Privileged Structures Research Articles

Development of selective HDAC6 inhibitors with in vitro and in vivo anti-multiple myeloma activity

Histone deacetylase 6 (HDAC6) is a promising therapeutic target for the treatment of cancers, neurodegenerative diseases and autoimmune disorders. Herein a novel series of pyrrolo[2,3-d]pyrimidine-based HDAC inhibitors were designed, synthesized and biologically evaluated, among which compounds 7a, 12a1, and 16a1 exhibited potent inhibitory activities and selectivities against HDAC6. Notably, compared with the well-known HDAC6 inhibitor Tubastatin A, our pyrrolo[2,3-d]pyrimidine-based HDAC6 inhibitors showed superior in vitro antiproliferative activity against human multiple myeloma cell lines RPMI 8226, U266 and MM.1S, while maintaining the low cytotoxicity against human breast cancer cell line MDA-MB-231 and two normal cell lines. The HDAC6 selective inhibition of one representative compound 12a1 in RPMI 8226 cells was confirmed by western blot analysis. Although pyrrolo[2,3-d]pyrimidine is a privileged structure in many kinase inhibitors, compound 12a1 showed negligible inhibition against several kinases including JAK family members and Akt1, indicating its acceptable off-target profile. Besides, compound 12a1 exhibited desirable metabolic stability in mouse liver microsome. The in vivo anti-multiple myeloma potency of 12a1, alone and in combination with bortezomib, was demonstrated in a RPMI 8226 xenograft model.

Thiophene-Based Compounds with Potential Anti-Inflammatory Activity.

Rheumatoid arthritis, arthrosis and gout, among other chronic inflammatory diseases are public health problems and represent major therapeutic challenges. Non-steroidal anti-inflammatory drugs (NSAIDs) are the most prescribed clinical treatments, despite their severe side effects and their exclusive action in improving symptoms, without effectively promoting the cure. However, recent advances in the fields of pharmacology, medicinal chemistry, and chemoinformatics have provided valuable information and opportunities for development of new anti-inflammatory drug candidates. For drug design and discovery, thiophene derivatives are privileged structures. Thiophene-based compounds, like the commercial drugs Tinoridine and Tiaprofenic acid, are known for their anti-inflammatory properties. The present review provides an update on the role of thiophene-based derivatives in inflammation. Studies on mechanisms of action, interactions with receptors (especially against cyclooxygenase (COX) and lipoxygenase (LOX)), and structure-activity relationships are also presented and discussed. The results demonstrate the importance of thiophene-based compounds as privileged structures for the design and discovery of novel anti-inflammatory agents. The studies reveal important structural characteristics. The presence of carboxylic acids, esters, amines, and amides, as well as methyl and methoxy groups, has been frequently described, and highlights the importance of these groups for anti-inflammatory activity and biological target recognition, especially for inhibition of COX and LOX enzymes.

Organocatalyzed Oxa-Diels–Alder Reactions: Recent Progress

AbstractThe oxa-Diels–Alder reaction is a straightforward, atom-economical process for the construction of six-membered oxacycles, which are privileged structures due to their very common occurrence in several pharmaceuticals and natural products. As with many other asymmetric transformations, organocatalysis provides an elegant pathway to their synthesis via [4+2] annulation under mild reaction conditions. The oxa-Diels–Alder reaction utilizes either an α,β-unsaturated carbonyl as an oxa-diene with a suitable dienophile or a simple carbonyl as a dienophile with other dienes. A range of organocatalysts has been explored in the past decade to execute this strategy. The catalysts induce stereoselectivities via two basic reactivities: (1) The formation of chiral intermediates, or (2) selectively activating suitable reactants via a transition state. The present short review compiles organocatalyzed asymmetric oxa-Diels–Alder reactions published over the last ten years, along with detailed discussions on mechanistic approaches.1 Introduction2 Catalysis through Covalent Activation2.1 N-Heterocyclic Carbenes2.2 Amines2.3 Isothiourea Catalysis2.4 Phosphines3 Catalysis through Non-Covalent Activation3.1 Bifunctional Amines3.2 Brønsted Acids3.3 Guanidines4 Multicatalysis through Both Covalent and Non-Covalent Activation5 Conclusion

Hollow structures as drug carriers: Recognition, response, and release.

Hollow structures have demonstrated great potential in drug delivery owing to their privileged structure, such as high surface-to-volume ratio, low density, large cavities, and hierarchical pores. In this review, we provide a comprehensive overview of hollow structured materials applied in targeting recognition, smart response, and drug release, and we have addressed the possible chemical factors and reactions in these three processes. The advantages of hollow nanostructures are summarized as follows: hollow cavity contributes to large loading capacity; a tailored structure helps controllable drug release; variable compounds adapt to flexible application; surface modification facilitates smart responsive release. Especially, because the multiple physical barriers and chemical interactions can be induced by multishells, hollow multishelled structure is considered as a promising material with unique loading and releasing properties. Finally, we conclude this review with some perspectives on the future research and development of the hollow structures as drug carriers.

An insight into the medicinal perspectives of mannich bases of benzimidazole derivatives: A review

The heterocyclic aromatic compound benzimidazole is made up of benzene and an imidazole ring. In medicinal chemistry, it's a crucial pharmacophore and a privileged structure. It's a component of the vitamin cobalamin. Antimicrobial, antiviral, antidiabetic, anti-cancer, anti-helminthic, antioxidant, anti-fungal, anti-allergic, anti-parasitic, anti-proliferative, anti-HIV, anti-convulsant, anti-inflammatory, anti-hypertensive and proton pump inhibitors are only a few of the pharmacological functions of benzimidazole derivatives play a critical role throughout the medical sector. The Mannich reaction is one of the most versatile reaction in organic synthesis. This reaction can be used to make N-methyl derivatives and a variety of drug molecules. Mannich base benzimidazole derivatives play a significant role in medicine, with several medicinal applications including antibacterial, anthelmintic, antifungal, anti-inflammatory, antiviral, analgesic and anti-convulsant. Changes in their composition have provided a high degree of variety, which has been beneficial in the case of new therapeutic agents with increased efficacy and lower toxicity. This analysis emphasises the significance of synthesis and various biological activities of newly synthesized mannich bases of benzimidazole derivatives, as well as a few key synthesis methodologies.

Aminopyrimidines: Recent synthetic procedures and anticancer activities

The pyrimidine scaffold represents one of the privileged structures in chemistry, and there has been an increase in number of studies utilizing this scaffold and its derivatives. The review compiles the strategies and methods of development of aminopyrimidine derivatives. The advances in organic and heterocyclic chemistry are considered in the targeted synthesis of aminopyrimidine derivatives whose series contains the most demanded and efficient antitumor pharmaceuticals. Optimization of synthetic protocols of cyclocondensation reaction and implement multicomponent reactions have been performed to obtain desired aminopyrimidines. In addition, this review aims to be a comprehensive and general summary of numerous aminopyrimidines, their use as medicinal agents and their main anticancer activities.

Isobornylchalcones as Scaffold for the Synthesis of Diarylpyrazolines with Antioxidant Activity.

The pyrazoline ring is defined as a “privileged structure” in medicinal chemistry. A variety of pharmacological properties of pyrazolines is associated with the nature and position of various substituents, which is especially evident in diarylpyrazolines. Compounds with a chalcone fragment show a wide range of biological properties as well as high reactivity which is primarily due to the presence of an α, β-unsaturated carbonyl system. At the same time, bicyclic monoterpenoids deserve special attention as a source of a key structural block or as one of the pharmacophore components of biologically active molecules. A series of new diarylpyrazoline derivatives based on isobornylchalcones with different substitutes (MeO, Hal, NO2, N(Me)2) was synthesized. Antioxidant properties of the obtained compounds were comparatively evaluated using in vitro model Fe2+/ascorbate-initiated lipid peroxidation in the substrate containing brain lipids of laboratory mice. It was demonstrated that the combination of the electron-donating group in the para-position of ring B and OH-group in the ring A in the structure of chalcone fragment provides significant antioxidant activity of synthesized diarylpyrazoline derivatives.

Determination of the "privileged structure" of 8-hydroxyquinoline

Determination of the "privileged structure" of 8-hydroxyquinoline

Determination of the "privileged structure" of 8-hydroxyquinoline

Determination of the "privileged structure" of 8-hydroxyquinoline

3 + n] Cycloaddition Reactions: A Milestone Approach for Elaborating Pyridazine of Potential Interest in Medicinal Chemistry and Optoelectronics.

During the last few decades, pyridazine derivatives have emerged as privileged structures in heterocyclic chemistry, both because of their excellent chemistry and because of their potential applications in medicinal chemistry and optoelectronics. This review is focused on the recent advances in [3 + n] cycloaddition reactions in the pyridazine series as well as their medicinal chemistry and optoelectronic applications over the last ten years. The stereochemistry and regiochemistry of the cycloaddition reactions are discussed. Applications in optoelectronics (in particular, as fluorescent materials and sensors) and medicinal chemistry (in particular, antimicrobials and anticancer) are also reviewed.

Synthesis of new 2-aminothiazolyl/benzothiazolyl-based 3,4-dihydropyrimidinones and evaluation of their effects on adenocarcinoma gastric cell migration.

Gastric cancer is one of the malignant tumors of the gastrointestinal tract that, despite its decrease in recent years, is still the fourth most common cancer and the second leading cause of cancer-related death. Various strategies including chemotherapy are used to keep cancer cells from spreading and induce apoptotic death in them. Recent studies have shown that dihydropyrimidinones (DHPMs) are privileged structures in medicinal chemistry due to their pharmacological effects. A number of new 2-aminothiazolyl/benzothiazolyl derivatives of 3,4-DHPMs (3-8) were synthesized and structurally identified, and then their effects on the migration behavior of human AGS cells (gastric cancer cells) were investigated. Molecular docking and molecular dynamics (MD) simulations were applied to explore binding potential and realistic binding model of the assessed derivatives through identification of key amino acid residues within L5/α2/α3 allosteric site of kinesin 5 (Eg5) as a validated microtubule-dependent target for monastrol as a privileged DHPM derivative.

A New Synthesis Strategy for Rhodanine and Its Derivatives

AbstractRhodanine and its derivatives have been known as privileged structures in pharmacological research because of their wide spectrum of biological activities, but the synthesis method of rhodanine skeleton is limited. In this paper, not only rhodanine skeleton, but also N-aryl rhodanines can be directly prepared via the reaction of thioureas and thioglycolic acid in one step catalyzed by protic acid, which provides a new approach of the synthesis of rhodanine and its derivatives. The developed strategy is straightforward, efficient, atom economical, and convenient in good yields.

Structure-based discovery of potent and selective small-molecule inhibitors targeting signal transducer and activator of transcription 3 (STAT3).

STAT3 has been validated as an attractive anticancer target due to its important roles in cancer initiation and progression. However, discovery of potent and selective STAT3 small-molecule inhibitors with druglike properties is still challenging. In this study, two series of substituted 2-phenylquinolines and 2-arylimidazo[1,2-a]pyridines were designed through structure-based drug discovery approach by condensing the privileged structures of STX-119 and SH4-54. Our study has resulted in the discovery of a number of highly potent and selective STAT3 inhibitors, exemplified by compound 39 with the privileged structure of 2-phenylimidazo[1,2-a]pyridine, which selectively inhibits phosphorylation of STAT3 and suppresses subsequent signaling pathway. Moreover, 39 inhibits cell growth, migration and invasion of human triple negative breast cancer (TNBC) cells lines. Consistently, it achieves significant and dose-dependent tumor growth inhibition in both cell line-derived and patient-derived xenograft tumor models in mice. These results clearly indicate that 39 is a highly potent and selective STAT3 inhibitor.

Fluorene-Based Multicomponent Reactions

AbstractFluorene and fluorenone are privileged structures with extensive utility in both materials science and drug discovery. Here, we describe syntheses of those moieties through isocyanide-based multicomponent reactions (IMCRs) and the incorporation of the products in diverse and complex derivatives that can be further utilized. We performed six different IMCRs, based on the dual functionality of 9-isocyano-9H-fluorene, and we describe 23 unprecedented adducts.

Investigating the phosphinic acid tripeptide mimetic DG013A as a tool compound inhibitor of the M1-aminopeptidase ERAP1

ERAP1 is a zinc-dependent M1-aminopeptidase that trims lipophilic amino acids from the N-terminus of peptides. Owing to its importance in the processing of antigens and regulation of the adaptive immune response, dysregulation of the highly polymorphic ERAP1 has been implicated in autoimmune disease and cancer. To test this hypothesis and establish the role of ERAP1 in these disease areas, high affinity, cell permeable and selective chemical probes are essential. DG013A 1, is a phosphinic acid tripeptide mimetic inhibitor with reported low nanomolar affinity for ERAP1. However, this chemotype is a privileged structure for binding to various metal-dependent peptidases and contains a highly charged phosphinic acid moiety, so it was unclear whether it would display the high selectivity and passive permeability required for a chemical probe. Therefore, we designed a new stereoselective route to synthesize a library of DG013A 1 analogues to determine the suitability of this compound as a cellular chemical probe to validate ERAP1 as a drug discovery target.

Time‐Economical Synthesis of Diarylacetates Enabled by TfOH‐Catalyzed Arylation of α‐Aryl‐α‐Diazoesters with Arenes

AbstractDiarylacetates are privileged structures of many bioactive natural products and pharmaceutical compounds. A time‐economical synthesis of diarylacetates by TfOH‐catalyzed arylation of α‐aryl‐α‐diazoesters with arenes is described. This protocol provides a variety of diarylacetates in good yields with broad substrate scope, excellent functional group compatibility, and mild reaction conditions. Also, a new mechanism for the arylation reaction of α‐aryl‐α‐diazoesters with arenes under TfOH catalysis is presented.

β-Lactone Derivatives and Their Anticancer Activities: A Short Review.

Cancers, a set of genetic diseases that can change the behavior and cell growth in body tissues, are the second leading cause of death across the world. Several treatment approaches, such as radiation, immunotherapy, and chemotherapy, can be applied to cure cancer, and among them, chemotherapy is one of the primary treatments for cancer, in which chemotherapeutic drugs are used. Great achievements have been made in the development of novel anticancer agents, but drug resistance is usually generated quickly, making overcoming drug resistance or developing more effective anticancer agents an imperative challenge. β-Lactones (2-oxetanones) are chemically diverse and often referred to as privileged structures for the discovery of new drugs, including anticancer agents. Marizomib (Salinosporamide A), a naturally occurring β-lactone proteasome inhibitor derived from the marine actinobacterium Salinispora tropica, has been termed as an orphan drug against multiple myeloma. Therefore, β-lactones are useful scaffolds for the discovery of novel anticancer agents. This review is an endeavour to highlight the advances in β-lactone derivatives with anticancer potential. The synthetic strategies, structure-activity relationships, as well as modes of action, are also discussed to pave the way for further rational design.

Synthetic Approaches to the New Drugs Approved during 2019

New drugs introduced to the market are privileged structures having affinities for biological targets implicated in human diseases and conditions. These new chemical entities (NCEs), particularly small molecules and antibody-drug conjugates, provide insight into molecular recognition and simultaneously function as leads for the design of future medicines. This review is part of a continuing series presenting the most likely process-scale synthetic approaches to 40 NCEs approved for the first time anywhere in the world in 2019.

The Alpha Keto Amide Moiety as a Privileged Motif in Medicinal Chemistry: Current Insights and Emerging Opportunities.

Over the years, researchers in drug discovery have taken advantage of the use of privileged structures to design innovative hit/lead molecules. The α-ketoamide motif is found in many natural products, and it has been widely exploited by medicinal chemists to develop compounds tailored to a vast range of biological targets, thus presenting clinical potential for a plethora of pathological conditions. The purpose of this perspective is to provide insights into the versatility of this chemical moiety as a privileged structure in drug discovery. After a brief analysis of its physical–chemical features and synthetic procedures to obtain it, α-ketoamide-based classes of compounds are reported according to the application of this motif as either a nonreactive or reactive moiety. The goal is to highlight those aspects that may be useful to understanding the perspectives of employing the α-ketoamide moiety in the rational design of compounds able to interact with a specific target.

A Review of the Pharmacological Activities and Recent Synthetic Advances of γ-Butyrolactones.

γ-Butyrolactone, a five-membered lactone moiety, is one of the privileged structures of diverse natural products and biologically active small molecules. Because of their broad spectrum of biological and pharmacological activities, synthetic methods for γ-butyrolactones have received significant attention from synthetic and medicinal chemists for decades. Recently, new developments and improvements in traditional methods have been reported by considering synthetic efficiency, feasibility, and green chemistry. In this review, the pharmacological activities of natural and synthetic γ-butyrolactones are described, including their structures and bioassay methods. Mainly, we summarize recent advances, occurring during the past decade, in the construction of γ-butyrolactone classified based on the bond formation in γ-butyrolactone between (i) C5-O1 bond, (ii) C4-C5 and C2-O1 bonds, (iii) C3-C4 and C2-O1 bonds, (iv) C3-C4 and C5-O1 bonds, (v) C2-C3 and C2-O1 bonds, (vi) C3-C4 bond, and (vii) C2-O1 bond. In addition, the application to the total synthesis of natural products bearing γ-butyrolactone scaffolds is described.