Synthesis of novel beta-lactone inhibitors of fatty acid synthase

Fatty acid synthase (FAS) is necessary for growth and survival of tumor cells and is a promising drug target for oncology. Here, we report on the syntheses and activity of novel inhibitors of the thioesterase domain of FAS. Using the structure of orlistat as a starting point, which contains a beta-lactone as the central pharmacophore, 28 novel congeners were synthesized and examined. Structural features such as the length of the alpha- and beta-alkyl chains, their chemical composition, and amino ester substitutions were altered and the resulting compounds explored for inhibitory activity toward the thioesterase domain of FAS. Nineteen congeners show improved potency for FAS in biochemical assays relative to orlistat. Three of that subset, including the natural product valilactone, also display an increased potency in inducing tumor cell death and improved solubility compared to orlistat. These findings support the idea that an orlistat congener can be optimized for use in a preclinical drug design and for clinical drug development.     

Recent advances in targeting the fatty acid biosynthetic pathway using fatty acid synthase inhibitors

ABSTRACT

Introduction: Elevated lipogenesis has been associated with a variety of diseases including obesity, cancer and nonalcoholic fatty liver disease (NAFLD). Fatty acid synthase (FASN) plays a pivotal role in de novo lipogenesis, making this multi-catalytic protein an attractive target for therapeutic intervention. Recently, the first FASN inhibitor successfully advanced through the drug development process and entered clinical evaluation in oncology.

Areas covered: This review discusses the biological roles of FASN in three prominent disease areas: cancer, obesity-related disorders and NAFLD. Recent advances in drug discovery strategies and design of newer FASN inhibitors are also highlighted.

Expert opinion: Despite the abundance of evidence linking the lipogenic pathway to cancer, progression of FASN-targeted molecules has been rather slow and challenging and no compounds have moved past the preclinical phase. The landscape has recently changed with the recent advancement of the first FASN inhibitor into clinical evaluation for solid tumors. Needless to say, the successful translation into the clinical setting will open opportunities for expanding the therapeutic utility of FASN inhibitors not just in oncology but in other diseases associated with elevated lipogenesis such as obesity, type 2 diabetes, and NAFLD.     

Angiogenesis inhibitors. New anticancer strategy

Neoangiogenesis has been proved to be crucial in neoplasmatic tumor growth and metastases. Over the last few years, the factors that have both a positive (angiogenic) and negative (antiangiogenic) influence on tumor growth have been identified. The potential use of natural and synthetic factors that suppress vasculature formation as anticancer drugs is currently under intense investigation. Recently, several antiangiogenic compounds, including TNP-470 or matrix metalloproteinase inhibitors, have entered clinical trials. This review will describe the main groups of angiogenesis inhibitors, their mechanisms of action and some data from clinical studies.     

Melatonin synthetic analogs as nitric oxide synthase inhibitors

Nitric oxide (NO), which is produced by oxidation of L-arginine to L-citrulline in a process catalyzed by different isoforms of nitric oxide synthase (NOS), exhibits diverse roles in several physiological processes, including neurotransmission, blood pressure regulation and immunological defense mechanisms. On the other hand, an overproduction of NO is related with several disorders as Alzheimer's disease, Huntington's disease and the amyotrophic lateral sclerosis. Taking melatonin as a model, our research group has designed and synthesized several families of compounds that act as NOS inhibitors, and their effects on the excitability of N-methyl-D-aspartate (NMDA)-dependent neurons in rat striatum, and on the activity on both nNOS and iNOS were evaluated. Structural comparison between the three most representative families of compounds (kynurenines, kynurenamines and 4,5-dihydro-1H-pyrazole derivatives) allows the establishment of structure-activity relationships for the inhibition of nNOS, and a pharmacophore model that fulfills all of the observed SARs were developed. This model could serve as a template for the design of other potential nNOS inhibitors. The last family of compounds, pyrrole derivatives, shows moderate in vitro NOS inhibition, but some of these compounds show good iNOS/nNOS selectivity. Two of these compounds, 5-(2-aminophenyl)-1H-pyrrole-2-carboxylic acid methylamide and cyclopentylamide, have been tested as regulators of the in vivo nNOS and iNOS activity. Both compounds prevented the increment of the inducible NOS activity in both cytosol (iNOS) and mitochondria (i-mtNOS) observed in a MPTP model of Parkinson's disease.     

Natural fatty acid synthase inhibitors as potent therapeutic agents for cancers: A review

Context Fatty acid synthase (FAS) is the only mammalian enzyme to catalyse the synthesis of fatty acid. The expression level of FAS is related to cancer progression, aggressiveness and metastasis. In recent years, research on natural FAS inhibitors with significant bioactivities and low side effects has increasingly become a new trend. Herein, we present recent research progress on natural fatty acid synthase inhibitors as potent therapeutic agents.

Objective This paper is a mini overview of the typical natural FAS inhibitors and their possible mechanism of action in the past 10 years (2004–2014).

Method The information was collected and compiled through major databases including Web of Science, PubMed, and CNKI.

Results Many natural products induce cancer cells apoptosis by inhibiting FAS expression, with fewer side effects than synthetic inhibitors.

Conclusion Natural FAS inhibitors are widely distributed in plants (especially in herbs and foods). Some natural products (mainly phenolics) possessing potent biological activities and stable structures are available as lead compounds to synthesise promising FAS inhibitors.     

Inhibition of fatty acid synthase by polyphenols

Recently, animal fatty acid synthase (FAS) is reported as a potential therapeutic target for obesity and cancer. Considerable interest has been developed in identifying novel inhibitors of the enzyme. It is found that tea polyphenols inhibit FAS in both reversible and irreversible manners. Epigallocatechin gallate (EGCG) and epicatechin gallate (ECG) inhibit FAS with IC(50) values of 52 microM and 42 microM mainly by reacting on the beta-ketoacyl reductase (KR) domain of FAS. The inhibitory ability of catechin gallate (CG) is 15 and 12 folds higher than that of EGCG and ECG. Its major reacting site on FAS is not KR. All of these irreversibly inactivate FAS on the KR domain with similar rates. Mulliken population analysis suggests that the positive charge is distributed on the carbon atom of galloyl ester, and this carbon becomes more susceptible for a nucleophilic attack. 12 flavonoids inhibit FAS with IC(50) values ranging from 2 to 112 microM. SAR analysis shows that the flavonoids containing two hydroxyl groups in B ring and 5, 7-hydroxyl groups in A ring with C-2, 3 double bond are the most potent inhibitors. The inhibition kinetics shows that they inhibit FAS competitively with acetyl CoA and most likely react mainly on acyl transferase domain. Further studies show that C ring of flavonoids is not necessary for the inhibition. Resveratrol, phlorizin and NDGA contain two phenyl rings connected by 2 to 4 atom chains instead of C ring. Their IC(50) values range from 5 microM to 40 microM. From these results, a common model for polyphenol inhibitor of FAS is conceived.     

New synthetic thiocolchicine derivatives as lowtoxic anticancer agents

New thiocolchicine derivatives (1-8) were designed as less toxic anticancer agents possessing the power full anticancer activity of colchicine. The synthesis and biological evaluation of these compounds were described. As a preliminary result of biological in vitro investigation, compounds 1, 6, and 7 showed lower toxicities than that of colchicine in combination with potent anticancer activities.     

脂肪酸合成酶抑制剂的研究进展

脂肪酸合成酶(FAS)是催化内源性长链脂肪酸合成的关键酶。目前的研究表明,源于FAS在肿瘤细胞和脂肪细胞中的高表达特性,FAS已成为一个有效控制肿瘤和肥胖等相关疾病的新靶标。目前对FAS抑制剂的研究越来越深入,但发现的FAS抑制剂的种类还不是很多,本文对目前FAS抑制剂的研究进展进行了综述。     

Antisense technologies targeting fatty acid synthetic enzymes

Fatty acid synthesis is a coordinated process involving multiple enzymes. Overexpression of some of these enzymes plays important roles in tumor growth and development. Therefore, these enzymes are attractive targets for cancer therapies. Antisense agents provide highly specific inhibition of the expression of target genes and thus have served as powerful tools for gene functional studies and potential therapeutic agents for cancers. This article reviews different types of antisense agents and their applications in the modulation of fatty acid synthesis. Patents of antisense agents targeting fatty acid synthetic enzymes are introduced. In addition, miR-122 has been shown to regulate the expression of fatty acid synthetic enzymes, and thus antisense agent patents that inhibit miR-122 expression are also discussed.     

Aurora激酶抑制剂的研究进展

在有丝分裂的过程中,Aurora激酶参与纺锤体形成,中心体成熟,染色体分化和胞质分裂.Aurora激酶的过度表达或分化易导致有丝分裂异常,与形成肿瘤的基因组不稳定性密切相关.以Aurora激酶为靶点设计、合成的药物已成为近年来肿瘤药物治疗的研究热点.本文综述了已经进入临床研究的Aurora小分子抑制剂在临床前、临床的研究进展.     

Anti-anginal effects of partial fatty acid oxidation inhibitors

Angina pectoris can result in an imbalance between oxygen supply and demand of the heart muscle, resulting in a compromised energy supply to the heart muscle. Currently, the primary approach to treating angina is aimed either at decreasing muscle oxygen demand, or increasing oxygen supply to the muscle. An alternative approach is to increase cardiac efficiency by increasing the amount of cardiac work at a given level of oxygen consumed. This can be achieved by inhibiting myocardial fatty acid oxidation, which leads to an increase in glucose oxidation. Consequently, lactate and proton production decrease, and as a result cardiac efficiency is improved. The approach of partial fatty acid oxidation (pFOX) inhibition is beneficial in the treatment of angina pectoris, both as a monotherapy and when used in combination with conventional therapy. pFOX inhibitors not only lessen the severity and symptoms of an angina attack, they also decrease the incidence of angina attacks in patients with coronary artery disease. The approach of optimizing energy substrate preference in the heart is a new and effective approach to treating angina pectoris.     

Anti-cancer drugs targeting fatty acid synthase (FAS)

Fatty acid synthase (FAS) is a key enzyme of the fatty acid biosynthetic pathway which catalyzes de novo lipid synthesis. FAS expression in normal adult tissues is generally very low or undetectable as majority of fatty acids obtained are from dietary sources, whereas it is significantly upregulated in cancer cells despite adequate nutritional lipid supply. Activation of FAS provides rapidly proliferating tumor cells sufficient amount of lipids for membrane biogenesis and confers growth and survival advantage possibly acting as a metabolic oncogene. Importantly, inhibition of FAS in cancer cells using the pharmacological FAS inhibitors results in tumor cell death by apoptosis whereas normal cells are resistant. Due to this differential expression of FAS, the inhibitors of this enzyme are selectively toxic to tumor cells and therefore FAS is considered an attractive therapeutic target for cancer. Several FAS inhibitors are already patented and commercially available; however, the potential toxicity of these FAS inhibitors remains to be tested in clinical trials. In this review, we discuss some of the potent FAS inhibitors along with their patent information, the mechanism of anti-cancer effects and the development of more specific and potent FAS inhibitors with lower side effects that are expected to emerge as anti-cancer treatment in the near future.     

Fatty acid synthase inhibitors: new directions for oncology

Fatty acid synthase (FASN) is the enzyme that catalyzes the de novo synthesis of fatty acids in cells. Because of the strong expression in many cancers, FASN is an attractive and tractable target for therapeutic intervention. The discovery and development of pharmacologic agents that block FASN activity highlight the promise of these anticancer compounds. FASN inhibitors have also proven to be invaluable in developing a better understanding of the contribution of FASN and fatty acid synthesis to tumor cells. Recent advances in the development of crystal structures of FASN have provided promise towards the development of novel FASN inhibitors. This review outlines the preclinical development of FASN inhibitors, their antitumor effects and the strategies underway to develop novel inhibitors.     

Fatty acid synthase inhibitors: new directions for oncology

Fatty acid synthase (FASN) is the enzyme that catalyzes the de novo synthesis of fatty acids in cells. Because of the strong expression in many cancers, FASN is an attractive and tractable target for therapeutic intervention. The discovery and development of pharmacologic agents that block FASN activity highlight the promise of these anticancer compounds. FASN inhibitors have also proven to be invaluable in developing a better understanding of the contribution of FASN and fatty acid synthesis to tumor cells. Recent advances in the development of crystal structures of FASN have provided promise towards the development of novel FASN inhibitors. This review outlines the preclinical development of FASN inhibitors, their antitumor effects and the strategies underway to develop novel inhibitors.     

Optimization of alpha-ketooxazole inhibitors of fatty acid amide hydrolase

A series of alpha-ketooxazoles containing conformational constraints in the flexible C2 acyl side chain of 2 (OL-135) and representative oxazole C5 substituents were prepared and examined as inhibitors of fatty acid amide hydrolase (FAAH). Exceptionally potent and selective FAAH inhibitors emerged from the series (e.g., 6, Ki = 200 and 260 pM for rat and rhFAAH). With simple and small C5 oxazole substituents, each series bearing a biphenylethyl, phenoxyphenethyl, or (phenoxymethyl)phenethyl C2 side chain was found to follow a well-defined linear relationship between -log Ki and Hammett sigmap of a magnitude (rho = 2.7-3.0) that indicates that the substituent electronic effect dominates, confirming its fundamental importance to the series and further establishing its predictive value. Just as significantly, the nature of the C5 oxazole substituent substantially impacts the selectivity of the inhibitors whereas the effect of the C2 acyl chain was more subtle but still significant even in the small series examined. Combination of these independent features, which display generalized trends across a range of inhibitor series, simultaneously improves FAAH potency and selectivity and can provide exquisitely selective and potent FAAH inhibitors.     

Partial fatty acid oxidation inhibitors for stable angina

Partial fatty acid oxidation inhibition is effective therapy for the treatment of chronic stable angina and is particularly useful in patients with persistent angina despite optimal traditional therapy. The heart derives most of its energy from the oxidation of fatty acids. Fatty acid oxidation strongly inhibits pyruvate oxidation in the mitochondria and the uptake and oxidation of glucose. The primary effect of demand-induced ischaemia is impaired aerobic formation of ATP in the mitochondria, resulting in activation of non-oxidative glycolysis and lactate production, despite a relatively high residual myocardial oxygen consumption and continued reliance on fatty acid oxidation. Traditional drugs for chronic stable angina act by reducing the use of ATP through suppression of heart rate and blood pressure or by increasing aerobic formation of ATP by increasing coronary blood flow. Partial inhibition of fatty acid oxidation increases glucose and pyruvate oxidation and decreases lactate production, resulting in higher pH and improved contractile function during ischaemia. These agents do not affect heart rate, coronary blood flow or arterial blood pressure. Clinical trials with ranolazine or trimetazidine, either alone or in combination with a Ca2+ channel antagonist or a beta-adrenergic receptor antagonist, have demonstrated reduced symptoms of exercise-induced angina.     

Pharmacological evaluation of C-3 modified Betulinic acid derivatives with potent anticancer activity

Summary In vitro and in vivo pharmacological screening of Betulinic acid (BA) and five dihydro-BA derivatives modified at C-3 position [4-nitrobenzyl-oximino (1), 2-4-difluoro-benzoyloxy (2), 2-4-difluoro-benzylidene-amino (3), benzoyl-hydrazono (4), and 4-fluorophenyl-hydrazono (5)], having potent in vitro anti-cancer activity was carried out using ADME, animal PK and tumor studies. We found that BA and the derivatives had poor aqueous solubility (<0.1 μg/ml), low to moderate permeability (log Pe < −5.0) and high plasma protein binding (>70%). Although BA and 5 were metabolized by human liver microsomes, derivatives 1, 2, 3 and 4 possessed good in vitro metabolic stability. Except 3 which inhibited CYP1A2 isoform by more than 50% none of the other compounds inhibited key cytochrome P450 enzyme isoforms (CYP1A2, CYP2C9, CYP2D6 and CYP3A4) at 10 μM. Based on in vitro results one derivative 1 was tested in rodent PK and tumor studies. We found that 1 exhibited favorable pharmacokinetic characteristics of a systemically administered drug and showed better in vivo anti-tumor efficacy as compared to BA in a human colon cancer xenograft model. Our results show that BA derivatives are potential anti-cancer compounds which need to be explored in detail.