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.

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 dose- and time-dependent radical scavenging activity for all of the compounds were assessed using the in vitro 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′-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.

Currently, cancer is one of the major health problems of the human population and prominent cause of death. Thiazole ring has demonstrated many pharmacological activities including anticancer. This scaffold has been found alone or incorporated into the diversity of therapeutic active agents such as tiazofurin, dasatinib, and bleomycin, which are well-known antineoplastic drugs. Recently, most of the compounds isolated from natural sources containing thiazole moiety exhibit notable cytotoxicities and present antitumor potential. In this context, several structural changes have been made in the original structure, such as the incorporation of different substituents or the fusion with other carbo- and heterocycles, in order to increase the antitumoral potency. Related to mechanism of action of these derivatives, some of them act through kinase modulation, polymerization inhibition of microtubule, pro-matrix metalloproteinase activation, signal transducer activation of transcription 3, histone deacetylase inhibition, etc.

Currently, cancer, leishmaniasis and bacterial infections represent a serious public health burden worldwide. Six cinnamyl and benzodioxyl derivatives incorporating selenium (Se) as selenocyanate, diselenide, or selenide were designed and synthesized through a nucleophilic substitution and/or a reduction using hydrides. Ferrocene was also incorporated by a Friedel–Crafts acylation. All the compounds were screened in vitro for their antiproliferative, antileishmanial, and antibacterial properties. Their capacity to scavenge free radicals was also assessed as a first approach to test their antioxidant activity. Benzodioxyl derivatives 2a–b showed cytotoxicity against colon (HT-29) and lung (H1299) cancer cell lines, with IC₅₀ values below 12 µM, and were also fairly selective when tested in nonmalignant cells. Selenocyanate compounds 1–2a displayed potent antileishmanial activity in L. major and L. infantum, with IC₅₀ values below 5 µM. They also exhibited antibacterial activity in six bacterial strains, notably in S. epidermidis with MIC and MBC values of 12.5 µg/mL. Ferrocene-containing selenide 2c was also identified as a potent antileishmanial agent with radical scavenging activity. Remarkably, derivative 2a with a selenocyanate moiety was found to act as a multitarget compound with antiproliferative, leishmanicidal, and antibacterial activities. Thus, the current work showed that 2a could be an appealing scaffold to design potential therapeutic drugs for multiple pathologies.

The Warburg effect (or aerobic glycolysis), which was first described in 1926 by Otto Heinrich Warburg, consists of the change in glucose metabolism in cancer cells. In normal cells, glucose metabolism finalizes in the mitochondria through oxidative phosphorylation (OXPHOS) in the presence of oxygen. However, the Warburg effect describes a change in the glucose metabolism in cancer cells, consuming excess glucose and converting it into lactate independently of the presence of oxygen. During this process, a wide variety of enzymes can modify their expression and activity to contribute to the mechanism of deregulated cancer metabolism. Therefore, the modulation of enzymes regulating aerobic glycolysis is a strategy for cancer treatment. Although numerous enzymes play a role in regulating aerobic glycolysis, hexokinase 2 (HK2), pyruvate dehydrogenase kinase (PDK), pyruvate kinase (PK), and lactate dehydrogenase (LDH) are worth mentioning. Numerous modulators of these enzymes have been described in recent years. This review aims to present and group, according to their chemical structure, the most recent emerging molecules targeting the above-mentioned enzymes involved in the Warburg effect in view of the future development of cancer treatments.

The introduction of selenium (Se) into organic scaffolds has been demonstrated to be a promising framework in the field of medicinal chemistry. A novel design of nonsteroidal anti-inflammatory drug (NSAID) derivatives based on a bioisosteric replacement via the incorporation of Se as diacyl diselenide is reported. The antioxidant activity was assessed using the DPPH radical scavenging assay. The new Se-NSAID derivatives bearing this unique combination showed antioxidant activity in a time- and dose-dependent manner, and also displayed different antiproliferative profiles in a panel of eight cancer cell lines as determined by the MTT assay. Ibuprofen derivative 5 was not only the most antioxidant agent, but also selectively induced toxicity in all the cancer cell lines tested (IC₅₀ < 10 µM) while sparing nonmalignant cells, and induced apoptosis partially without enhancing the caspase 3/7 activity. Furthermore, NSAID derivative 5 significantly suppressed tumor growth in a subcutaneous colon cancer xenograft mouse model (10 mg/kg, TGI = 72%, and T/C = 38%) without exhibiting any apparent toxicity. To our knowledge, this work constitutes the first report on in vitro and in vivo anticancer activity of an unprecedented Se-NSAID hybrid derivative and its rational use for developing precursors for bioisosteric selenocompounds with appealing therapeutic applications.