Synthesis and In Vitro and Silico Anti-inflammatory Activity of New Thiazolidinedione-quinoline Derivatives.

BACKGROUND: Inflammation is a series of complex defense-related reactions. The inflammation cascade produces various pro-inflammatory mediators. Unregulated production of these pro-inflammatory mediators can lead to a wide range of diseases, including rheumatoid arthritis, sepsis, and inflammatory bowel disease. In the literature, the anti-inflammatory action of quinoline and thiazolidinedione nuclei are well established, alone, and associated with other nuclei. The synthesis of hybrid molecules is a strategy for obtaining more efficient molecules due to the union of pharmacophoric nuclei known to be related to pharmacological activity. OBJECTIVE: Based on this, this work presents the synthesis of thiazolidinedione-quinoline molecular hybrids and their involvement in the modulation of cytokines involved in the inflammatory reaction cascade. METHODS: After synthesis and characterization, the compounds were submitted to cell viability test (MTT), ELISA IFN-γ and TNF-α, adipogenic differentiation, and molecular docking assay with PPARy and COX-2 targets. RESULTS: LPSF/ZKD2 and LPSF/ZKD7 showed a significant decrease in the concentration of IFN- γ and TNF-α, with a dose-dependent behavior. LPSF/ZKD4 at a concentration of 50 µM significantly reduced IL-6 expression. LPSF/ZKD4 demonstrates lipid accumulation with significant differences between the untreated and negative control groups, indicating a relevant agonist action on the PPARγ receptor. Molecular docking showed that all synthesized compounds have good affinity with PPARγ e COX-2, with binding energy close to -10,000 Kcal/mol. CONCLUSION: These results demonstrate that the synthesis of quinoline-thiazolidinedione hybrids may be a useful strategy for obtaining promising candidates for new anti-inflammatory agents.

PPARγ partial agonist LPSF/GQ-16 prevents dermal and pulmonary fibrosis in HOCl-induced systemic sclerosis (SSc) and modulates cytokine production in PBMC of SSc patients.

Thiazolidinediones (TZD) are synthetic molecules that have a range of biological effects, including antifibrotic and anti-inflammatory, and they may represent a promising therapeutic strategy for systemic sclerosis (SSc). The aim of this study was to investigate the immunomodulatory and antifibrotic properties of LPSF/GQ-16, a TZD derivative, in peripheral blood mononuclear cells (PBMC) from SSc patients and in a murine model of SSc HOCl-induced. The PBMC of 20 SSc patients were stimulated with phytohemagglutinin (PHA) and treated with LPSF/GQ-16 for 48 h, later cytokines in the culture supernatants were quantified by sandwich enzyme-linked immunosorbent assay (ELISA) or cytometric bead array (CBA). Experimental SSc was induced by intradermal injections of hypochlorous acid (HOCl) for 6 weeks. HOCl-induced SSc mice received daily treatment with LPSF/GQ-16 (30 mg/kg) through intraperitoneal injections during the same period. Immunological parameters were evaluated by flow cytometry and ELISA, and dermal and pulmonary fibrosis were evaluated by RT-qPCR, hydroxyproline dosage and histopathological analysis. In PBMC cultures, it was possible to observe that LPSF/GQ-16 modulated the secretion of cytokines IL-2 (p < 0.001), IL-4 (p < 0.001), IL-6 (p < 0.001), IL-17A (p = 0.006), TNF (p < 0.001) and IFN-γ (p < 0.001). In addition, treatment with LPSF/GQ-16 in HOCl-induced SSc mice promoted a significant reduction in dermal thickening (p < 0.001), in the accumulation of collagen in the skin (p < 0.001), down-regulated the expression of fibrosis markers in the skin (Col1a1, α-Sma and Tgfß1, p < 0.001 for all) and lungs (Il4 and Il13, p < 0.001 for both), as well as reduced activation of CD4 + T cells (p < 0.001), B cells (p < 0.001) and M2 macrophages (p < 0.001). In conclusion, LPSF/GQ-16 showed immunomodulatory and antifibrotic properties, demonstrating the therapeutic potential of this molecule for SSc.

Cytotoxicity evaluation of haloperidol, clozapine and a new molecule with antipsychotic potential, PT-31, in NIH-3T3 cells

Abstract Schizophrenia is an illness that affects 26 million people worldwide. However, conventional antipsychotics present side effects and toxicity, highlighting the need for new antipsychotics. We aimed to evaluate the cytotoxicity of haloperidol (HAL), clozapine (CLO), and a new molecule with antipsychotic potential, PT-31, in NIH-3T3 cells. The neutral red uptake assay and the MTT assay were performed to evaluate cell viability and mitochondrial activity, morphological changes were assessed, and intracellular reactive oxygen species (ROS) detection was performed. HAL and CLO (0.1 µM) showed a decrease in cell viability in the neutral red uptake assay and in the MTT assay. In addition, cell detachment, content decrease, rounding and cell death were also observed at 0.1 µM for both antipsychotics. An increase in ROS was observed for HAL (0.001, 0.01 and 1 µM) and CLO (0.01 and 1 µM). PT-31 did not alter cell viability in any of the assays, although it increased ROS at 0.01 and 1 µM. HAL and CLO present cytotoxicity at 0.1 µM, possibly through apoptosis and necrosis. In contrast, PT-31 does not present cytotoxicity to NIH-3T3 cells. Further studies must be performed for a better understanding of these mechanisms and the potential risk of conventional antipsychotics

Study of the acute and repeated dose 28-day oral toxicity in mice treated with PT-31, a molecule with a potential antipsychotic profile.

Schizophrenia is a psychiatric disorder that affects 1% of the world population and is treated with antipsychotics, which may induce important biochemical and hematological alterations. Since it is necessary to verify the safety of new molecules with antipsychotic potential, the present study aimed to evaluate the oral toxicity of PT-31, a putative α2-adrenoreceptor agonist, after acute (2000 mg/kg) and repeated doses (28 days) gavage treatment, in three different doses: minimum effective dose in animal models (10 mg/kg), twice the dose (20 mg/kg), and four times the dose (40 mg/kg), as recommended by the OECD guidelines. Balb/C female adult mice were used, and biochemical, hematological, and histopathological analyses were performed. PT-31 10 and 20 mg/kg did not cause biochemical alterations related to hepatic and renal toxicity, and neither altered glycemic and lipid profiles. The preclinical dose of PT-31 also did not promote mice histopathological changes in the liver, kidney, and brain. In the hematimetric parameters, PT-31 only increased HGB at 20 mg/kg, and MCH and MCHC at 40 mg/kg. However, all the tested doses of PT-31 showed platelet increase, which must be better investigated. Therefore, further studies are needed to investigate the safety of PT-31 as a potential antipsychotic drug.

Synthesis, Assessment of Antineoplastic Activity, and Molecular Docking of Novel 2-Thioxo-oxazolidin-4-one Derivatives.

BACKGROUND: Oxazolidinones display several biological effects, including anticancer activity. The purpose of this present work was to investigate a series of novel oxazolidinone derivatives with potential antineoplastic activity. Their mechanisms of death induction and effects in the cell cycle were also evaluated. A molecular docking study was accomplished through proteins of the Cyclin-Dependent Kinases family (CDK). The new compound LPSF/NBM-2 was appeared to promote cell cycle arrest at the G2/M phase and increase the percentage of apoptotic cells. METHODS: Oxazolidinone derivatives were obtained through Knoevenagel condensation. The cytotoxic assay was evaluated through the MTT method. Moreover, flow cytometry was performed in order to investigate the effects of the new compounds on the cell cycle, induction of cell death, and apoptosis. A blind docking was performed through the SwissDock online server and the analysis of the results was performed using the UCSF Chimera and Biovia discovery studio software. RESULTS: LPSF/NBM-1 and LPSF/NBM-2 displayed the most cytotoxic activity against HL-60 (IC50 = 54.83 µM) and MOLT-4 (IC50 = 51.61 µM) cell lines. LPSF/NBM-2 showed an increased percentage of cell population at the G2/M phase. Molecular-docking results of LPSF/NBM-1 and LPSF/NBM-2 suggested a binding affinity with the evaluated CDK proteins. CONCLUSION: LPSF/NBM-1 and LPSF/NBM-2 displayed cytotoxic profiles against Hl-60 and MOLT-4. LPSF/NBM-2 increased cell population percentage at the G2/M phase and promoted cell death compared to non-treated cells in the MOLT-4 cell line. Based on these findings, oxazolidinone derivatives could be highlighted as possible cytostatic agents against lymphoma cells. Molecular docking results suggested the action of LPSF/NBM-1 and LPSF/NBM-2 compounds on enzymes of cyclin-dependent kinases family, however, more studies are needed to establish this correlation.

Ischemia-reperfusion damage is attenuated by GQ-11, a peroxisome proliferator-activated receptor (PPAR)-α/γ agonist, after aorta clamping in rats.

INTRODUCTION: Ischemia-Reperfusion (I/R) damage is one of the major challenges in cardiothoracic surgeries and in a pathological manner, is identified by exacerbated damage signals resulted from blood supply restriction and subsequent flow restoration and re­oxygenation. I/R damage includes cellular dysfunction and death, impairing tissue and organ function. Inflammation and oxidative stress are known to underlie either ischemia or reperfusion, leaded by HIF, TNF-α, NF-κB, IL-6 and ROS formation. However, the available approaches to prevent I/R damage has been unsuccessful so far. As agonists of peroxisome-proliferation activation receptor (PPAR) are described as transcription factors related to anti-inflammatory factors, we proposed to observe the effects of novel dual agonist, GQ-11, in I/R-related damage. METHODS: Male, Wistar rats, 60 days age and 305 g body weight average were treated with vehicle, pioglitazone or GQ-11 (20 mg/kg) for 7 consecutive days and were submitted to aorta clamping for 30 min followed by 3 h of reperfusion. 18F-fluorodeoxyglucose (18F-FDG), an analog of glucose associated with inflammation when accumulated, was observed in liver and bowel by positron emission tomography (PET). RESULTS: GQ-11 decreased 18F-FDG uptake in liver and bowel when compared to vehicle and pioglitazone. The treatment also modulated inflammatory markers IL-10, TGF-ß, IL-6, IL1-ß, TNFα, and CCL-2, besides antioxidant enzymes such as catalase, GPx and SOD. CONCLUSION: Inflammation and oxidative stress showed to be important processes to be regulated in I/R in order to prevent exacerbated responses that leads to cell/tissue dysfunction and death. PPAR agonists - including GQ-11 - might be promising agents in a strategy to avoid tissue dysfunction and death after cardiothoracic surgeries.

Selective modulator of nuclear receptor PPARγ with reduced adipogenic potential ameliorates experimental nephrotic syndrome.

Glomerular disease manifests as nephrotic syndrome (NS) with high proteinuria and comorbidities, and is frequently refractory to standard treatments. We hypothesized that a selective modulator of PPARγ, GQ-16, will provide therapeutic advantage over traditional PPARγ agonists for NS treatment. We demonstrate in a pre-clinical NS model that proteinuria is reduced with pioglitazone to 64%, and robustly with GQ-16 to 81% of nephrosis, comparable to controls. Although both GQ-16 and pioglitazone restore glomerular-Nphs1, hepatic-Pcsk9 and serum-cholesterol, only GQ-16 restores glomerular-Nrf2, and reduces hypoalbuminemia and hypercoagulopathy. GQ-16 and pioglitazone restore common and distinct glomerular gene expression analyzed by RNA-seq and induce insulin sensitizing adipokines to various degrees. Pioglitazone but not GQ-16 induces more lipid accumulation and aP2 in adipocytes and white adipose tissue. We conclude that selective modulation of PPARγ by a partial agonist, GQ-16, is more advantageous than pioglitazone in reducing proteinuria, NS associated comorbidities, and adipogenic side effects of full PPARγ agonists.

New Trends in Biological Activities and Clinical Studies of Quinolinic Analogues: A Review.

The quinolinic ring, present in several molecules, possesses a great diversity of biological activities. Therefore, this ring is in the structural composition of several candidates of drugs in preclinical and clinical studies; thus, it is necessary to compile these results to facilitate the design of new drugs. For this reason, some of the activities of compounds are selected to examine in this review, such as antimalarial, antimicrobial, anticancer, anti-inflammatory, antidiabetic, anti-rheumatic, and antiviral activities. All publications of scientific articles chosen are dated between 2000 and 2020. In addition to presenting the structures of some natural and synthetic compounds with their activities, we have listed the clinical studies of phases III and IV on antimalarial drugs containing the quinoline nucleus and phase III clinical studies on hydroxychloroquine and chloroquine to assess their possible role in COVID-19. Finally, we have reviewed some of the mechanisms of action, as well as the side effects of some of the quinolinic derivatives.

Imidazolidine Derivatives in Cancer Research: What is known?

It is well known that cancer is the second leading cause of death worldwide. Due to this fact, new results for the treatment of cancer are constantly being introduced and verified. Imidazolidine derivatives regulate cell cycle progression and DNA stability. Structurally, a heterocyclic nucleus favors a direct DNA interaction and therefore, control of the DNA replication process. This review aims not only to discuss the role of imidazolidines in cancer therapy but also explore the functionality of such agents in the future aspects of cancer prognosis and treatment. Convincing data from 1996 to 2021 has presented imidazolidine derivatives as a relevant therapeutic tool to modulate cancer progression and malignancy. Here we highlight these aspects in a variety of cell lines, cancer types, involving in vitro and in vivo techniques.

Synthesis of novel thiazolidinic-phthalimide derivatives evaluated as new multi-target antiepileptic agents.

Epilepsy is a disease that affects millions of people around the globe and has a multifactorial cause. Inflammation is a process that can be involved in the development of seizures. Thus, the present study proposed the design and synthesis of new candidates for antiepileptic drugs that would also control the inflammatory process. Nine new derivatives of the substituted thiazophthalimide hybrid core were obtained with satisfactory purity ≥99% and yields between 27% and 87%. All compounds showed cell viability values greater than 90% in the culture of PBMC cells from healthy volunteers and, therefore, were not considered cytotoxic. These compounds modulated proinflammatory cytokines IFN-y and IL-17A and can mitigate inflammation. Acute toxicity studies of compound 7i in an animal model indicated that the compound has low toxicity and an LD50 greater than 2 g/kg in healthy adult rats. The same compound did not show positive results for anticonvulsant activity through the PTZ test. However, 7i demonstrates the interaction with the target GABA-A receptor in silico, indicating a possible activity as an agonist of that receptor. Thus, further studies are needed to investigate the anticonvulsant activity, in particular, using models in which the inflammatory process triggers epileptic seizures.

Evaluation of the action of LPSF/GQ-16 on cytokines and PPAR-γ gene expression after in vitro irradiation of peripheral blood mononuclear cells.

PURPOSE: Patients submitted to radiotherapy (RT) may present in their healthy tissues surrounding the treated tumor, some typical acute inflammatory reactions induced by ionizing radiation (IR). The manifestation of inflammatory processes is a result of exacerbation of the immune system, as a response to radiation exposure, and this can be a limiting factor for RT protocols. To counteract this, some thiazolidinediones, such as LPSF/GQ-16, may be useful for modulating the patient's radioinduced inflammatory response in normal tissues. In this context, the present work aims to evaluate the activity of LPSF/GQ-16 on the levels of cytokines and the expression of the gene PPARγ in mononuclear cells irradiated in vitro, to analyze the immunomodulatory activity of the molecule and its action on radiomitigation. MATERIALS AND METHODS: For this, blood samples from eight donors were collected and irradiated with 2 Gy, then the PBMC (peripheral blood mononuclear cells) were cultured and treated with LPSF/GQ-16. The levels of cytokines TNF-α, IFN-γ, IL-2 and IL-4 were quantified by CBA, while the genes of TNF-α, IFN-γ and PPARγ were analyzed by RT-PCR. RESULTS: LPSF/GQ-16 significantly reduced the expression of proinflammatory cytokines (IFN-γ and TNF-α) in irradiated and nonirradiated groups. There was no significant reduction of anti-inflammatory cytokines (IL-2 and IL-4) by LPSF/GQ-16. The mRNA expression of PPAR-γ, IFN-γ and TNF-α in the presence of LPSF/GQ-16 was higher in the nonirradiated sample. CONCLUSION: LPSF/GQ-16 showed effective activity after irradiation, with an important immunomodulatory activity in irradiated PBMCs.

Advances in Synthesis and Medicinal Applications of Compounds Derived from Phthalimide.

Phthalimide derivatives have been presenting several promising biological activities in the literature, such as anti-inflammatory, analgesic, antitumor, antimicrobial and anticonvulsant. The most well-known and studied phthalimide derivative (isoindoline-1,3-dione) is thalidomide: this compound initially presented important sedative effects, but it is now known that thalidomide has effectiveness against a wide variety of diseases, including inflammation and cancer. This review approaches some of the recent and efficient chemical synthesis pathways to obtain phthalimide analogues and also presents a summary of the main biological activities of these derivatives found in the literature. Therefore, this review describes the chemical and therapeutic aspects of phthalimide derivatives.

Synthesis, Antitumor Activity and Molecular Docking Studies on Seven Novel Thiazacridine Derivatives.

AIM AND OBJECTIVE: In the last decades, cancer has become a major problem in public health all around the globe. Chimeric chemical structures have been established as an important trend on medicinal chemistry in the last years. Thiazacridines are hybrid molecules composed of a thiazolidine and acridine nucleus, both pharmacophores that act on important biological targets for cancer. By the fact it is a serious disease, seven new 3-acridin-9-ylmethyl-thiazolidine-2,4-dione derivatives were synthesized, characterized, analyzed by computer simulation and tested in tumor cells. In order to find out if the compounds have therapeutic potential. MATERIALS AND METHODS: Seven new 3-acridin-9-ylmethyl-thiazolidine-2,4-dione derivatives were synthesized through Michael addition and Knoevenagel condensation strategies. Characterization was performed by NMR and Infrared spectroscopy techniques. Regarding biological activity, thiazacridines were tested against solid and hematopoietic tumoral cell lines, namely Jurkat (acute T-cell leukemia); HL-60 (acute promyelocytic leukemia); DU 145 (prostate cancer); MOLT-4 (acute lymphoblastic leukemia); RAJI (Burkitt's lymphoma); K562 (chronic myelogenous leukemia) and normal cells PBMC (healthy volunteers). Molecular docking analysis was also performed in order to assess major targets of these new compounds. Cell cycle and clonogenic assay were also performed. RESULTS: Compound LPSF/AA-62 (9f) exhibited the most potent anticancer activity against HL-60 (IC50 3,7±1,7 µM), MOLT-4 (IC50 5,7±1,1 µM), Jurkat (IC50 18,6 µM), Du-145 (IC50 20±5 µM) and Raji (IC50 52,3±9,2 µM). While the compound LPSF/AA-57 (9b) exhibited anticancer activity against the K562 cell line (IC50 51,8±7,8 µM). Derivative LPSF/AA-62 (9f) did not interfere in the cell cycle phases of the Molt-4 lineage. However, the LPSF/AA-62 (9f) derivative significantly reduced the formation of prostate cancer cell clones. The compound LPSF/AA-62 (9f) has shown strong anchorage stability with enzymes topoisomerases 1 and 2, in particular due the presence of chlorine favored hydrogen bonds with topoisomerase 1. CONCLUSION: The 3-(acridin-9-ylmethyl)-5-((10-chloroanthracen-9-yl)methylene)thiazolidine-2,4-dione (LPSF/AA-62) presented the most promising results, showing anti-tumor activity in 5 of the 6 cell types tested, especially inhibiting the formation of colonies of prostate tumor cells (DU-145).

Tutorial on Diarrhea and Enteral Nutrition: A Comprehensive Step-By-Step Approach.

This tutorial suggests a current strategy toward a multiprofessional therapy based upon a comprehensive step-by-step approach to the course of intensive care unit diarrhea episodes. Evidence published in the last 10 years, obtained through a database search (PubMed), shows that its prevalence is quite variable. Although multicausal, it is often erroneously associated with the supply of enteral nutrition. Several complications affect not only nutrition status but also the development of skin lesions, which can become the focus of infections, and the length of hospital stay. Here, we propose an early, objective, directed, and multimodal approach, aiming at optimizing care for these patients. In a dynamic walkthrough, the reader will find a guide for the general diagnosis and for colitis resulting from Clostridium difficile infections, as well as current instructions and recommendations for drug treatment and supportive therapy for these 2 modalities. We also bring together ways to prevent and treat associated skin lesions in this setting. Because it is neglected in the critical environment, diarrhea is still a poorly addressed disease, and its complications bring about a significant worsening in quality of life and hospital stay.

New Peroxisome Proliferator-Activated Receptor Agonist (GQ-11) Improves Wound Healing in Diabetic Mice.

Objective: Chronic wounds associated with diabetes are an important public health problem demanding new treatments to improve wound healing and decrease amputations. Monocytes/macrophages play a key role in sustained inflammation associated with impaired healing and local administration of peroxisome proliferator-activated receptor (PPAR)γ agonists may modulate macrophage, improving healing. In this study, we investigated the effects of GQ-11, a partial/dual PPARα/γ agonist, on macrophage function and wound healing in diabetes. Approach: Wounds were surgically induced at the dorsum of C57BL/6J and BKS.Cg-Dock7m +/+ Leprdb/J (db/db) mice and treated with hydrogel (vehicle), pioglitazone or GQ-11, for 7 or 10 days, respectively. After treatment, wounds were analyzed histologically and by quantitative PCR (qPCR). In addition, bone marrow-derived macrophages (BMDM) were cultured from C57BL/6J mice and treated with vehicle, pioglitazone, or GQ-11, after challenge with lipopolysaccharide or interleukin-4 to be analyzed by qPCR and flow cytometry. Results: GQ-11 treatment upregulated anti-inflammatory/pro-healing factors and downregulated pro-inflammatory factors both in wounds of db/db mice and in BMDM. Innovation: Wounds of db/db mice treated with GQ-11 exhibited faster wound closure and re-epithelization, increased collagen deposition, and less Mac-3 staining compared with vehicle, providing a new approach to treatment of diabetic wound healing to prevent complications. Conclusion: GQ-11 improves wound healing in db/db mice, regulating the expression of pro- and anti-inflammatory cytokines and wound growth factors, leading to increased re-epithelization and collagen deposition.

PT-31, a putative α2-adrenoceptor agonist, is effective in schizophrenia cognitive symptoms in mice.

Evidence of changes in central noradrenergic activity has been reported in schizophrenic patients and studies indicate that activation of the α2-adrenoceptor improves memory and neuroprotection. In this study, a new imidazolidine derivative 3-(2-chloro-6-fluorobenzyl)-imidazolidine-2,4-dione, PT-31, a putative α2A-adrenoceptor agonist, was evaluated in mouse models predictive of efficacy in the treatment of positive and cognitive symptoms of schizophrenia, as well as its ability to promote cerebellar granule cell survival in vitro, in the presence or absence of glutamate (100 µmol/l). PT-31 prevented apomorphine-induced climbing and the ketamine-induced hyperlocomotion, without inducing catalepsy or motor impairment. PT-31 protected against the impairment of prepulse inhibition induced by apomorphine, (±)-DOI, and ketamine. The molecule did not affect mouse short nor long-term memory per se, but it protected against ketamine-induced memory impairment when administered at different stages of the memory process (acquisition, consolidation, and retrieval) in the novel object recognition task. When added to cultured cerebellar granule neurons, PT-31 was not toxic per se and protected neurons from glutamate-induced apoptosis. In conclusion, PT-31 displayed a preclinical pharmacology predictive of neuroprotective effects and efficacy in relieving schizophrenia symptoms, without inducing motor side effects, suggesting that it could represent a molecular scaffold for antipsychotic drug development.

Study of the in vitro metabolic profile of a new α2-adrenergic agonist in rat and human liver microsomes by using liquid chromatography-multiple-stage mass spectrometry and nuclear magnetic resonance.

A potent synthetic α2-adrenergic agonist called PT-31, (3-(2-chloro-6-fluorobenzyl)-imidazolidine-2,4-dione), was recently detected as a potential drug to be used as an adjuvant drug to treat chronic pain. The excellent pharmacological property of PT-31 highlights the importance in elucidating its metabolism, which could provide valuable information about its metabolite profile for further pharmacokinetics studies and additionally to estimate the impact of its metabolites on the efficacy, safety and elimination of PT-31. In this work, the study of the in vitro metabolism of PT-31 was initially carried out by using a liquid chromatography coupled to ion trap multiple-stage mass spectrometer (LC-IT-MSn) and a hybrid triple quadrupole/linear ion trap mass spectrometer (LC-QTrap). The production of at least three unknown oxidative metabolites was observed. Structural identification of the unknown metabolites was carried out by combination of LC-MS experiments, including selected reaction monitoring (SRM) and multi-stage full scan experiments. Further analysis of 1H-NMR led to the structural confirmation of the major metabolite. The results indicated that PT-31 was metabolized by a hydroxylation reaction in the imidazolidine-2,4-dione ring in rat and human liver microsomes, producing the metabolite 3-(2-chloro-6-fluorobenzyl)-5-hydroxyimidazolidine-2,4-dione in rat liver microsomes. A carbon hydroxylation onto the benzyl ring, produced two other minor metabolites of the PT-31 in rat liver microsomes.

Potential Therapeutic Agents Against Par-4 Target for Cancer Treatment: Where Are We Going?

One of the greatest challenges of cancer therapeutics nowadays is to find selective targets successfully. Prostate apoptosis response-4 (Par-4) is a selective tumor suppressor protein with an interesting therapeutic potential due to its specificity on inducing apoptosis in cancer cells. Par-4 activity and levels can be downregulated in several tumors and cancer cell types, indicating poor prognosis and treatment resistance. Efforts to increase Par-4 expression levels have been studied, including its use as a therapeutic protein by transfection with adenoviral vectors or plasmids. However, gene therapy is very complex and still presents many hurdles to be overcome. We decided to review molecules and drugs with the capacity to upregulate Par-4 and, thereby, be an alternative to reach this druggable target. In addition, Par-4 localization and function are reviewed in some cancers, clarifying how it can be used as a therapeutic target.