Synthetic and Naturally Occurring Heterocyclic Anticancer Compounds with Multiple Biological Targets.

Cancer is a complex group of diseases initiated by abnormal cell division with the potential of spreading to other parts of the body. The advancement in the discoveries of omics and bio- and cheminformatics has led to the identification of drugs inhibiting putative targets including vascular endothelial growth factor (VEGF) family receptors, fibroblast growth factors (FGF), platelet derived growth factors (PDGF), epidermal growth factor (EGF), thymidine phosphorylase (TP), and neuropeptide Y4 (NY4), amongst others. Drug resistance, systemic toxicity, and drug ineffectiveness for various cancer chemo-treatments are widespread. Due to this, efficient therapeutic agents targeting two or more of the putative targets in different cancer cells are proposed as cutting edge treatments. Heterocyclic compounds, both synthetic and natural products, have, however, contributed immensely to chemotherapeutics for treatments of various diseases, but little is known about such compounds and their multimodal anticancer properties. A compendium of heterocyclic synthetic and natural product multitarget anticancer compounds, their IC50, and biological targets of inhibition are therefore presented in this review.

New perspectives in bronchial asthma: pathological, immunological alterations, biological targets, and pharmacotherapy.

Asthma is the most common, long-lasting inflammatory airway disease that affects more than 10% of the world population. It is characterized by bronchial narrowing, airway hyperresponsiveness, vasodilatation, airway edema, and stimulation of sensory nerve endings that lead to recurring events of breathlessness, wheezing, chest tightness, and coughing. It is the main reason for global morbidity and occurs as a result of the weakening of the immune system in response to exposure to allergens or environmental exposure. In asthma condition, it results in the activation of numerous inflammatory cells like the mast and dendritic cells along with the accumulation of activated eosinophils and lymphocytes at the inflammation site. The structural cells such as airway epithelial cells and smooth muscle cells release inflammatory mediators that promote the bronchial inflammation. Long-lasting bronchial inflammation can cause pathological alterations, viz. the improved thickness of the bronchial epithelium and friability of airway epithelial cells, epithelium fibrosis, hyperplasia, and hypertrophy of airway smooth muscle, angiogenesis, and mucus gland hyperplasia. The stimulation of bronchial epithelial cell would result in the release of inflammatory cytokines and chemokines that attract inflammatory cells into bronchial airways and plays an important role in asthma. Asthma patients who do not respond to marketed antiasthmatic drugs needed novel biological medications to regulate the asthmatic situation. The present review enumerates various types of asthma, etiological factors, and in vivo animal models for the induction of asthma. The underlying pathological, immunological mechanism of action, the role of inflammatory mediators, the effect of inflammation on the bronchial airways, newer treatment approaches, and novel biological targets of asthma have been discussed in this review.

Emerging drugs for treating the acute respiratory distress syndrome.

INTRODUCTION: The acute respiratory distress syndrome (ARDS) is a common and catastrophic condition, with a high mortality rate and economic burden on society. Despite 50 years of study, there is no specific pharmacological therapy for ARDS. Areas covered: This review outlines the definitions, epidemiology, risk factors and pathophysiology of ARDS. The priority of developing a clinically-relevant model for ARDS to test pre-clinical candidates is discussed, together with the limitations of current models. The scientific rationale of emerging therapeutic candidates is outlined in the setting of the biological mechanisms implicated in the complex pathogenesis of ARDS. Emerging therapies, currently in clinical trials, are discussed, including the pre-clinical basis for their use and the expected timeline to trial completion. Expert opinion: We highlight the necessity of improving pre-clinical models of ARDS and the design of clinical trials for the development of novel pharmacological therapies. We reflect on the most promising emerging strategies and their potential role in ARDS management.

iVS analysis to evaluate the impact of scaffold diversity in the binding to cellular targets relevant in cancer.

This study reports the application of inverse virtual screening (iVS) methodologies to identify cellular proteins as suitable targets for a library of heterocyclic small-molecules, with potential pharmacological implications. Standard synthetic procedures allow facile generation of these ligands showing a high degree of core scaffold diversity. Specifically, we have computationally investigated the binding efficacy of the new series for target proteins which are involved in cancer pathogenesis. As a result, nine macromolecules demonstrated efficient binding interactions for the molecular dataset, in comparison to the co-crystallised ligand for each target. Moreover, the iVS analysis led us to confirm that 27 analogues have high affinity for one or more examined cellular proteins. The additional evaluation of ADME and drug score for selected hits also highlights their capability as drug candidates, demonstrating valuable leads for further structure optimisation and biological studies.

Design of a tripartite network for the prediction of drug targets.

Drug-target networks have aided in many target prediction studies aiming at drug repurposing or the analysis of side effects. Conventional drug-target networks are bipartite. They contain two different types of nodes representing drugs and targets, respectively, and edges indicating pairwise drug-target interactions. In this work, we introduce a tripartite network consisting of drugs, other bioactive compounds, and targets from different sources. On the basis of analog relationships captured in the network and so-called neighbor targets of drugs, new drug targets can be inferred. The tripartite network was found to have a stable structure and simulated network growth was accompanied by a steady increase in assortativity, reflecting increasing correlation between degrees of connected nodes leading to even network connectivity. Local drug environments in the tripartite network typically contained neighbor targets and revealed interesting drug-compound-target relationships for further analysis. Candidate targets were prioritized. The tripartite network design extends standard drug-target networks and provides additional opportunities for drug target prediction.

Current advances in screening for bioactive components from medicinal plants by affinity ultrafiltration mass spectrometry.

INTRODUCTION: Medicinal plants have played an important role in maintaining human health for thousands of years. However, the interactions between the active components in medicinal plants and some certain biological targets during a disease are still unclear in most cases. OBJECTIVE: To conduct the high-throughput screening for small active molecules that can interact with biological targets, which is of great theoretical significance and practical value. METHODOLOGY: The ultrafiltration mass spectrometry (UF-LC/MS) is a powerful bio-analytical method by combining affinity ultrafiltration and liquid chromatography-mass spectrometry (LC/MS), which could rapidly screen and identify small active molecules that bind to biological targets of interest at the same time. Compared with other analytical methods, affinity UF-LC/MS has the characteristics of fast, sensitive and high throughput, and is especially suitable for the complicated extracts of medicinal plants. RESULTS: In this review, the basic principle, characteristics and some most recent challenges in UF-LC/MS have been demonstrated. Meanwhile, the progress and applications of affinity UF-LC/MS in the discovery of the active components from natural medicinal plants and the interactions between small molecules and biological target proteins are also briefly summarised. In addition, the future directions for UF-LC/MS are also prospected. CONCLUSION: Affinity UF-LC/MS is a powerful tool in studies on the interactions between small active molecules and biological protein targets, especially in the high-throughput screening of active components from the natural medicinal plants.

Biological activity and binding properties of [Ru(II)(dcbpy)2Cl2] complex to bovine serum albumin, phospholipase A2 and glutathione.

Ruthenium compounds are highly regarded as metallo-drug candidates. Many studies have focused their attention on the interaction between ruthenium complexes with their possible biological targets. The interaction of ruthenium complexes with transport proteins, enzymes and peptides is of great importance for understanding their biodistribution and mechanism of action, therefore, the development of an anti-cancer therapy involving ruthenium complexes has recently shifted from DNA targeting towards protein targeting. With the aim of gaining insight into possible interactions between ruthenium complexes with biologically relevant proteins, we have studied the interaction of cis-dichlorobis(2,2'-bipyridyl-4,4'-dicarboxylic acid)ruthenium(II) complex [Ru(II)(dcbpy)2Cl2], which previously showed good potency in photo-dynamic chemotherapy, with bovine serum albumin (BSA), phospholipase A2 (PLA2) and glutathione (GSH). Binding constants and possible number of binding sites to mentioned proteins and peptide are investigated by ultraviolet-visible spectroscopy and Matrix-Assisted Laser Desorption Ionization Mass Spectrometry (MALDI TOF MS). The complex binding affinities were in the following order: PLA2 > BSA > GSH. Moreover, genotoxic profile of the complex, tested on peripheral blood lymphocytes as a model system, was also promising.

Anticancer Gold(III) Porphyrins Target Mitochondrial Chaperone Hsp60.

Identification of the molecular target(s) of anticancer metal complexes is a formidable challenge since most of them are unstable toward ligand exchange reaction(s) or biological reduction under physiological conditions. Gold(III) meso-tetraphenylporphyrin (gold-1 a) is notable for its high stability in biological milieux and potent in vitro and in vivo anticancer activities. Herein, extensive chemical biology approaches employing photo-affinity labeling, click chemistry, chemical proteomics, cellular thermal shift, saturation-transfer difference NMR, protein fluorescence quenching, and protein chaperone assays were used to provide compelling evidence that heat-shock protein 60 (Hsp60), a mitochondrial chaperone and potential anticancer target, is a direct target of gold-1 a in vitro and in cells. Structure-activity studies with a panel of non-porphyrin gold(III) complexes and other metalloporphyrins revealed that Hsp60 inhibition is specifically dependent on both the gold(III) ion and the porphyrin ligand.

Advancing the drug discovery and development process.

The current state of affairs in the drug discovery and development process is briefly summarized and then ways to take advantage of the ever-increasing fundamental knowledge and technical knowhow in chemistry and biology and related disciplines are discussed. The primary motivation of this Essay is to celebrate the great achievements of chemistry, biology, and medicine and to inform and inspire students and academics to enter the field of drug discovery and development while, at the same time, continue to advance the fundamentals of their disciplines. It is also meant to encourage and catalyze multidisciplinary partnerships between academia and industry as scientists attempt to merge their often complementary interests and expertise to achieve new improvements and breakthroughs in their respective fields, and the common goal of applying them to the discovery and invention of new and better medicines, especially in areas of unmet needs.

Calycosin action against atherosclerosis: integrating network pharmacology and in-silico investigation.

Atherosclerosis, caused by lipid deposit in the arterial wall for narrowing the arteries, is an increased risk factor of developing heart failure. Presently, clinical first-line drug therapy can be found with side effects, and thus new substitute medication should be developed needfully. Calycosin is one of the most bioactive products refined from natural plant, and it exerts promising cardiovascular protective effect. However, the pharmacological mechanisms of calycosin against atherosclerosis have not been elaborated. In this study, a systematic network pharmacology combined with molecular docking analysis was used to reveal the interaction activity and biological target in calycosin against atherosclerosis. We screened all preparative targets linked to calycosin and atherosclerosis from the available public databases. These results indicated total 409 putative targets in calycosin action, 71 of which were interacted with atherosclerosis. Further biological docking analysis suggested that calycosin displayed the powerful binding affinities with target proteins, including interleukin-6 (IL6) and mitogen-activated protein kinase 3 (MAPK3) MAPK3. Then enrichment findings revealed that calycosin action to treat atherosclerosis might be related to inhibition of inflammatory reaction and oxidative stress through modulating nucleolus transcription factor for improving lipid metabolism. In conclusion, the anti-atherosclerotic targets and molecular mechanisms in calycosin action were revealed systematically through preclinical evaluation. And calycosin may be a potential natural compound for the treatment of atherosclerosis.

Research on marine flexible biological target detection based on improved YOLOv8 algorithm.

To address the challenge of suboptimal object detection outcomes stemming from the deformability of marine flexible biological entities, this study introduces an algorithm tailored for detecting marine flexible biological targets. Initially, we compiled a dataset comprising marine flexible biological subjects and developed a Contrast Limited Adaptive Histogram Equalization (CLAHE) algorithm, supplemented with a boundary detection enhancement module, to refine underwater image quality and accentuate the distinction between the images' foregrounds and backgrounds. This enhancement mitigates the issue of foreground-background similarity encountered in detecting marine flexible biological entities. Moreover, the proposed adaptation incorporates a Deformable Convolutional Network (DCN) network module in lieu of the C2f module within the YOLOv8n algorithm framework, thereby augmenting the model's proficiency in capturing geometric transformations and concentrating on pivotal areas. The Neck network module is enhanced with the RepBi-PAN architecture, bolstering its capability to amalgamate and emphasize essential characteristics of flexible biological targets. To advance the model's feature information processing efficiency, we integrated the SimAM attention mechanism. Finally, to diminish the adverse effects of inferior-quality labels within the dataset, we advocate the use of WIoU (Wise-IoU) as a bounding box loss function, which serves to refine the anchor boxes' quality assessment. Simulation experiments show that, in comparison to the conventional YOLOv8n algorithm, our method markedly elevates the precision of marine flexible biological target detection.

Recent Developments and Future Perspectives of Purine Derivatives as a Promising Scaffold in Drug Discovery.

Numerous purine-containing compounds have undergone extensive investigation for their medical efficacy across various diseases. The swift progress in purine-based medicinal chemistry has brought to light the therapeutic capabilities of purine-derived compounds in addressing challenging medical conditions. Defined by a heterocyclic ring comprising a pyrimidine ring linked with an imidazole ring, purine exhibits a diverse array of therapeutic attributes. This review systematically addresses the multifaceted potential of purine derivatives in combating various diseases, including their roles as anticancer agents, antiviral compounds (anti-herpes, anti-HIV, and anti-influenzae), autoimmune and anti-inflammatory agents, antihyperuricemic and anti-gout solutions, antimicrobial agents, antitubercular compounds, anti-leishmanial agents, and anticonvulsants. Emphasis is placed on the remarkable progress made in developing purine-based compounds, elucidating their significant target sites. The article provides a comprehensive exploration of developments in both natural and synthetic purines, offering insights into their role in managing a diverse range of illnesses. Additionally, the discussion delves into the structure-activity relationships and biological activities of the most promising purine molecules. The intriguing capabilities revealed by these purine-based scaffolds unequivocally position them at the forefront of drug candidate development. As such, this review holds potential significance for researchers actively involved in synthesizing purine-based drug candidates, providing a roadmap for the continued advancement of this promising field.

Mycobacterium tuberculosis: Pathogenesis and therapeutic targets.

Tuberculosis (TB) remains a significant public health concern in the 21st century, especially due to drug resistance, coinfection with diseases like immunodeficiency syndrome (AIDS) and coronavirus disease 2019, and the lengthy and costly treatment protocols. In this review, we summarize the pathogenesis of TB infection, therapeutic targets, and corresponding modulators, including first-line medications, current clinical trial drugs and molecules in preclinical assessment. Understanding the mechanisms of Mycobacterium tuberculosis (Mtb) infection and important biological targets can lead to innovative treatments. While most antitubercular agents target pathogen-related processes, host-directed therapy (HDT) modalities addressing immune defense, survival mechanisms, and immunopathology also hold promise. Mtb's adaptation to the human host involves manipulating host cellular mechanisms, and HDT aims to disrupt this manipulation to enhance treatment effectiveness. Our review provides valuable insights for future anti-TB drug development efforts.

Computational Discovery of Marine Molecules of the Cyclopeptide Family with Therapeutic Potential.

Stellatolides are natural compounds that have shown promising biological activities, including antitumor, antimicrobial, and anti-inflammatory properties, making them potential candidates for drug development. Chemical Reactivity Theory (CRT) is a branch of chemistry that explains and predicts the behavior of chemical reactions based on the electronic structure of molecules. Conceptual Density Functional Theory (CDFT) and Computational Peptidology (CP) are computational approaches used to study the behavior of atoms, molecules, and peptides. In this study, we present the results of our investigation of the chemical reactivity and ADMET properties of Stellatolides A-H using a novel computational approach called Conceptual DFT-based Computational Peptidology (CDFT-CP). Our study uses CDFT and CP to predict the reactivity and stability of molecules and to understand the behavior of peptides at the molecular level. We also predict the ADMET properties of the Stellatolides A-H to provide insight into their effectiveness, potential side effects, and optimal dosage and route of administration, as well as their biological targets. This study sheds light on the potential of Stellatolides A-H as promising candidates for drug development and highlights the potential of CDFT-CP for the study of other natural compounds and peptides.

Molecular Targets of Triple-Negative Breast Cancer: Where Do We Stand?

Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer. Due to its heterogeneity and lack of hormone receptor expression, this subtype is more likely to metastasize and resist treatment attempts than are other forms of breast cancer. Due to the absence of targetable receptors, chemotherapy and breast conserving surgery have been the predominant treatment options for patients. However, resistance to chemotherapy and local recurrence of the tumors is frequent. Emerging immunotherapies have begun to change treatment plans for patients diagnosed with TNBC. In this review, we discuss the various immune pathways identified in TNBC and the role they play as targets for new potential treatment choices. Various therapeutic options that inhibit key pathways in cellular growth cycles, DNA repair mechanisms, epithelial mesenchymal transition, and immunosuppression have been shown to improve survival in patients with this disease. With promising results thus far, continued studies of immunotherapy and neoadjuvant therapy options for TNBC are likely to alter the treatment course for these diagnoses in the future.

A comprehensive review on acridone based derivatives as future anti-cancer agents and their structure activity relationships.

The development of drug resistance and severe side-effects has reduced the clinical efficacy of the existing anti-cancer drugs available in the market. Thus, there is always a constant need to develop newer anti-cancer drugs with minimal adverse effects. Researchers all over the world have been focusing on various alternative strategies to discover novel, potent, and target specific molecules for cancer therapy. In this direction, several heterocyclic compounds are being explored but amongst them one promising heterocycle is acridone which has attracted the attention of medicinal chemists and gained huge biological importance as acridones are found to act on different therapeutically proven molecular targets, overcome ABC transporters mediated drug resistance and DNA intercalation in cancer cells. Some of these acridone derivatives have reached clinical studies as these heterocycles have shown huge potential in cancer therapeutics and imaging. Here, the authors have attempted to compile and make some recommendations of acridone based derivatives concerning their cancer biological targets and in vitro-cytotoxicity based on drug design and novelty to increase their therapeutic potential. This review also provides some important insights on the design, receptor targeting and future directions for the development of acridones as possible clinically effective anti-cancer agents.

Intrinsic drug potential of oxazolo[5,4-d]pyrimidines and oxazolo[4,5-d]pyrimidines.

The oxazole and pyrimidine rings are widely displayed in natural products and synthetic molecules. They are known as the prime skeletons for drug discovery. On the account of structural and chemical diversity, oxazole and pyrimidine-based molecules, as central scaffolds, not only provide different types of interactions with various receptors and enzymes, showing broad biological activities, but also occupy a core position in medicinal chemistry, showing their importance for development and discovery of newer potential therapeutic agents (Curr Top Med Chem, 16, 2016, 3133; Int J Pharm Pharm Sci, 8, 2016, 8; BMC Chem, 13, 2019, 44). For a long time, relatively little attention has been paid to their fused rings that are oxazolopyrimidines, whose chemical structure is similar to that of natural purines because probably none of these compounds were found in natural products or their biological activities turned out to be unexpressed (Bull Chem Soc Jpn, 43, 1970, 187). Recently, however, a significant number of studies have been published on the biological properties of oxazolo[5,4-d]pyrimidines, showing their significant activity as agonists and antagonists of signaling pathways involved in the regulation of the cell life cycle, whereas oxazolo[4,5-d]pyrimidines, on the contrary, represent a poorly studied class of compounds. Limited access to this scaffold has resulted in a corresponding lack of biological research (Eur J Organ Chem, 18, 2018, 2148). Actually, oxazolo[5,4-d]pyrimidine is a versatile scaffold used for the design of bioactive ligands against enzymes and receptors. This review focuses on biological targets and associated pathogenetic mechanisms, as well as pathological disorders that can be modified by well-known oxazolopyrimidines that have been proven to date. Many molecular details of these processes are omitted here, which the interested reader will find in the cited literature. This work also does not cover the methods for the synthesis of the oxazolopyrimidines, which are exhaustively described by De Coen et al. (Eur J Organ Chem, 18, 2018, 2148). The review as well does not discuss the structure-activity relationship, which is described in detail in the original works and deliberately, whenever possible, cites not primary sources, but mostly relevant review articles, so that the reader who wants to delve into a particular problem will immediately receive more complete information. It is expected that the information presented in this review will help readers better understand the purpose of the development of oxazolopyrimidines and the possibility of their development as drugs for the treatment of a wide range of diseases.

Branched-Chain Amino Acids Catabolism Pathway Regulation Plays a Critical Role in the Improvement of Leukopenia Induced by Cyclophosphamide in 4T1 Tumor-Bearing Mice Treated With Lvjiaobuxue Granule.

Background: Cyclophosphamide is a common tumor chemotherapy drug used to treat various cancers. However, the resulting immunosuppression leads to leukopenia, which is a serious limiting factor in clinical application. Therefore, the introduction of immunomodulators as adjuvant therapy may help to reduce the hematological side effects of cyclophosphamide. Lvjiaobuxue granule has been widely used in the clinical treatment of gynecological diseases such as anemia and irregular menstruation. Recently, it has been found to increase the function of white blood cells, but its mechanism of action is still unclear. We aimed to reveal the mechanisms of Lvjiaobuxue granule against acute leukopenia by an integrated strategy combining metabolomics with network pharmacology. Methods: Subcutaneously inoculated 4T1 breast cancer cells to prepare tumor-bearing mice, intraperitoneal injection of cyclophosphamide to establish a 4T1 tumor-bearing mice leukopenia animal model, using pharmacodynamic indicators, metabolomics, network pharmacology and molecular biology and other technical methods. To comprehensively and systematically elucidate the effect and mechanism of Lvjiaobuxue granule in improving cyclophosphamide-induced leukopenia in 4T1 tumor-bearing mice. Results: Lvjiaobuxue granule can improve the blood routine parameters and organ index levels of the leukopenia model of 4T1 tumor-bearing mice. Metabolomics studies revealed that 15 endogenous metabolites in the spleen of mice were considered as potential biomarkers of Lvjiaobuxue granule for their protective effect. Metabonomics and network pharmacology integrated analysis indicated that Lvjiaobuxue granule exerted the leukocyte elevation activity by inhibiting the branched-chain amino acids (BCAAs) degradation pathway and increasing the levels of valine, leucine and isoleucine. The results of molecular biology also showed that Lvjiaobuxue granule can significantly regulate the key enzymes in the catabolism of BCAAs, which further illustrates the importance of BCAAs in improving leukopenia. Conclusion: Lvjiaobuxue granule exerts obvious pharmacological effects on the leukopenia model of 4T1 tumor-bearing mice induced by cyclophosphamide, which could be mediated by regulating the branched-chain amino acid degradation pathway and the levels of valine, leucine and isoleucine.

Different Surface Interactions between Fluorescent Conjugated Polymers and Biological Targets.

Fluorescent conjugated polymers (CPs) have attracted considerable interest in biosensing owing to their high fluorescence, tunable bandgap, and good biocompatibility. Aiming at acquiring the desired optical responses of CPs for bioapplications, it is essential that the CPs bind to biological targets with high efficacy and affinity. However, the efficient binding of CPs is largely driven by their effective interaction with target surfaces. In this Review, we will focus on the different surface interactions that pervade between CPs and biological targets. The multiple surface interactions can lead to changes in spatial conformation and distribution of CPs, which manifest alterable optical properties of CPs based on accumulation of target-directed CPs, Förster resonance energy transfer mechanism, and metal-enhanced fluorescence mechanism. Then, we display diverse bioapplications applying CPs-based surface interactions, such as cell imaging, imaging-guided detection, and photodynamic therapy. Finally, the challenges and future developments to control the efficient attachment of CPs to biological targets are discussed. We expect that the understanding of surface interactions between CPs and biological targets benefits the CPs-based system design and expands their applications in biological detections and therapies.

Pt(II) and Au(III) complexes containing Schiff-base ligands: A promising source for antitumor treatment.

The effective application of cisplatin in the clinic as an antitumor treatment has stimulated widespread interest in inorganic metal drugs. In particular, complexes containing the transition metals platinum and gold have attracted considerable attention due to their antitumor effects. The Pt(II) and Au(III) Schiff-base complexes are potential antitumor agents because of their remarkable biological activities and good stability, lipophilicity, and electroluminescent properties. These complexes act via various antitumor mechanisms that are unlike those of the classic platinum drugs, providing a feasible solution for improving the serious side effects caused by metal chemotherapy. In this review, promising antitumor agents based on Pt(II) and Au(III) complexes containing Schiff-base ligands, and their biological targets, including G-quadruplex DNA and thioredoxin reductase, are comprehensively summarized.