α/β-Hydrolase Domain (ABHD) Inhibitors as New Potential Therapeutic Options against Lipid-Related Diseases

Much of the experimental evidence in the literature has linked altered lipid metabolism to severe diseases such as cancer, obesity, cardiovascular pathologies, diabetes, and neurodegenerative diseases. Therefore, targeting key effectors of the dysregulated lipid metabolism may represent an effective strategy to counteract these pathological conditions. In this context, α/β-hydrolase domain (ABHD) enzymes represent an important and diversified family of proteins, which are involved in the complex environment of lipid signaling, metabolism, and regulation. Moreover, some members of the ABHD family play an important role in the endocannabinoid system, being designated to terminate the signaling of the key endocannabinoid regulator 2-arachidonoylglycerol. This Perspective summarizes the research progress in the development of ABHD inhibitors and modulators: design strategies, structure-activity relationships, action mechanisms, and biological studies of the main ABHD ligands will be highlighted

Discovery and optimization of benzoylpiperidine derivatives as new reversible, potent and selective MAGL inhibitors

The serine hydrolase monoacylglycerol lipase (MAGL) is the main responsible of the degradation of 2-arachidonoylglycerol, an endocannabinoid implicated in several physiological processes. Moreover, MAGL is involved in the formation of pro-tumorigenic signaling molecules. MAGL inhibition is considered a valid therapeutic approach to treat several pathological conditions, including several types of cancer.[1] So far, only a limited number of MAGL inhibitors have been discovered and most of them are characterized by an irreversible mechanism of action, determining the occurrence of undesired effects. In this study we identified a reversible MAGL inhibitor by a structure-based virtual screening analysis. With the aim of identifying more potent and selective MAGL inhibitors, chemical modifications were introduced to the original compound to improve both potency and selectivity.[2] The structural optimization led to the obtainment of nanomolar inhibitors (Figure 1), which are selective over other hydrolases and cannabinoid receptors. These new inhibitors exert an appreciable antiproliferative activity in cancer cells and are able to inhibit MAGL in in vivo assays. [1] Mulvihill MM, Nomura DK, Life Sci. 2013; 92(8-9):492-497. [2] Granchi C, Rizzolio F, Palazzolo S, Carmignani S, Macchia M, Saccomanni G, Manera C, Martinelli A, Minutolo F, Tuccinardi T, J Med Chem. 2016; 59(22):10299-10314

Reversible Monoacylglycerol Lipase Inhibitors: Discovery of a New Class of Benzylpiperidine Derivatives.

Monoacylglycerol lipase (MAGL) is the enzyme responsible for the metabolism of 2-arachidonoylglycerol in the brain and the hydrolysis of peripheral monoacylglycerols. Many studies demonstrated beneficial effects deriving from MAGL inhibition for neurodegenerative diseases, inflammatory pathologies, and cancer. MAGL expression is increased in invasive tumors, furnishing free fatty acids as pro-tumorigenic signals and for tumor cell growth. Here, a new class of benzylpiperidine-based MAGL inhibitors was synthesized, leading to the identification of 13, which showed potent reversible and selective MAGL inhibition. Associated with MAGL overexpression and the prognostic role in pancreatic cancer, derivative 13 showed antiproliferative activity and apoptosis induction, as well as the ability to reduce cell migration in primary pancreatic cancer cultures, and displayed a synergistic interaction with the chemotherapeutic drug gemcitabine. These results suggest that the class of benzylpiperidine-based MAGL inhibitors have potential as a new class of therapeutic agents and MAGL could play a role in pancreatic cancer

Design, synthesis, ADME and biological evaluation of benzylpiperidine and benzylpiperazine derivatives as novel reversible monoacylglycerol lipase (MAGL) inhibitors.

The degradation of the endocannabinoid 2-arachidonoylglycerol is mediated by the enzyme monoacylglycerol lipase (MAGL), thus generating arachidonic acid, the precursor of prostaglandins and other pro-inflammatory mediators. MAGL also contributes to the hydrolysis of monoacylglycerols into glycerol and fatty acids in peripheral body districts, which may act as pro-tumorigenic signals. For this reason, MAGL inhibitors have been considered as interesting therapeutic agents for their anti-nociceptive, anti-inflammatory, antioxidant and anti-cancer properties. So far, only a limited series of reversible MAGL inhibitors, which are devoid of side effects shown by irreversible inhibitors in animal models, have been reported. Here we optimized a class of benzylpiperidine and benzylpiperazine-based compounds for a reversible MAGL inhibition. The best MAGL inhibitors of this class, compounds 28 and 29, showed a very good inhibition potency, both on the isolated enzyme and in U937 cells, as confirmed by molecular modeling studies that predicted their binding mode into the MAGL active site. Both compounds are characterized by a high selectivity for MAGL versus other serine hydrolases including enzymes of the endocannabinoid system, as confirmed by ABPP experiments in mouse brain membranes. Moreover, very good properties concerning ADME parameters and low in vivo toxicity have been observed for both compounds

Synthesis and biological evaluation of benzoylpiperidine derivatives as MAGL inhibitors

Monoacylglycerol lipase (MAGL) is a cytosolic serine hydrolase that plays a major role in the degradation of 2-arachidonoylglycerol, an endocannabinoid neurotransmitter implicated in many physiological and pathological processes, such as pain, inflammation, neuroprotection and cancer. MAGL is upregulated in aggressive cancer cells and primary tumors, where it has a unique role of providing a lipolytic source of free fatty acids for the synthesis of oncogenic signalling lipids, which promote cancer aggressiveness. Recent studies have suggested the possible use of MAGL inhibitors as anti-inflammatory, anti-nociceptive and anti-cancer agents. However, the administration of irreversible MAGL inhibitors may determine an unwanted chronic MAGL inactivation, which causes physical dependence, impairs endocannabinoid-dependent synaptic plasticity and desensitises brain CB1 receptors. Therefore, the aim of my thesis is the synthesis of reversible MAGL inhibitors

Development of therapeutic and diagnostic agents targeting tumor lipid and sugar metabolism

Cancer cells are characterized by an uncontrolled and rapid proliferation due to defects in the regulatory system that controls cells’ growth and division. This unbridled proliferation of cancer cells requires a big amount of nutrients and energy that consequently causes changes and adaptations in their metabolic profile. Indeed, the metabolic reprogramming is necessary to satisfy the rapid growth of the tumor and to allow its survival in adverse conditions. Dysregulation in carbohydrate, aminoacid (especially glutamine) and lipid metabolism are the main characteristics of cancer cells alterations. Therefore, the aim of my PhD Thesis was the development of therapeutic and diagnostic agents able to interfere with tumor lipid and sugar metabolism. For what concerns the reprogrammed lipid metabolism, I focused on one key enzyme: monoacylglycerol lipase (MAGL), which is involved in cancer progression, invasiveness and aggressiveness. Especially, I aimed to design and synthesize small organic molecules able to reversibly inhibit MAGL with potential anti-cancer activity. Another aim of this Thesis was the development of the first PROteolysis Targeting Chimera (PROTAC) small molecules targeting MAGL (anti-MAGL PROTACs) able to induce enzyme ubiquitination followed by its degradation. Regarding altered glucose metabolism, the last goal of this this Thesis was to develop glycoconjugated metal complexes as diagnostic probes for the selective IR visualization of glycolytic cancer cells by exploiting the well-characterized metabolic switch of tumors called Warburg effect

An Update on Patents Covering Agents That Interfere with the Cancer Glycolytic Cascade

Many tumors exhibit altered metabolic characteristics relative to normal and healthy tissues. Their metabolic profile highlights a strong prevalence of glycolysis over oxidative phosphorylation, regardless their exposure to different oxygen levels (“Warburg effect”). This condition originates from a set of gene regulations, consisting in the overexpression of some enzymes or transporters involved in the glycolytic pathway. Therefore, these effectors may constitute appealing targets for the implementation of selective therapeutic interventions against cancer. Recently, significant progress has been made in the discovery of molecules acting at various levels of the glycolytic pathway of tumor cells. So far, some of the most widely explored targets of the glycolytic cascade are represented by glucose transporters, hexokinase, 6‐phosphofructokinase, enolase, pyruvate kinase, lactate dehydrogenase, and monocarboxylate transporters. The purpose of this mini‐review is to provide an update about some of the most recently patented bioactive molecules, that are able to interfere with cancer glycolysis, as well as about their use in specific combination therapies

Historical perspective of tumor glycolysis: a century with Otto Warburg

Tumors have long been known to rewire their metabolism to endorse their proliferation, growth, survival, and invasiveness. One of the common characteristics of these alterations is the enhanced glucose uptake and its subsequent transformation into lactic acid by means of glycolysis, regardless the availability of oxygen or the mitochondria effectiveness. This phenomenon is called the “Warburg effect”, which has turned into a century of age now, since its first disclosure by German physiologist Otto Heinrich Warburg. Since then, this peculiar metabolic switch in tumors has been addressed by extensive studies covering several areas of research. In this historical perspective, we aim at illustrating the evolution of these studies over time and their implication in various fields of science

Glycoconjugated metal complexes as cancer diagnostic and therapeutic agents

The possibility of selectively delivering metal complexes to a defined cohort of cells on the basis of their metabolic features is a highly challenging goal, which may be extremely useful for a series of purposes, including diagnosis and therapy of pathological states, such as cancer. Tumor cells display augmented requests for carbohydrates and, in particular, for glucose in order to sustain their high proliferation rate, which causes an increased glycolytic process (Warburg effect). Since several metal complexes display diagnostic and/or therapeutic properties, their conjugation to carbohydrate portions often induce their preferential accumulation in cancer cells, similarly to what is observed with FDG. In this review we have considered the latest developments of glycoconjugates containing metal complexes in their structures. These compounds are classified as diagnostic or therapeutic agents and are further systematically discussed on the basis of the metal atom they contain. Several diagnostic techniques are possible with these probes, since, depending on the metal species included in their structures, they may be employed in nuclear medicine (PET, SPECT), magnetic resonance imaging, luminescence and phosphorescence. At the same time, the lack of selective cytotoxicity displayed by several metal-based chemotherapeutic agents, may also be solved by the conjugation of these agents to carbohydrate portions. Overall, data so far available reveal the great potential of this chemical class in the early detection and in the cure of severe neoplastic diseases, which still needs to be fully explored in the clinic