Synthesis and Anticancer Evaluation of New Indole-Based Tyrphostin Derivatives and Their (p-Cymene)dichloridoruthenium(II) Complexes.

New N-alkylindole-substituted 2-(pyrid-3-yl)-acrylonitriles with putative kinase inhibitory activity and their (p-cymene)Ru(II) piano-stool complexes were prepared and tested for their antiproliferative efficacy in various cancer models. Some of the indole-based derivatives inhibited tumor cell proliferation at (sub-)micromolar concentrations with IC50 values below those of the clinically relevant multikinase inhibitors gefitinib and sorafenib, which served as positive controls. A focus was set on the investigation of drug mechanisms in HCT-116 p53-knockout colon cancer cells in order to evaluate the dependence of the test compounds on p53. Colony formation assays as well as experiments with tumor spheroids confirmed the excellent antineoplastic efficacy of the new derivatives. Their mode of action included an induction of apoptotic caspase-3/7 activity and ROS formation, as well as anti-angiogenic properties. Docking calculations with EGFR and VEGFR-2 identified the two 3-aryl-2-(pyrid-3-yl)acrylonitrile derivatives 2a and 2b as potential kinase inhibitors with a preferential activity against the VEGFR-2 tyrosine kinase. Forthcoming studies will further unveil the underlying mode of action of the promising new derivatives as well as their suitability as an urgently needed novel approach in cancer treatment.

New 4,5-Diarylimidazol-2-ylidene-iodidogold(I) Complexes with High Activity against Esophageal Adenocarcinoma Cells.

Inspired by the vascular-disrupting agent combretastatin A-4 and recently published anticancer active N-heterocyclic carbene (NHC) complexes of Au(I), a series of new iodidogold(I)-NHC complexes was synthesized and characterized. The iodidogold(I) complexes were synthesized by a route involving van Leusen imidazole formation and N-alkylation, followed by complexation with Ag2O, transmetalation with chloro(dimethylsulfide)gold(I) [Au(DMS)Cl], and anion exchange with KI. The target complexes were characterized by IR spectroscopy, 1H and 13C NMR spectroscopy, and mass spectrometry. The structure of 6c was validated via single-crystal X-ray diffraction. A preliminary anticancer screening of the complexes using two esophageal adenocarcinoma cell lines showed promising nanomolar activities for certain iodidogold(I) complexes accompanied with apoptosis induction, as well as c-Myc and cyclin D1 suppression in esophageal adenocarcinoma cells treated with the most promising derivative 6b.

Anticancer Activity of Novel Difluorinated Curcumin Analog and Its Inclusion Complex with 2-Hydroxypropyl-ß-Cyclodextrin against Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is the primary reason for cancer-related deaths in the US. Genetic mutations, drug resistance, the involvement of multiple signaling pathways, cancer stem cells (CSCs), and desmoplastic stroma, which hinders drug penetrance, contribute to poor chemotherapeutic efficacy. Hence, there is a need to identify novel drugs with improved delivery to improve treatment outcomes. Curcumin is one such compound that can inhibit multiple signaling pathways and CSCs. However, curcumin's clinical applicability for treating PDAC is limited because of its poor solubility in water and metabolic instability. Hence, we developed a difluorinated curcumin (CDF) analog that accumulates selectively in the pancreas and inhibits PDAC growth in vitro and in vivo. In the present work, we developed its 2-hydroxy-propyl-ß-cyclodextrin (HCD) inclusion complex to increase its water solubility and hydrolytic stability. The CDFHCD inclusion complex was characterized by spectroscopic, thermal, and microscopic techniques. The inclusion complex exhibited increased aqueous solubility, hydrolytic stability, and antiproliferative activity compared to parent CDF. Moreover, CDF and CDFHCD inhibited colony and spheroid formation, and induced cell cycle and apoptosis in PDAC cell lines. Hence, CDFHCD self-assembly is an efficient approach to increase water solubility and anticancer therapeutic efficacy, which now warrants advancement towards a clinical proof of concept in PDAC patients.

Fluorinated and N-Acryloyl-Modified 3,5-Di[(E)-benzylidene]piperidin-4-one Curcuminoids for the Treatment of Pancreatic Carcinoma.

Pancreatic carcinoma is a cancer disease with high mortality. Thus, new and efficient treatments for this disease are badly needed. Curcumin has previously shown promising effects in pancreatic cancer patients; however, this natural compound suffers from inadequate efficacy and bioavailability, preventing its clinical approval. The synthetic curcuminoid EF24 was developed with activities superior to curcumin against various cancer types. In this study, a series of analogs of EF24 were investigated for anticancer effects on pancreatic carcinoma models. A distinct activity boost was achieved by straightforward N-acrylation of EF24 analogs, in particular, of compounds bearing 3-fluoro-4-methoxybenzylidene, 3,4-difluorobenzylidene, and 4-trifluoromethylbenzylidene moieties, while no improvement was seen for N-acryloyl-modified EF24. Apoptosis induction and suppression of phospho-STAT3 levels were determined, the latter corroborated by docking of active curcuminoids into STAT3. Hence, promising new clues for the development of efficient and superior curcuminoids as valuable treatment options for one of the most lethal cancer diseases were discovered in this study.

Differential expression and interaction of melatonin and thyroid hormone receptors with estrogen receptor α improve ovarian functions in letrozole-induced rat polycystic ovary syndrome.

AIMS: The objective of the present study was to investigate the effect of melatonin and L-thyroxine (T4) on the expression of various receptors, and some metabolic, reproductive, and gonadotropic hormones in letrozole-induced polycystic ovary syndrome (PCOS) in rats. MATERIAL AND METHODS: Assessment of gravimetric, hormonal profile and thyroid histology and relative expression of melatonin receptors (MT1, MT2) and estrogen receptor α (Erα) in thyroid and ovary, and type II iodothyronine deiodinase (Dio2) and thyroid hormone receptor α (TRα) in the ovary were performed using standard protocols. KEY FINDINGS: A significant increase in thyroid follicles numbers was noted in the hyperthyroid rat. T4 treatment to PCOS showed the expected increment in the circulating level of triiodothyronine (T3) and T4. Melatonin and T4 treatment of PCOS rats resulted in a significant decrease in the circulating level of T3 and T4. Hyperthyroid rats showed a decrement in plasma melatonin levels. However, T4 treatment to PCOS rats showed increased circulating melatonin levels, and a decrease in the circulating level of gonadotropins (LH and FSH), and testosterone. Melatonin treatment to PCOS-hyperthyroid rats resulted in the normal expression of ovarian and thyroid MT1 and ERα, receptors, which had been altered in PCOS and hyperthyroid rats, without any significant change in the MT2 receptor. SIGNIFICANCE: The present findings suggest a fine interplay and cross-talk via melatonin and its two receptors with ERα, TRα, and Dio2in thyroid and ovarian tissue during PCOS and hyperthyroidism pathogenicity.

Modulation of human ovarian function by melatonin.

Melatonin, a hormone which is primarily released by the pineal gland, has a wide range of actions in the female reproductive tract. While the melatonin receptor subtype, MT3, has been identified in amphibian animals and birds, in humans and other mammals, melatonin acts through, MT1 and MT2 receptor subtypes which are expressed in human ovaries. The rhythmic release of melatonin starts at puberty and continues throughout fertile female life, affecting and regulating diverse ovarian functions. Here, we discuss the importance of melatonin in regulating folliculogenesis, oocyte quality, ovulation and luteal function, sex steroid receptor gene expression, ovarian steroidogenesis including the production and steroidogenic enzyme activities in the egg and thecal cells. Melatonin improves the egg quality and increases the chance of success of in vitro fertilization (IVF). In view of such extensive actions, melatonin is central to the fertility in females. The objective of this review is to recapitulate the current understanding of the role of melatonin and its receptors.

Combined administration of exogenous melatonin and insulin ameliorates streptozotocin induced toxic alteration on hematological parameters in diabetic male Wistar rats.

The aim of the present was to ameliorate the protective effect of exogenous melatonin and insulin against the diabetes induced alterations in the different hematological variables. Albino rats were administrated streptozotocin at the dose of 15 mg/kg for 6 days. Total 54 rats were randomly selected for the experimental purpose and were divided into two major groups. Group-1 consisting twenty four (24) and were further sub-divided into four (4) different groups viz. group-I served as normal control, group-II served as melatonin treated, group-III served as insulin treated and group-IV served as glibenclamide treated. Group-2 consisting thirty (30) rats were given streptozotocin (STZ) injection (15 mg/kg) for 6 days. After confirmation of diabetes by measuring blood glucose level, animals having blood glucose level above 250 mg/dl) confirmed as diabetic. Thirty (30) Diabetic rats were further subdivided into following sub-groups and were given different therapeutic treatments, Viz group-I served as Diabetic control, group-II treated with melatonin, group-III treated with insulin, group-IV given treatment of melatonin and insulin and group-V were given treatment of glibenclamide respectively. Diabetic rats showed modulation in all the studied hematological variables. Diabetic rats displayed significant decline in RBCs count, HB level and its associated indices (HCT, RDW, MCV, MCH, MCHC), WBCs and its related indices (polymorphs and lymphocytes) and platelet distribution width (PDW %) whereas platelet count showed significant increase. Nonetheless alone as well as combined treatment of exogenous melatonin and insulin restored all altered hematological parameters. However, significant recovery was found in the group in which combined dose of melatonin and insulin was administrated. Therefore, it might be concluded that combined administration of melatonin and insulin will be better remedy to normalize the altered blood profile during the diabetic condition.

Therapeutic Efficacy of Melatonin Against Polycystic Ovary Syndrome (PCOS) Induced by Letrozole in Wistar Rat.

BACKGROUND AND OBJECTIVES: Polycystic ovary syndrome (PCOS) is a common heterogeneous endocrinological and metabolic disorder in women of reproductive age which leads to infertility/subfertility. The present study was commenced to elucidate the therapeutic efficacy of melatonin in the pathogenesis of letrozole induced polycystic ovary syndrome (PCOS) in Wistar rat. MATERIALS AND METHODS: Letrozole was administered orally (1 mg kg-1) to induce PCOS condition in Wistar female rats for a period of 2-3 weeks followed by a dose of melatonin (200 µg/100 g b.wt.) to PCOS induced rats. On the completion of experimental period the level of cytokines and expression level of different receptors was assessed. RESULTS: The PCOs rats showed down regulation in melatonin (MT1 and MT2), estrogen (ER-α) and cytokine (IL-2R and IL-6R) receptors expression and high circulatory level of IL-6 and TNF-α during PCO condition. These anomalies in expression pattern and circulatory level of cytokines were restored following the treatment. CONCLUSION: Finding of present study showed the role of melatonin supplementation at receptor level and also suggesting a crosstalk between MT1R / MT2R via cytokine IL-2R and IL-6R resulting in modulation of ER-α receptors.

Protective Role of Melatonin in Streptozotocin Induced Pancreatic Damages in Diabetic Wistar Rat.

BACKGROUND AND OBJECTIVE: Hyperglycemia is a representative hallmark and risk factor for diabetes and is closely linked to diabetes associated complications. The aim of the present study was to evaluate the therapeutic potential of exogenous melatonin against the streptozotocin induced pancreatic damages in rats. MATERIALS AND METHODS: Streptozotocin was injected for consecutive 6 days. Diabetes was confirmed by blood glucose measurement after 72 h and on 7th day after injection. Animals having blood glucose level above 250 mg dL-1 were considered as diabetic and were administered exogenous melatonin for 4 weeks. Animals were euthanized after last dose, pancreas were dissected out, weighed and fixed in Bouin's fixative for histology and further tissues were kept at -20°C for biochemistry. RESULTS: Diabetic rats displayed significant increase in lipid peroxidation, but pancreatic weight index, antioxidant system (GSH, SOD and CAT) showed decrease. Melatonin treatment to diabetic rats restored the alteration in physiological and biochemical markers. Results were supported by the histopathological observations, STZ treated pancreas showed damage in islets of langerhans, while as melatonin treated diabetic rats recovered the cellular architecture which inturn normalize the function of the pancreas. CONCLUSION: Therefore, melatonin might be considered as a molecule to protect the pancreatic damages.