33 research outputs found
Metal-based compounds containing selenium: An appealing approach towards novel therapeutic drugs with anticancer and antimicrobial effects
In recent years, both metal-based complexes and selenium-containing compounds have been widely explored for
their therapeutic properties due to their roles in biological processes and modulation of diverse molecular tar-
gets. However, despite their growing interest, there is no review to date that covers the potential use of the
combination of these entities to design new therapeutic derivatives. This review highlights the latest achieve-
ments in this particular field, with a focus on compounds with anticancer and/or antimicrobial properties. With
this aim, the formation of coordination compounds including several metals bearing selenium either with direct
interaction with the metal center or as part of the organic ligand elsewhere is covered. Besides, coordination
compounds with a Se(IV) center have been assessed. The biological properties of several selenium-containing
organometallic complexes have also been discussed, including metallocenes, half-sandwich complexes, and
compounds with N-heterocyclic carbenes, CO, and π-ligands, and other σ-bonded entities. The information
compiled in this review may be helpful to design and develop novel, more potent, and safer metal-based com-
pounds for the treatment of several pathologies
Small molecules containing chalcogen elements (S, Se, Te) as new warhead to fight neglected tropical diseases
Neglected tropical diseases (NTDs) encompass a group of infectious diseases with a protozoan etiology, high
incidence, and prevalence in developing countries. As a result, economic factors constitute one of the main
obstacles to their management. Endemic countries have high levels of poverty, deprivation and marginalization
which affect patients and limit their access to proper medical care. As a matter of fact, statistics remain un-
collected in some affected areas due to non-reporting cases. World Health Organization and other organizations
proposed a plan for the eradication and control of the vector, although many of these plans were halted by the
COVID-19 pandemic. Despite of the available drugs to treat these pathologies, it exists a lack of effectiveness
against several parasite strains. Treatment protocols for diseases such as American trypanosomiasis (Chagas
disease), leishmaniasis, and human African trypanosomiasis (HAT) have not achieved the desired results. Un-
fortunately, these drugs present limitations such as side effects, toxicity, teratogenicity, renal, and hepatic
impairment, as well as high costs that have hindered the control and eradication of these diseases. This review
focuses on the analysis of a collection of scientific shreds of evidence with the aim of identifying novel chalcogen-
derived molecules with biological activity against Chagas disease, leishmaniasis and HAT. Compounds illustrated
in each figure share the distinction of containing at least one chalcogen element. Sulfur (S), selenium (Se), and
tellurium (Te) have been grouped and analyzed in accordance with their design strategy, chemical synthesis
process and biological activity. After an exhaustive revision of the related literature on S, Se, and Te compounds,
183 compounds presenting excellent biological performance were gathered against the different causative agents
of CD, leishmaniasis and HAT
Novel N,N'-disubstituted selenoureas as potential antioxidant and cytotoxic agents
A series of 30 novel N,N disubstituted selenoureas were synthesized, characterized, and
their antioxidant ability was tested using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,20-azinobis(
3-ethylbenzthiazoline-6-sulfonic acid (ABTS) assays. Additionally, their cytotoxic activity was
tested in vitro in a panel of three different cancer (breast, lung and colon) and two normal cell lines.
Each selenourea entity contains a para-substituted phenyl ring with different electron-withdrawing
and electron-donating groups, and different aliphatic and aromatic nuclei. All of the synthesized
selenoureas present antioxidant capacity at high concentrations in the DPPH assay, and three of them
(2b, 2c and 2d) showed greater radical scavenging capacity than ascorbic acid at lower concentrations.
These results were confirmed by the ABTS assay, where these novel selenoureas present even higher
antioxidant capacity than the reference compound Trolox. On the other hand, 10 selenoureas present
IC50 values below 10 M in at least one cancer cell line, resulting in the adamantyl nucleus (6a¿
6e), the most interesting in terms of activity and selectivity. Outstanding results were found for
selenourea 6c, tested in the NCI60 cell line panel and showing an average GI50 of 1.49 M for the
60 cell lines, and LC50 values ranging from 9.33 M to 4.27 M against 10 of these cancer cell lines.
To gain insight into its anticancer activity mechanism, we investigated the cell cycle progression
of the promising
Design, synthesis and anticancer evaluation of novel Se-NSAID hybrid molecules: Identification of a Se-indomethacin analog as a potential therapeutic for breast cancer
A total of twenty-five novel carboxylic acid, methylester, methylamide or cyano nonsteroidal anti-inflammatory
drug (NSAID) derivatives incorporating Se in the chemical form of selenoester were reported. Twenty Se-NSAID
analogs exhibited an increase in cytotoxic potency compared with parent NSAID scaffolds (aspirin, salicylic acid,
naproxen, indomethacin and ketoprofen). Top five analogs were selected to further study their cytotoxicity in a
larger panel of cancer cells and were also submitted to the DTP program of the NCI’s panel of 60 cancer cell lines.
Compounds 4a and 4d stood out with IC50 values below 10 μM in several cancer cells along with a selectivity
index higher than 5 in breast cancer cells. Remarkably, analog 4d was found to inhibit cell growth notably in two
breast cancer cell lines by inducing apoptosis, and to be metabolized to release the parent NSAID along with the
Se fragment. Taken together, our results show that Se-NSAID analog 4d could be a potential chemotherapeutic
drug for breast cancer
A diphenyldiselenide derivative induces autophagy via JNK in HTB-54 lung cancer cells
Symmetric aromatic diselenides are potential anticancer agents with strong cytotoxic activity. In this study, the in vitro anticancer activities of a novel series of diarylseleno derivatives from the diphenyldiselenide (DPDS) scaffold were evaluated. Most of the compounds exhibited high efficacy for inducing cytotoxicity against different human cancer cell lines. DPDS 2, the compound with the lowest mean GI50 value, induced both caspase-dependent apoptosis and arrest at the G0/G1 phase in acute lymphoblastic leucemia CCRF-CEM cells. Consistent with this, PARP cleavage; enhanced caspase-2, -3, -8 and -9 activity; reduced CDK4 expression and increased levels of p53 were detected in these cells upon DPDS 2 treatment. Mutated p53 expressed in CCRF-CEM cells retains its transactivating activity. Therefore, increased levels of p21CIP1 and BAX proteins were also detected. On the other hand, DPDS 6, the compound with the highest selectivity index for cancer cells, resulted in G2/M cell cycle arrest and caspase-independent cell death in p53 deficient HTB-54 lung cancer cells. Autophagy inhibitors 3-methyladenine, wortmannin and chloroquine inhibited DPDS 6-induced cell death. Consistent with autophagy, increased LC3-II and decreased SQSTM1/p62 levels were detected in HTB-54 cells in response to DPDS 6. Induction of JNK phosphorylation and a reduction in phospho-p38 MAPK were also detected. Moreover, the JNK inhibitor SP600125-protected HTB-54 cells from DPDS 6-induced cell death indicating that JNK activation is involved in DPDS 6-induced autophagy. These results highlight the anticancer effects of these derivatives and warrant future studies examining their clinical potential
Novel N,N' -Disubstituted Acylselenoureas as Potential Antioxidant and Cytotoxic Agents
Selenium compounds are pivotal in medicinal chemistry for their antitumoral and
antioxidant properties. Forty seven acylselenoureas have been designed and synthesized following
a fragment-based approach. Different scaffolds, including carbo- and hetero-cycles, along with
mono- and bi-cyclic moieties, have been linked to the selenium containing skeleton. The doseand time-dependent radical scavenging activity for all of the compounds were assessed using the
in vitro 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,20
-azino-bis(3-ethylbenzthiazoline-6-sulfonic
acid) (ABTS) assays. Some of them showed a greater radical scavenging capacity at low doses and
shorter times than ascorbic acid. Therefore, four compounds were evaluated to test their protective
effects against H2O2-induced oxidative stress. One derivative protected cells against H2O2-induced
damage, increasing cell survival by up to 3.6-fold. Additionally, in vitro cytotoxic activity of all
compounds was screened against several cancer cells. Eight compounds were selected to determine
their half maximal inhibitory concentration (IC50) values towards breast and lung cancer cells, along
with their selectivity indexes. The breast cancer cells turned out to be much more sensitive than the
lung. Two compounds (5d and 10a) stood out with IC50 values between 4.2 µM and 8.0 µM towards
MCF-7 and T47D cells, with selectivity indexes greater than 22.9. In addition, compound 10b exhibited
dual antioxidant and cytotoxic activities. Although further evidence is needed, the acylselenourea
scaffold could be a feasible frame to develop new dual agents
Next generation of selenocyanate and diselenides with upgraded leishmanicidal activity
Nowadays, leishmaniasis is still treated with outdated drugs that present several obstacles related to their high toxicity, long duration, parenteral administration, high costs and drug resistance. Therefore, there is an urgent demand for safer and more effective novel drugs. Previous studies indicated that selenium compounds are promising derivatives for innovative therapy in leishmaniasis treatment. With this background, a new library of 20 selenocyanate and diselenide derivatives were designed based on structural features present in the leishmanicidal drug miltefosine. Compounds were initially screened against promastigotes of L. major and L. infantum and their cytotoxicity was evaluated in THP-1 cells. Compounds B8 and B9 were the most potent and less cytotoxic and were further screened for the intracellular back transformation assay. The results obtained revealed that B8 and B9 showed EC50 values of 7.7 µM and 5.7 µM, respectively, in L. major amastigotes, while they presented values of 6.0 µM and 7.4 µM, respectively, against L. infantum amastigotes. Furthermore, they exerted high selectivity (60 70) towards bone marrow-derived macrophages. Finally, these compounds exhibited higher TryR inhibitory activity than mepacrine (IC50 7.6 and 9.2 µM, respectively), and induced nitric oxide (NO) and reactive oxygen species (ROS) production in macrophages. These results suggest that the compounds B8 and B9 could not only exert a direct leishmanicidal activity against the parasite but also present an indirect action by activating the microbicidal arsenal of the macrophage. Overall, these new generation of diselenides could constitute promising leishmanicidal drug candidates for further studies
Novel seleno-aspirinyl compound AS-10 induces apoptosis, G1 arrest of pancreatic ductal adenocarcinoma cells, inhibits their NF-kappa B signaling and synergizes with gemcitabine cytotoxicity
Current available therapies for pancreatic ductal adenocarcinoma (PDAC) provide minimal
overall survival benefits and cause severe adverse effects. We have identified a novel molecule
AS-10, a selenazolidine-bis-aspirinyl derivative, that was two to three orders of magnitude more
potent than aspirin and at least one to two orders of magnitude more potent than gemcitabine in
inhibiting PDAC cancer cell growth/viability against three PDAC cell lines while sparing mouse
embryonic fibroblasts in the same exposure range. In Panc-1 cells, AS-10 induced apoptosis without
necrosis, principally through caspase-3/7 cascade and reactive oxygen species, in addition to an
induction of G1 cell cycle block. Transcriptomic profiling with RNA-seq indicated the top responses
to AS-10 exposure as CDKN1A (P21Cip1), CCND1, and nuclear transcription factor-kappa B (NF-B)
complex and the top functions as cell cycle, cell death, and survival without inducing the DNA
damage gene signature. AS-10 pretreatment (6 h) decreased cytokine tumor necrosis factor-alpha
(TNF-)-stimulated NF-B nuclear translocation, DNA binding activity, and degradation of cytosolic
inhibitor of B (IB) protein. As NF-B activation in PDAC cells confers resistance to gemcitabine,
the AS-10 combination with gemcitabine increased the in vitro cytotoxicity more than the additivity
of both compounds. Overall, our results suggest AS-10 may be a promising drug lead for PDAC,
both as a single agent and in combination therapy
Identification of a novel quinoxaline-isoselenourea targeting the STAT3 pathway as a potential melanoma therapeutic
The prognosis for patients with metastatic melanoma remains very poor. Constitutive
signal transducer and activator of transcription 3 (STAT3) activation has been correlated to metastasis,
poor patient survival, larger tumor size, and acquired resistance against vemurafenib (PLX-4032),
suggesting its potential as a molecular target. We recently designed a series of isoseleno- and
isothio-urea derivatives of several biologically active heterocyclic scaffolds. The cytotoxic effects
of lead isoseleno- and isothio-urea derivatives (compounds 1 and 3) were studied in a panel of
five melanoma cell lines, including B-RAFV600E-mutant and wild-type (WT) cells. Compound 1
(IC50 range 0.8–3.8 µM) showed lower IC50 values than compound 3 (IC50 range 8.1–38.7 µM) and
the mutant B-RAF specific inhibitor PLX-4032 (IC50 ranging from 0.4 to >50 µM), especially at a
short treatment time (24 h). These effects were long-lasting, since melanoma cells did not recover
their proliferative potential after 14 days of treatment. In addition, we confirmed that compound 1
induced cell death by apoptosis using Live-and-Dead, Annexin V, and Caspase3/7 apoptosis assays.
Furthermore, compound 1 reduced the protein levels of STAT3 and its phosphorylation, as well as
decreased the expression of STAT3-regulated genes involved in metastasis and survival, such as
survivin and c-myc. Compound 1 also upregulated the cell cycle inhibitor p21. Docking studies
further revealed the favorable binding of compound 1 with the SH2 domain of STAT3, suggesting it
acts through STAT3 inhibition. Taken together, our results suggest that compound 1 induces apoptosis
by means of the inhibition of the STAT3 pathway, non-specifically targeting both B-RAF-mutant and
WT melanoma cells, with much higher cytotoxicity than the current therapeutic drug PLX-4032
Library of Seleno-Compounds as Novel Agents against Leishmania Species
The in vitro leishmanicidal activities of a series of 48 recently synthesized selenium derivatives against Leishmania infantum and Leishmania braziliensis parasites were tested using promastigotes and intracellular amastigote forms. The cytotoxicity of the tested compounds for J774.2 macrophage cells was also measured in order to establish their selectivity. Six of the tested compounds (compounds 8, 10, 11, 15, 45, and 48) showed selectivity indexes higher than those of the reference drug, meglumine antimonate (Glucantime), for both Leishmania species; in the case of L. braziliensis, compound 20 was also remarkably selective. Moreover, data on infection rates and amastigote numbers per macrophage showed that compounds 8, 10, 11, 15, 45, and 48 were the most active against both Leishmania species studied. The observed changes in the excretion product profile of parasites treated with these six compounds were also consistent with substantial cytoplasmic alterations. On the other hand, the most active compounds were potent inhibitors of Fe superoxide dismutase (Fe-SOD) in the two parasite species considered, whereas their impact on human CuZn-SOD was low. The high activity, low toxicity, stability, low cost of the starting materials, and straightforward synthesis make these compounds appropriate molecules for the development of affordable antileishmanicidal agents