphingolipid metabolic pathway that has been shown to play a role in numerous hyperproliferative/inflammatory diseases. The SphK isoforms (SphK1 and SphK2) catalyze the conversion of the proapoptotic substrate d-erythrosphingosine to the promitogenic/migratory product sphingosine 1-phosphate (S1P). Accumulation of S1P has been linked to the development/progression of cancer and various other diseases including, but not limited to, asthma, inflammatory bowel disease, rheumatoid arthritis, and diabetic nephropathy. SphK therefore represents a potential new target for developing novel therapeutics for cancer and other diseases. This finding has stimulated the development and evaluation of numerous SphK inhibitors over the past decade or so. In this review, we highlight the recent advancement in the field of SphK inhibitors including SphK1 and SphK2 specific inhibitors. Both sphingolipid based and nolipidic small molecule inhibitors and their importance in treatment of cancer and other diseases are discussed.
Bisacylimidoselenocarbamate derivatives (BSC) are potent anticancer agents with a strong cytotoxi... more 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.
Arkivoc Archive For Organic Chemistry, Aug 23, 2013
A series of 22 quinazolines, pyrido [2,3-d]pyrimidines and their hydroselenite salts were synthes... more A series of 22 quinazolines, pyrido [2,3-d]pyrimidines and their hydroselenite salts were synthesized with the aim of evaluating in vitro their cytotoxicity against PC-3 cell line and their antioxidant properties related to DPPH (1,1-diphenyl-2-picrylhydrazylradical) activity, showing some of them better profile than the respective controls. Three of these derivatives (5d, 6d and 7f) were selected in order to gain preliminary insights to establish the mechanism of action. Caspase-3 activity and cell cycle regulation studies revealed that compound 6d provoked an increase in caspase-3 level accompanied by cell cycle perturbation in a time-dependent manner. a: POCl 3 /DMF; b: The corresponding amine, TEA, EtOH; c: SeO 2 , EtOH:H 2 O (1:1).
In the search for new molecules with potential antiangiogenic activity, we found that several imi... more In the search for new molecules with potential antiangiogenic activity, we found that several imidoselenocarbamate derivatives effectively suppressed the expression of vascular endothelial growth factor (VEGF) induced by hypoxia in NCI-H157 tumor cells. Mechanistic studies indicated that these compounds inhibited STAT3 phosphorylation triggered by hypoxia, suggesting that inhibition of STAT3 function may play a role in VEGF inhibition. Moreover, these molecules showed interesting proapoptotic and antiproliferative effects. Both the presence of selenium, but not sulfur, and the nature of the radical substituents were important for activity. Interestingly, under hypoxic conditions, several methyl imidoselenocarbamate derivatives released methylselenol, a highly reactive and cytotoxic gas, which was responsible for their biological activities. The kinetics of the release of methylselenol by these molecules was highly dependent on the nature of the substituent radicals and correlated with their early proapoptotic activity. Our results support the notion that pharmacological activities reported for methyl imidoselenocarbamate derivatives are dependent on the release of methylselenol. Given the wellknown antitumor activities of this compound, imidoselenocarbamate derivatives represent a promising approach to develop new drugs that release methylselenol in a controlled way.
Selenium is a trace element whose derivatives fulfil important biological functions and have bein... more Selenium is a trace element whose derivatives fulfil important biological functions and have being widely studied in cancer prevention and chemotherapy due to their roles as antioxidant and antiproliferative agents(1). Hence, our group has explored recently the anticancer properties of different selenoderivatives. In this research, twenty-six carboxymethylselenoesters were synthesized and biologically evaluated(2), and, although most active ones had noteworthy antiproliferative values in the cancer cell line (PC-3), overall activity was below the expectatives. In order to improve the biological activity fifteen methyl, tert-butyl and phenyl carboxylic esters of the most active carboxymethylselenoesters were synthesized. As preliminary results in prostate cancer cells (PC-3) showed that methyl esterification enhances the biological effect(3), nine selected derivatives were more-in-depth studied in the Université Paris Descartes against a panel of eight cell lines using the Crystal Vi...
Selenium is a trace element with several biological functions. It has been reported to be an anti... more Selenium is a trace element with several biological functions. It has been reported to be an antioxidant and low serum levels of selenium raise the risk of suffer common diseases such as viral infections, cardiovascular diseases or cancer. Some compounds with selenium, like methylseleninic acid and diphenyldiselenide, are being investigated due to their antiproliferative, chemopreventive and anticarcinogenic properties. In order to broaden the knowledge about the relationship between organoselenium compounds and cancer we planned the synthesis and biological evaluation of twenty-six novel selenylacetic acids derivatives according to the general structure shown below. Novel selenocompounds were tested against a prostate cell line (PC-3), and five of them resulted to be more cytotoxic than etoposide, a drug commonly employed in cancer theraphy. These more active compounds were tested against and one mammary gland-derived non-malignant cell line 184B5 and four tumoral cell lines: CCRF-...
Selenium and its organic and inorganic derivatives fullfil a lot of biological functions and have... more Selenium and its organic and inorganic derivatives fullfil a lot of biological functions and have been used in cancer prevention and chemotherapy(1). Several selenocompounds, like diphenyldiselenide(2) and Se-methylselenocysteine(3), are under investigation because of their cytotoxic and anticarcinogenic properties. Due to these antecedents, our research group designed, synthesized and determined biological activity parameters of twenty-six novel selenocompounds with the general formula Ar/Het-CO-Se-CH2-COOH(4). The five most active selenylacetic acids obtained had a good cytotoxicity activity in prostate cancer cell line (PC-3), but activity of the remaining ones was below our expectatives. Consequently, we decided to study esterification, a logical structural modification of the previous compounds, and planned the chemical synthesis of carboxylic esters of selected selenylacetic acids. Methyl, tert-butyl and phenyl esters had been isolated and the compounds evaluated in PC-3 cance...
The understanding of the essential role of selenium (Se) in human health has increased substantia... more The understanding of the essential role of selenium (Se) in human health has increased substantially in recent decades. Micronutrient deficiencies are very common in the general population and may be even more common in patients with different pathologies due to genetic or environmental causes and prescription drug use.
Several selenoxo (C=Se) derivatives, including selenoureas, have shown potent cytotoxic activitie... more Several selenoxo (C=Se) derivatives, including selenoureas, have shown potent cytotoxic activities in various cancer models acting through different mechanisms of action, such as superoxide anion scavenging and iNOS inhibition. We have now designed a series of seleno- and corresponding thio-urea derivatives of several biologically active heterocyclic scaffolds such as acridine, anthracene-9,10- dione, benzo[d][1,3]dioxole, 5-nitrofuran, 2H-chromen-2-one, quinaxoline, pyrrole benzyl, isoxazol and 1,3-dioxoindoline. The in vitro effects on cell viability was assessed using a colorimetric MTT assay at 24, 48 and 72 h in several cancer cell lines, including pancreatic (Panc-1 and BxPC-3), melanoma (1205Lu) and colon (HCT116) cancer cell lines. Most of these derivatives reduced cell viability in a dose dependent manner; derivatives of 2H-chromen-2-one and anthracene-9,10-dione moieties were more effective, with EC50 values ranging from 5 to 25 μM in all of the cell lines tested at 72 h. ...
The generation of new antileishmanial drugs has become a priority. Selenium and its derivatives a... more The generation of new antileishmanial drugs has become a priority. Selenium and its derivatives are standing out as having promising leishmanicidal activity. In fact, some parasites express selenoproteins, and metabolize selenium. Recently, selenium derivatives have shown the potential to reduce parasitemia, clinical manifestations and mortality in parasite-infected mice. In this paper, after selecting four candidates according to drug-likeness parameters, we observed that two of them, called 2B: (Methyl N,N' -di(thien-2-ylcarbonyl)-imidoselenocarbamate) and 4B: (Methyl N,N' -di(5-nitrothien-3-ylcarbonyl)-imidoselenocarbamate), exhibit in Leishmania major promastigotes low IC50s (<3μM), good selectivity index (SI>5) and lack toxicity on macrophages. In addition, analyzing their therapeutic potential against L. major in vitro infection, both compounds display a dramatic reduction of amastigote burden (∼ 80%) with sub-lethal concentrations. Furthermore, in macrophages, these selenocompounds induce nitric oxide production, which has been described to be critical for the defence against intracellular pathogens. 2B: and 4B: demonstrated to cause cell cycle arrest in G1. Interestingly, evaluation of gene expression related to proliferation (PCNA), treatment resistance (ABC-transporter and α-tubulin) and virulence (QDPR) showed several alterations in gene expression profiling. All these aforementioned results prompt us to propose both compounds as candidates to treat leishmanial infections.
A molecular modeling study has been carried out on two previously reported series of symmetric di... more 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.
Dietary intake of selenium was suggested to reduce methylmercury (MeHg) toxicity in the 1970s. He... more Dietary intake of selenium was suggested to reduce methylmercury (MeHg) toxicity in the 1970s. Here, we report the molecular mechanisms of MeHg detoxification by the novel selenium-containing imidazole compound, 2-selenyl-trimethyl-histidine, selenoneine. (Yamashita and Yamashita, JBC, 285, 18134-18138, 2010). This compound has a strong radical scavenging activity, and is incorporated by a specific transporter, organic cations/carnitine transporter-1 (OCTN1). We characterized that both selenoneine and OCTN1 mediated MeHg detoxification by the exosomal secretory pathway in zebrafish embryos. The embryos at 8 h post fertilization were microinjected with MeHg-Cys (0.2 ng Hg/embryo) into yolk sac, and cultured in embryonic water for 24 h. The secreted exosomes released into rearing water from the embryos were collected by ultracentrifugation at 100,000 x g for 3 h, and their mercury and selenium contents and protein components were examined. The exosomes released in rearing water contained exosomal marker CD63, endosome marker rab5, lysosomal and autophagic proteins (MAP1-LC3B, cathepsin L, exosomal serine protease), molecular chaperones (HSC70, CDC48), OCTN1 transporter, and ceramide, and the exosomal formation was enhanced by MeHg exposure, and such cellular function was accelerated in the presence of selenoneine. In addition, the treatment of embryos with H + -ATPase inhibitor, bafilomycin A1, and the knockdown of ATG7, CDC48 or OCTN1 genes enhanced MeHg toxicity and caused severe apoptosis in central nervous system in the MeHg-injected embryos. Therefore, the exosomal secretory pathway triggered by endosomal sorting complexes required for transport (ESCRT) might involve in MeHg detoxification.
Our recent reports have demonstrated potent antitumor activity for several classes of organo-Se c... more Our recent reports have demonstrated potent antitumor activity for several classes of organo-Se compounds, particularly where Se atom is present in functional groups such as selenomethyl, selenocyanate, isoselenocyanate, diselenide, selenol or selenourea. We have now designed a series of seleno-and corresponding thio-urea derivatives of several biologically active heterocyclic scaffolds such as acridine, anthracene-9,10-dione, benzo[d][1,3]dioxole, 5-nitrofuran, 2H-chromen-2-one and quinaxoline. The in vitro effects on cell viability was assessed using a colorimetric MTT assay at 24, 48 and 72 h in several cancer cell lines, including pancreatic (Panc-1 and BxPC-3), melanoma (1205Lu) and colon (HCT116) cancer cell lines. Most of these derivatives reduced cell viability in a dose dependent manner; derivatives of 2H-chromen-2-one and anthracene-9,10-dione moieties were more effective, with EC 50 values ranging from 5 to 25 µM in all of the cell lines tested at 72 h. Interestingly, while in most cases Se compounds were more effective than the corresponding sulfur analogs, in the case of anthracene-9,10-dione scaffold, thiourea analog (VA8G) was more cytotoxic, particularly in pancreatic cancer cell lines tested (EC 50 values of 6.6 and 7.6 µM versus 43.3 and 14.2 µM for the sulfur and Se analogs in BxPC3 and Panc-1 cell lines, respectively, at 72 h treatment). Notably, this analog was very effective in BxPC-3 cells, which are resistant to current chemotherapy compounds and to other derivatives prepared here. Based on these studies we identified two selenourea derivatives (VA7G and VA7I) and a thiourea derivative (VA8G) as the most potent compounds. These agents effectively induced PARP cleavage. Detailed results of these investigations will be presented.
Metallomics : integrated biometal science, Jan 11, 2015
The biological activity of thyroid hormones (TH) is regulated by selenoenzymes of the iodothyroni... more The biological activity of thyroid hormones (TH) is regulated by selenoenzymes of the iodothyronine deiodinase (DIO) family catalysing TH activating and inactivating reactions. Besides TH metabolism, several studies indicate an important role of DIO isoenzymes in tumorigenesis and cancer growth. It is therefore of therapeutic importance to identify modulators of DIO expression. We have synthesized and studied a series of selenocompounds containing a methyl- or benzyl-imidoselenocarbamate backbone. One of these novel compounds had chemotherapeutic activities in a murine xenograft tumour model by an unknown mechanism. Therefore, we tested their effects on DIO expression in vitro. In HepG2 hepatocarcinoma cells, DIO1 activity was strongly (up to 10-fold) increased by the methyl- but not by the corresponding benzyl-imidoselenocarbamates. Steady-state mRNA levels remained unaltered under these conditions indicating a post-transcriptional mode of action. The effects were further character...
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