The Benzoylpiperidine Fragment as a Privileged Structure in Medicinal Chemistry: A Comprehensive Review.

The phenyl(piperidin-4-yl)methanone fragment (here referred to as the benzoylpiperidine fragment) is a privileged structure in the development of new drugs considering its presence in many bioactive small molecules with both therapeutic (such as anti-cancer, anti-psychotic, anti-thrombotic, anti-arrhythmic, anti-tubercular, anti-parasitic, anti-diabetic, and neuroprotective agents) and diagnostic properties. The benzoylpiperidine fragment is metabolically stable, and it is also considered a potential bioisostere of the piperazine ring, thus making it a feasible and reliable chemical frame to be exploited in drug design. Herein, we discuss the main therapeutic and diagnostic agents presenting the benzoylpiperidine motif in their structure, covering articles reported in the literature since 2000. A specific section is focused on the synthetic strategies adopted to obtain this versatile chemical portion.

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.

Machine Learning-Based Virtual Screening for the Identification of Cdk5 Inhibitors.

Cyclin-dependent kinase 5 (Cdk5) is an atypical proline-directed serine/threonine protein kinase well-characterized for its role in the central nervous system rather than in the cell cycle. Indeed, its dysregulation has been strongly implicated in the progression of synaptic dysfunction and neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD), and also in the development and progression of a variety of cancers. For this reason, Cdk5 is considered as a promising target for drug design, and the discovery of novel small-molecule Cdk5 inhibitors is of great interest in the medicinal chemistry field. In this context, we employed a machine learning-based virtual screening protocol with subsequent molecular docking, molecular dynamics simulations and binding free energy evaluations. Our virtual screening studies resulted in the identification of two novel Cdk5 inhibitors, highlighting an experimental hit rate of 50% and thus validating the reliability of the in silico workflow. Both identified ligands, compounds CPD1 and CPD4, showed a promising enzyme inhibitory activity and CPD1 also demonstrated a remarkable antiproliferative activity in ovarian and colon cancer cells. These ligands represent a valuable starting point for structure-based hit-optimization studies aimed at identifying new potent Cdk5 inhibitors.

Sirtuin 1-Activating Compounds: Discovery of a Class of Thiazole-Based Derivatives.

Sirtuin 1 (SIRT1) is a NAD+-dependent deacetylase implicated in various biological and pathological processes, including cancer, diabetes, and cardiovascular diseases. In recent years, SIRT1-activating compounds have been demonstrated to exert cardioprotective effects. Therefore, this enzyme has become a feasible target to treat cardiovascular diseases, and many SIRT1 activators, of a natural or synthetic origin, have been identified. In the present work, we developed thiazole-based SIRT1 activators, which showed remarkably higher SIRT1 activation potencies compared with those of the reference compound resveratrol when tested in enzymatic assays. Thiazole 8, a representative compound of this series, was also subjected to further pharmacological investigations, where it was proven to reduce myocardial damage induced by an in vivo occlusion/reperfusion event, thus confirming its cardioprotective properties. In addition, the cardioprotective effect of compound 8 was significantly higher than that of resveratrol. Molecular modeling studies suggest the binding mode of these derivatives within SIRT1 in the presence of the p53-AMC peptide. These promising results could pave the way to further expand and optimize this chemical class of new and potent SIRT1 activators as potential cardioprotective agents.

The dichotomous role of the glycolytic metabolism pathway in cancer metastasis: Interplay with the complex tumor microenvironment and novel therapeutic strategies.

Cancer metastasis to distant organs is initiated by tumor cells that disseminate from primary heterogeneous tumors. The subsequent growth and survival of tumor metastases depend on different metabolic changes, which constitute one of the enigmatic properties of tumor cells. Aerobic glycolysis, 'the Warburg effect', contributes to tumor energy supply, by oxidizing glucose in a faster manner compared to oxidative phosphorylation, leading to an increased lactate production by lactate dehydrogenase A (LDH-A), which in turn affects the immune response. Surrounding stromal cells contribute to feedback mechanisms further prompting the acquisition of pro-invasive metabolic features. Hence, therapeutic strategies targeting the glycolytic pathway are intensively investigated, with a special interest on their anti-metastatic properties. Various small molecules, such as LDH-A inhibitors, have shown pre-clinical activity against different cancer types, and blocking LDH-A could also help in designing future complimentary therapies. Modulation of specific targets in cells with an altered glycolytic metabolism should indeed result in a milder and distinct toxicity profile, compared to conventional cytotoxic therapy, while a combination treatment with vitamin C leading to increasing reactive oxygen species levels, should further inhibit cancer cell survival and invasion. In this review we describe the impact of metabolic reprogramming in cancer metastasis, the contribution of lactate in this aberrant process and its effect on oncogenic processes. Furthermore, we discuss experimental compounds that target glycolytic metabolism, such as LDH-A inhibitors, and their potential to improve current and experimental therapeutics against metastatic tumors.

New Phenylethanoid Glycosides from Cistanche phelypaea and Their Activity as Inhibitors of Monoacylglycerol Lipase (MAGL).

Four new phenylethanoid glycosides (1: -4: ), 1-ß-p-hydroxyphenyl-ethyl-2-O-acetyl-3,6-di-α-l-rhamnopyranosyl-ß-d-glucopyranoside (1: ), 1-ß-p-hydroxyphenyl-ethyl-3,6-O-di-α-l-rhamnopyranosyl-ß-d-glucopyranoside (2: ), 1-ß-p-hydroxyphenyl-ethyl-2-O-acetyl-3,6-di-α-l-rhamnopyranosyl-4-p-coumaroyl-ß-d-glucopyranoside (3: ), and 1-ß-p-hydroxyphenyl-ethyl-3,6-di-α-l-rhamnopyranosyl-4-p-coumaroyl-ß-d-glucopyranoside (4: ), together with three known compounds, were isolated from the n-butanol extract of Cistanche phelypaea aerial parts. The structural characterization of all compounds was performed by spectroscopic analyses, including 1D and 2D NMR, and HRESIMS experiments. The isolated compounds were assayed for their inhibitory activity on two enzymes involved in the peculiar glycolytic or lipidic metabolism of cancer cells, human lactate dehydrogenase (LDH), and monoacylglycerol lipase (MAGL), respectively. All the compounds showed negligible activity on LDH, whereas some of them displayed a certain inhibition activity on MAGL. In particular, compound 1: was the most active on MAGL, showing an IC50 value of 88.0 µM, and modeling studies rationalized the supposed binding mode of 1: in the MAGL active site.

Sirtuin 1-activating derivatives belonging to the anilinopyridine class displaying in vivo cardioprotective activities.

Sirtuin 1 (SIRT1) is an enzyme that relies on NAD+ cofactor and functions as a deacetylase. It has been associated with various biological and pathological processes, including cancer, diabetes, and cardiovascular diseases. Recent studies have shown that compounds that activate SIRT1 exhibit protective effects on the heart. Consequently, targeting SIRT1 has emerged as a viable approach to treat cardiovascular diseases, leading to the identification of several SIRT1 activators derived from natural or synthetic sources. In this study, we developed anilinopyridine-based SIRT1 activators that displayed significantly greater potency in activating SIRT1 compared to the reference compound resveratrol, as demonstrated in enzymatic assays. In particular, compounds 8 and 10, representative 6-aryl-2-anilinopyridine derivatives from this series, were further investigated pharmacologically and found to reduce myocardial damage caused by occlusion and subsequent reperfusion in vivo, confirming their cardioprotective properties. Notably, the cardioprotective effects of 8 and 10 were significantly superior to that of resveratrol. Significantly, compound 10 emerged as the most potent among the tested compounds, demonstrating the ability to substantially decrease the size of the ischemic area at a dosage one hundred times lower (0.1 mg kg-1) than that of resveratrol/compound 1. These promising findings open avenues for expanding and optimizing this chemical class of potent SIRT1 activators as potential agents for cardioprotection.

New Synthetic Analogues of Natural Polyphenols as Sirtuin 1-Activating Compounds.

NAD+-dependent deacetylase SIRT1 regulates many different biological processes, thus being involved in pathogenic conditions such as metabolic diseases, neurogenerative disorders and cancer. Notably, experimental evidence underlined that the activation of SIRT1 had promising cardioprotective effects. Consequently, many efforts have been so far devoted to finding new SIRT1 activators, both derived from natural sources or prepared by synthetic procedures. Herein, we discovered new SIRT1-activating derivatives, characterized by phenolic rings spaced by sulfur, nitrogen or oxygen-based central linkers. The newly synthesized derivatives were analyzed in enzymatic assays to determine their ability to activate SIRT1, as compared with that of resveratrol. Among the tested molecules, bisarylaniline compound 10 proved to be the most efficient SIRT1 activator. An evaluation of the effects caused by focused structural variations revealed that its para-hydroxy-substituted diphenyl moiety of 10 was the fundamental structural requirement for achieving good SIRT1 activation. Compound 10 was further investigated in ex vivo studies in isolated and perfused rat hearts submitted to ischemia/reperfusion (I/R), where it showed significant protection of the myocardium against I/R injury. Molecular modeling studies suggest the binding mode of 10 within SIRT1 in the presence of the p53-AMC peptide. Our findings reveal that this chemical scaffold may be used as the starting point to develop a new class of more potent SIRT1 activators as cardioprotective agents.

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.

α/ß-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/ß-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.

An updated patent review of monoacylglycerol lipase (MAGL) inhibitors (2018-present).

INTRODUCTION: Monoacylglycerol lipase (MAGL) belongs to the endocannabinoid system and is responsible for the inactivation of endocannabinoid 2-arachidonoylglycerol. Importantly, it was found that MAGL degradation of lipids in cancer cells enhances the availability of free fatty acids for new cellular membrane formation and pro-oncogenic lipid modulators. The multifaceted role of MAGL has greatly stimulated the search for MAGL inhibitors, which could be effective to treat diseases, such as inflammation, neurodegeneration and cancer. AREAS COVERED: This review covers patents published since 2018 up to now, concerning new MAGL inhibitors and their potential therapeutic applications. EXPERT OPINION: In the years 2018-2020, several well-known chemical scaffolds of MAGL inhibitors have been further optimized and developed and some new chemical classes have also been identified as MAGL inhibitors. Moreover, an increasing number of scientific publications covering MAGL inhibitors is focused on MAGL-specific positron emission tomography (PET) ligands. The numerous efforts of pharmaceutical companies and academic research groups finalized to find new potent MAGL inhibitors confirm that this research area is rapidly growing. Nevertheless, most of the patented compounds still belong to the large group of irreversible MAGL inhibitors, highlighting that the development of reversible MAGL inhibitors is still an unmet pharmaceutical need.

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 fluorodeoxyglucose (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.

Monoacylglycerol lipase (MAGL) inhibitors based on a diphenylsulfide-benzoylpiperidine scaffold.

Monoacylglycerol lipase (MAGL) is an enzyme belonging to the endocannabinoid system that mainly metabolizes the endocannabinoid 2-arachidonoylglycerol (2-AG). Numerous studies have shown the involvement of this enzyme in various pathological conditions such as pain, cancer progression, Parkinson's and Alzheimer's disease, thus encouraging the development of new MAGL modulators. In this context, we developed new diphenylsulfide-benzoylpiperidine derivatives characterized by a high enzymatic MAGL inhibition activity in the low nanomolar range, a reversible mechanism of action and selectivity. The three most active compounds (15-17) induced an appreciable inhibition of cell viability in a panel of nine cancer cell lines, with IC50 values ranging between 0.32 and 10 µM, thus highlighting their potential as novel anticancer agents.

Design, synthesis and biological evaluation of second-generation benzoylpiperidine derivatives as reversible monoacylglycerol lipase (MAGL) inhibitors.

An interesting enzyme of the endocannabinoid system is monoacylglycerol lipase (MAGL). This enzyme, which metabolizes the endocannabinoid 2-arachidonoylglycerol (2-AG), has attracted great interest due to its involvement in several physiological and pathological processes, such as cancer progression. Experimental evidences highlighted some drawbacks associated with the use of irreversible MAGL inhibitors in vivo, therefore the research field concerning reversible inhibitors is rapidly growing. In the present manuscript, the class of benzoylpiperidine-based MAGL inhibitors was further expanded and optimized. Enzymatic assays identified some compounds in the low nanomolar range and steered molecular dynamics simulations predicted the dissociation itinerary of one of the best compounds from the enzyme, confirming the observed structure-activity relationship. Biological evaluation, including assays in intact U937 cells and competitive activity-based protein profiling experiments in mouse brain membranes, confirmed the selectivity of the selected compounds for MAGL versus other components of the endocannabinoid system. An antiproliferative ability in a panel of cancer cell lines highlighted their potential as potential anticancer agents. Future studies on the potential use of these compounds in the clinical setting are also supported by the inhibition of cell growth observed both in cancer organoids derived from high grade serous ovarian cancer patients and in pancreatic ductal adenocarcinoma primary cells, which showed genetic and histological features very similar to the primary tumors.

Optimization of a Benzoylpiperidine Class Identifies a Highly Potent and Selective Reversible Monoacylglycerol Lipase (MAGL) Inhibitor.

Monoacylglycerol lipase (MAGL) is the enzyme degrading the endocannabinoid 2-arachidonoylglycerol, and it is involved in several physiological and pathological processes. The therapeutic potential of MAGL is linked to several diseases, including cancer. The development of MAGL inhibitors has been greatly limited by the side effects associated with the prolonged MAGL inactivation. Importantly, it could be preferable to use reversible MAGL inhibitors in vivo, but nowadays only few reversible compounds have been developed. In the present study, structural optimization of a previously developed class of MAGL inhibitors led to the identification of compound 23, which proved to be a very potent reversible MAGL inhibitor (IC50 = 80 nM), selective for MAGL over the other main components of the endocannabinoid system, endowed of a promising antiproliferative activity in a series of cancer cell lines and able to block MAGL both in cell-based as well as in vivo assays.

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 of their exposure to different oxygen levels (the Warburg effect). This condition originates from a set of gene regulations, consisting of 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 that act 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 minireview is to provide an update on some of the most recently patented bioactive molecules that are able to interfere with cancer glycolysis, and on their use in specific combination therapies.

Discovery of long-chain salicylketoxime derivatives as monoacylglycerol lipase (MAGL) inhibitors.

Monoacylglycerol lipase (MAGL) is the enzyme hydrolyzing the endocannabinoid 2-arachidonoylglycerol (2-AG) to free arachidonic acid and glycerol. Therefore, MAGL is implicated in many physiological processes involving the regulation of the endocannabinoid system and eicosanoid network. MAGL inhibition represents a potential therapeutic target for many diseases, including cancer. Nowadays, most MAGL inhibitors inhibit this enzyme by an irreversible mechanism of action, potentially leading to unwanted side effects from chronic treatment. Herein, we report the discovery of long-chain salicylketoxime derivatives as potent and reversible MAGL inhibitors. The compounds herein described are characterized by a good target selectivity for MAGL and by antiproliferative activities against a series of cancer cell lines. Finally, modeling studies suggest a reasonable hypothetical binding mode for this class of compounds.