Antiproliferative oxime derivatives that inhibit glucose transporter 1 (GLUT1) in cancer cells

The Warburg effect, consisting in alterations of the glucose metabolism in cancer cells, where glucose mostly undergoes glycolysis with production of lactate, is currently being considered as one of the most intriguing hallmarks of cancer [1]. Therefore, the discovery of new agents able to block the glycolytic processes in tumor cells holds promise for developing relatively nontoxic anticancer treatments [2]. In terms of energy (ATP) production, glycolysis is dramatically less efficient than oxidative phosphorylation (OXPHOS). In fact, most normal cells rely on OXPHOS for glucose degradation, since they are generally well-oxygenated. On the contrary, invasive tumor tissues are often exposed to more-or-less transient hypoxia, which cannot guarantee the proper functioning of OXPHOS. Under these hypoxic conditions glycolysis leading to lactate production is mainly preferred, since it does not depend on oxygen availability. However, due to the lower efficiency of the glycolytic process, cancer cells commonly show a remarkably high glucose uptake, which is supported by the overexpression of the glucose transporters (GLUTs). GLUT1 is one of the most commonly transporters that are overexpressed by cancer cells and, therefore, represent a potential target for selectively hitting them [3], although only a very limited number of GLUT1-inhibitors have been reported so far [4]. On the basis of an analysis of the pharmacophoric features displayed by some previously reported GLUT1-inhibitors, we have identified a series of oxime derivatives [5] as potentially active on this transporter. A preliminary screening of these compounds in H1299 lung cancer cells demonstrated that some of them are able to effectively counteract glucose uptake and cell growth, displaying IC50 values in the low micromolar range. We have then developed a new computational model of GLUT1, which provided us with valuable clues about the possible binding site and the most important interactions occurring with some representative oxime derivatives and GLUT1. These indications may prove to be very valuable for the future development of novel potent and selective GLUT1-inhibitors. References: [1] Hanahan, D.; Weinberg, R. A. Cell 2011, 144, 646-674. [2] Granchi, C.; Minutolo, F. ChemMedChem 2012, 7, 1318-1350. [3] Rastogi, S.; Banerjee, S.; Chellappan, S.; Simon, G. R. Cancer Lett. 2007, 257, 244-251. [4] Liu, Y.; Cao, Y.; Zhang, W.; Bergmeier, S.; Qian, Y.; Akbar, H.; Colvin, R.; Ding, J.; Tong, L.; Wu, S.; Hines, J.; Chen, X. Mol. Cancer Ther. 2012, 11, 1672-1682, and references therein. [5] Minutolo, F.; Bertini, S.; Granchi, C.; Marchitiello, T.; Prota, G.; Rapposelli, S.; Tuccinardi, T.; Martinelli, A.; Gunther, J. R.; Carlson, K. E.; Katzenellenbogen, J. A.; Macchia, M. J. Med. Chem. 2009, 52, 858-867

Antiglycolytic strategies in cancer therapy: study of molecules interfering with the altered cancer cell metabolism.

Although the number of cancer hallmarks is increasing with the progressive understanding of molecular pathways involved in tumors, the origin of cancer is still unclear, thus representing a challenging field for researchers. One of the main hallmarks of cancer is represented by an altered metabolism of neoplastic cells, also known as the "Warburg effect", in which energy production is mainly shifted from oxidative phosphorylation (OXPHOS) to an increased rate of glycolysis. This feature correlates with malignant tumors and poor prognosis. My PhD was focused on the design and synthesis of new compounds, which can interfere with the altered metabolism of cancer cells by targeting the "Warburg effect" at different levels. In particular, our attention was focused on two of the main glycolytic targets, the LDH-5 enzyme and the glucose transporter GLUT-1, which were found to be overexpressed in several malignant tumors. Then, the third target investigated is estrogen receptor beta (ERβ), which was recently found to correlate with cancer cell metabolism, and part of my thesis was dedicated to the synthesis of new ketoxime-based compounds as ERβ selective agonists

Sintesi di derivati chetossimici aromatici, quali agonisti selettivi del recettore β degli estrogeni

È noto che gli estrogeni, oltre ad essere coinvolti nello sviluppo e nel mantenimento dei caratteri secondari femminili e ad intervenire nella regolazione dei processi riproduttivi maschili, influenzano molti processi fisiologici e metabolici in entrambi i sessi. Gli estrogeni mediano le loro azioni andando ad interagire con i propri recettori (ER). Ad oggi sono stati individuati due sottotipi del recettore nucleare per gli estrogeni, ERα e ERβ, che differiscono per la struttura e per la distribuzione in organi e tessuti. Lo sviluppo di ligandi selettivi per il recettore β è, dal 1996, anno in cui è stato identificato, oggetto di numerose ricerche. Ad oggi, sebbene siano state esplorate molte classi chimiche di composti, sono poche le molecole che risultano essere selettive per ERβ, tra queste le più potenti sono DPN e ERB-041. Negli ultimi anni è emerso un interesse crescente nello sviluppo di ligandi selettivi per ERβ, dovuto al fatto che ERβ sembra svolgere un ruolo cruciale in molti processi fisiologici e patologici. Si ritiene infatti che questi ligandi promuovano effetti benefici a livello di diversi organi, senza però causare un effetto proliferativo (mediato invece da ERα) in tessuti quali utero e mammella. Potrebbero quindi risultare utili nel trattamento di alcune patologie quali cancro, disturbi del SNC, patologie infiammatorie, disfunzioni metaboliche. In questa tesi sono stati sviluppati e sintetizzati nuovi ligandi con struttura metil-chetossimica ed etil-chetossimica. Dai risultati ottenuti, è emerso come lo scaffold chetossimico sia molto promettente nello sviluppo di ligandi selettivi per ERβ

Risks and Benefits Related to Alimentary Exposure to Xenoestrogens

Xenoestrogens are widely diffused in the environment and in food, thus a large portions of human population is worldwide exposed to them. Among alimentary xenoestrogens, phytoestrogens (PhyEs) are increasingly being consumed because of their potential health benefits, although there are also important risks associated to their ingestion. Furthermore, other xenoestrogens that may be present in food are represented by other chemicals possessing estrogenic activities, that are commonly defined as endocrine disrupting chemicals (EDCs). EDCs pose a serious health concern since they may cause a wide range of health problems, starting from pre-birth till adult lifelong exposure. We herein provide an overview of the main classes of xenoestrogens, which are classified on the basis of their origin, their structures and their occurrence in the food chain. Furthermore, their either beneficial or toxic effects on human health are discussed in this review

Small-molecule inhibitors of human LDH5

Latest findings on the role played by human isoform 5 of lactate dehydrogenase (hLDH5) in the promotion of glycolysis in invasive tumour cells are indicating this enzyme subtype as a promising therapeutic target for invasive cancer. Compounds able to selectively inhibit hLDH5 hold promise for the cure of neoplastic diseases. hLDH5 has so far been a rather unexplored target, since its importance in the promotion of cancer progression has been neglected for decades. This enzyme should also be considered as a challenging target due the high polar character (mostly cationic) of its ligand cavity. Recently, significant progresses have been reached with small-molecule inhibitors of hLDH5displaying remarkable potencies and selectivities. This review provides an overview of the newly developed hLDH5-inhibitors. The roles of hLDH isoforms will be briefly discussed, then the inhibitors will be grouped into chemical classes. Furthermore, general pharmacophore features will be emphasized throughout the structural subgroups analyzed

Estrogen Receptors Alpha (ERα) and Beta (ERβ): Subtype-Selective Ligands and Clinical Potential

Estrogen receptors alpha (ERα) and beta (ERβ) are nuclear transcription factors that are involved in the regulation of many complex physiological processes in humans. Modulation of these receptors by prospective therapeutic agents is currently being considered for prevention and treatment of a wide variety of pathological conditions, such as, cancer, metabolic and cardiovascular diseases, neurodegeneration, inflammation, and osteoporosis. This review provides an overview and update of compounds that have been recently reported as modulators of ERs, with a particular focus on their potential clinical applications

Estrogen receptor ligands: a patent review update

Introduction: The role of estrogens is mostly mediated by two nuclear receptors (ERα and ERβ) and a membrane-associated G-protein (GPR30 or GPER), and it is not limited to reproduction, but it extends to the skeletal, cardiovascular and central nervous systems. Various pathologies such as cancer, inflammatory, neurodegenerative and metabolic diseases are often associated to dysfunctions of the estrogenic system. Therapeutic interventions by agents that affect the estrogenic signaling pathway might be useful in the treatment of many dissimilar diseases. Areas covered: The massive chemodiversity of ER-ligands, limited to patented small molecules, is herein reviewed. The reported compounds are classified on the basis of their chemical structures. Nonsteroidal derivatives, which mostly consist in diphenolic compounds, are further segregated into chemical classes based on their central scaffold. Expert opinion: Estrogens have been used for almost a century and their earlier applications have concerned interventions in the female reproductive functions, as well as the treatment of some estrogen-dependent cancers and osteoporosis. Since the discovery of ERβ in 1996 the patent literature has started to pay a progressively increasing attention to this newer receptor subtype, which holds promise as a target for new indications, most of which still need to be clinically validated

Assessing the differential action on cancer cells of LDH-A inhibitors based on the N-hydroxyindole-2-carboxylate (NHI) and malonic (Mal) scaffolds

A head-to-head study of representative examples of N-hydroxyindole-2-carboxylates (NHI) and malonic derivatives (Mal) as LDH-A inhibitors was conducted, comparing enzyme inhibition potency, cellular uptake, reduction of lactate production in cancer cells and anti-proliferative activity. Among the compounds tested, methyl 1-hydroxy-6-phenyl-4-(trifluoromethyl)-1H-indole-2-carboxylate (2, NHI-2), a methyl ester belonging to the NHI class, displayed optimal properties in the cell-based assays, proving to be an efficient anti-glycolytic agent against cancer cells

Oxime-based inhibitors of glucose transporter 1 displaying antiproliferative effects in cancer cells

An analysis of the main pharmacophoric features present in the still limited number of inhibitors of glucose transporter GLUT1 led to the identification of new oxime-based inhibitors, which proved to be able to efficiently hinder glucose uptake and cell growth in H1299 lung cancer cells. The most important interactions of a representative inhibitor were indicated by a novel computational model of GLUT1, which was purposely developed to explain these results and to provide useful indications for the design and the development of new and more efficient GLUT1 inhibitors

Highly Selective Salicylketoxime-Based Estrogen Receptor beta Agonists Display Antiproliferative Activities in a Glioma Model

Estrogen receptor beta (ER beta) selective agonists are considered potential therapeutic agents for a variety of pathological conditions, including several types of cancer. Their development is particularly challenging, since differences in the ligand binding cavities of the two ER subtypes a and beta are minimal. We have carried out a rational design of new salicylketoxime derivatives which display unprecedentedly high levels of ER beta selectivity for this class of compounds, both in binding affinity and in cell-based functional assays. An endogenous gene expression assay was used to further characterize the pharmacological action of these compounds. Finally, these ER beta-selective agonists were found to inhibit proliferation of a glioma cell line in vitro. Most importantly, one of these compounds also proved to be active in an in vivo xenograft model of human glioma, thus demonstrating the high potential of this type of compounds against this devastating disease