Poor Pharmacokinetic Properties Research Articles

Synthesis, Cytotoxicity, and Mechanistic Evaluation of Tetrahydrocurcumin-Amino Acid Conjugates as LAT1-Targeting Anticancer Agents in C6 Glioma Cells.

Glioblastoma, a fatal brain cancer with limited treatments and poor prognosis, could benefit from targeting the L-type amino acid transporter I (LAT1). LAT1 is essential for cancer cells to acquire necessary amino acids. Tetrahydrocurcumin (THC), a key curcumin derivative, shows potential for glioblastoma treatment. However, its effectiveness is hindered by poor physicochemical and pharmacokinetic properties. Therefore, this study aims to improve the therapeutic efficacy of THC against glioblastoma by chemically modifying it to target LAT1. A novel series of THC-amino acid conjugates were synthesized by conjugating five amino acids: glycine, leucine, isoleucine, and phenylalanine to THC via carbamate bonds. The therapeutic efficacy of THC-amino acid conjugates was further examined in C6 glioma cells, including the role of LAT1 in their therapeutic effects. Among the conjugates tested, THC conjugated with two phenylalanines (THC-di-Phe) showed remarkably higher cytotoxicity against C6 glioma cells (35.8 μM) compared to THC alone (110.7 μM). THC-di-Phe induced cellular death via necrosis and apoptosis, outperforming THC. Additionally, THC-di-Phe inhibited C6 cell proliferation and migration more effectively than THC. Co-incubation of THC-di-Phe with the LAT1 inhibitor 2-Aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH) further increased cellular death. THC-di-Phe also significantly inhibited the P70SK/S6 pathway, regulated by LAT1 inhibitors, more effectively than THC and displayed a similar binding mode with both JX-075 and BCH to the active site of LAT1. Findings suggest the potential role of THC-di-Phe as a LAT1 inhibitor and provide novel insight into its use as a potent antitumor agent in glioma with increased therapeutic efficacy.

Discovery of Thiadiazoleamide Derivatives as Potent, Selective, and Orally Available Antagonists Disrupting Androgen Receptor Homodimer.

Androgen receptor (AR) is an important therapeutic target for prostate cancer (PCa) treatment, but prolonged use of AR antagonists has led to variant drug-resistant mutations. Since all marketed AR antagonists target the ligand binding pocket (LBP) of AR, to mitigate cross-resistance, a new drug pocket named Dimer Interface Pocket was discovered and a novel AR antagonist M17-B15 was identified. M17-B15 showed strong in vitro efficacy against PCa but had poor pharmacokinetic properties in vivo. In this study, through rational design and structure-activity relationship exploration, a series of thiadiazoleamide derivatives represented by N29 (IC50 = 0.018 μM) were identified with dominant AR antagonistic activity and remarkable anti-PCa activity in vitro. Furthermore, N29 effectively inhibited a series of typical drug-resistant AR mutants. The improved oral bioavailability of N29 facilitated its efficacy via oral administration, significantly inhibiting LNCaP xenograft tumor in vivo, presenting a promising therapeutic application for PCa.

Delivery of N-heterocyclic drugs, acids, phenols, and thiols via Tailor−made Self−immolative linkers

Heterocyclic drugs display diverse pharmacological activities and metabolic stability. However, their poor solubility and pharmacokinetic properties often compromise bioavailability and clinical outcomes. Nevertheless, the prodrug approach provides a viable strategy to overcome unwanted attributes of drug candidates. In this proof-of-concept study, we report the synthesis and biological evaluation of glycol methylene-bridged phosphate (GMBP) prodrugs developed for heterocyclic drug delivery. Through methylene bridging, the heterocyclic nitrogen was directly attached to the phosphate, whereas the glycol moiety enabled drug release via cyclization, as confirmed by 31P NMR spectroscopy. Additional prodrugs of carboxylic acids, phenols, and thiols confirmed the broad application scope of our GMPB approach. Heterocyclic GMBP prodrugs were stable in aqueous buffers and activated by phospholipase CAL-B in vitro. Select prodrugs, including zidovudine prodrug 33, were even more potent (3 nM on HIV-1) than the parent compound. These findings demonstrate that our GMBP approach is not only feasible but also highly versatile.

Resveratrol: Challenges and prospects in extraction and hybridization with nanoparticles, polymers, and bio-ceramics.

Resveratrol (RSV), a bioactive natural phenolic compound found in plants, fruits, and vegetables, has garnered significant attention in pharmaceutical, food, and cosmetic industries due to its remarkable biological and pharmacological activities. Despite its potential in treating various diseases, its poor pharmacokinetic properties, such as low solubility, stability, bioavailability, and susceptibility to rapid oxidation, limit its biomedical applications. Recent advancements focus on incorporating resveratrol into innovative materials like nanoparticles, polymers, and bio-ceramics to enhance its properties and bioavailability. In this review, an exhaustive literature search was conducted from PubMed, Google Scholar, Science Direct, Scopus, and Web of Science databases to explore these advancements, to compares conventional and innovative extraction methods, and to highlights resveratrol's therapeutic potential, including its anti-inflammatory, anti-oxidative, anti-cancerogenic, antidiabetic, neuroprotective, and cardio-protective properties. Additionally, we discuss the challenges and prospects of hybrid materials combining resveratrol with nanoparticles, polymers, and bio-ceramics for therapeutic applications. Rigorous studies are still needed to confirm their clinical efficacy.

Design, synthesis and bioactivity evaluation of isobavachin derivatives as hURAT1 inhibitors for hyperuricemia agents

Previously, we reported a novel natural scaffold compound, isobavachin (4′,7-dihydroxy-8-prenylflavanone), as a highly potent hURAT1 inhibitor with anti-hyperuricemia effect. However, the structure-activity relationship remains unknown and the poor pharmacokinetic (PK) parameters may limit further clinical use. Herein, a series of isobavachin derivatives were rationally designed and synthesized to explore the structure-activity relationship of isobavachin target hURAT1, and to improve their PK properties. Among them, compounds 15d, 15f, 15g, 27b and 27d showed promising hURAT1 inhibitory activities, which could comparable to that of isobavachin (IC50 = 0.24 μM). In addition, 27b also inhibited another urate reabsorption transporter GLUT9 with an IC50 of 4.47 μM. Compound 27b displayed greater urate-lowering activity in a hyperuricemia mouse model at a dose of 10 mg/kg compared to isobavachin and lesinurad. Overall, our results suggest that compound 27b represents a novel, safe hURAT1 and GLUT9 dual-target inhibitor with excellent drug availability and is worthy of further investigation as an anti-hyperuricemia agent.

Computational structural prediction and chemical inhibition of the human mitochondrial pyruvate carrier protein heterodimer complex.

The mitochondrial pyruvate carrier (MPC) plays a role in numerous diseases including neurodegeneration, metabolically dependent cancers, and the development of insulin resistance. Several previous studies in genetic mouse models or with existing inhibitors suggest that inhibition of the MPC could be used as a viable therapeutic strategy in these diseases. However, the MPC structure is unknown, making it difficult to screen for and develop therapeutically viable inhibitors. Currently known MPC inhibitors would make for poor drugs due to their poor pharmacokinetic properties, or in the case of the thiazolidinediones (TZDs), off-target specificity for peroxisome-proliferator activated receptor gamma (PPARgamma) leads to unwanted side effects. In this study, we develop several structural models for the MPC heterodimer complex and investigate the chemical interactions required for the binding of these known inhibitors to MPC and PPARgamma. Based on these models, the MPC most likely takes on outward-facing (OF) and inward-facing (IF) conformations during pyruvate transport, and inhibitors likely plug the carrier to inhibit pyruvate transport. Although some chemical interactions are similar between MPC and PPARgamma binding, there is likely enough difference to reduce PPARgamma specificity for future development of novel, more specific MPC inhibitors.

Fabrication of folic acid-conjugated pyrimidine-2(5H)-thione-encapsulated curdlan gum-PEGamine nanoparticles for folate receptor targeting breast cancer cells

In this study 5-((2-((3-methoxy benzylidene)-amino)-phenyl)-diazenyl)-4,6-diphenyl pyrimidine-2(5H)-thione was synthesized. The pharmacological applications of pyrimidine analogs are restricted due to their poor pharmacokinetic properties. As a solution, a microbial exopolysaccharide (curdlan gum) was used to synthesize folic acid-conjugated pyrimidine-2(5H)-thione-encapsulated curdlan gum-PEGamine nanoparticles (FA-Py-CG-PEGamine NPs). The results of physicochemical properties revealed that the fabricated FA-Py-CG-PEGamine NPs were between 100 and 400 nm in size with a majorly spherical shaped, crystalline nature, and the encapsulation efficiency and loading capacity were 79.04 ± 0.79 %, and 8.12 ± 0.39 % respectively. The drug release rate was significantly higher at pH 5.4 (80.14 ± 0.79 %) compared to pH 7.2. The cytotoxic potential of FA-Py-CG-PEGamine NPs against MCF-7 cells potentially reduced the number of cells after 24 h with 42.27 μg × mL−1 as IC50 value. The higher intracellular accumulation of pyrimidine-2(5H)-thione in MCF-7 cells leads to apoptosis, observed by AO/EBr staining and flow cytometry analysis. The highest pyrimidine-2(5H)-thione internalization in MCF-7 cells may be due to folate conjugated on the surface of curdlan gum nanoparticles. Further, internalized pyrimidine-2(5H)-thione increases the intracellular ROS level, leading to apoptosis and inducing the decalin in mitochondrial membrane potential. These outcomes demonstrated that the FA-Py-CG-PEGamine NPs were specificity-targeting folate receptors on the plasma membranes of MCF-7 Cells.

Stimulating the Antitumor Immune Response Using Immunocytokines: A Preclinical and Clinical Overview.

Cytokines are immune modulators which can enhance the immune response and have been proven to be an effective class of immunotherapy. Nevertheless, the clinical use of cytokines in cancer treatment has faced several challenges associated with poor pharmacokinetic properties and the occurrence of adverse effects. Immunocytokines (ICKs) have emerged as a promising approach to overcome the pharmacological limitations observed with cytokines. ICKs are fusion proteins designed to deliver cytokines in the tumor microenvironment by taking advantage of the stability and specificity of immunoglobulin-based scaffolds. Several technological approaches have been developed. This review focuses on ICKs designed with the most impactful cytokines in the cancer field: IL-2, TNFα, IL-10, IL-12, IL-15, IL-21, IFNγ, GM-CSF, and IFNα. An overview of the pharmacological effects of the naked cytokines and ICKs tested for cancer therapy is detailed. A particular emphasis is given on the immunomodulatory effects of ICKs associated with their technological design. In conclusion, this review highlights active ways of development of ICKs. Their already promising results observed in clinical trials are likely to be improved with the advances in targeting technologies such as cytokine/linker engineering and the design of multispecific antibodies with tumor targeting and immunostimulatory functional properties.

Preparation, Characterization, and Skin Permeation Evaluation of Naproxen Microemulsions for Transdermal Delivery

: Microemulsions (MEs) are considered for preparing drug delivery carriers, especially transdermal vehicles. Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to manage chronic and acute pain and inflammatory diseases. However, NSAIDs have drawbacks such as gastrointestinal tract disorders and poor pharmacokinetic properties for oral administration. To address these issues, we evaluated the potential of ME as a transdermal system for locally delivering naproxen (NPX) as an NSAIDs model (NPX-MEs). Phase diagrams were constructed for MEs composed of tween 80, span 80, and propylene glycol (PG) as surfactant (S)/cosurfactant (CS), transcutol® P (TRC-P), and LabrafacTM PG as oil. The final concentration of NPX in MEs was 1% (w/v). The MEs were analyzed for particle size, refractive index, and viscosity. In vitro permeability studies of NPX-MEs were conducted using Franz diffusion cells on rat skin samples. Additionally, the effects of Eucalyptus oil (EU oil), oleic acid (OLA), and TRC-P as enhancers on the skin permeation of NPX were investigated. The particle size and viscosity values of the NPX-MEs ranged from 7.05 ± 0.03 to 79.56 ± 0.58 nm and 222.4 ± 0.87 to 681.13 ± 1.97, respectively. The optimal formulation, ME-3, consisted of 20% oil, 10% water, and 70% S/C phases. The skin permeation rates of NPX from ME-3 were higher than those of other formulations (Dapp = 1.36 ± 0.616, ERD=527.989 ± 313.627) with a lower lag time. Additionally, OLA-treated skin showed the highest transdermal permeation rate (ERD = 75.55 ± 23.532). Based on these results, the formulated NPX-ME may be a desirable carrier for transdermal delivery compared to traditional formulations, potentially reducing side effects and improving the therapeutic efficacy of NPX.

Strategies and Recent Advances on Improving Efficient Antitumor of Lenvatinib Based on Nanoparticle Delivery System.

Lenvatinib (LVN) is a potentially effective multiple-targeted receptor tyrosine kinase inhibitor approved for treating hepatocellular carcinoma, metastatic renal cell carcinoma and thyroid cancer. Nonetheless, poor pharmacokinetic properties including poor water solubility and rapid metabolic, complex tumor microenvironment, and drug resistance have impeded its satisfactory therapeutic efficacy. This article comprehensively reviews the uses of nanotechnology in LVN to improve antitumor effects. With the characteristic of high modifiability and loading capacity of the nano-drug delivery system, an active targeting approach, controllable drug release, and biomimetic strategies have been devised to deliver LVN to target tumors in sequence, compensating for the lack of passive targeting. The existing applications and advances of LVN in improving therapeutic efficacy include improving longer-term efficiency, achieving higher efficiency, combination therapy, tracking and diagnosing application and reducing toxicity. Therefore, using multiple strategies combined with photothermal, photodynamic, and immunoregulatory therapies potentially overcomes multi-drug resistance, regulates unfavorable tumor microenvironment, and yields higher synergistic antitumor effects. In brief, the nano-LVN delivery system has brought light to the war against cancer while at the same time improving the antitumor effect. More intelligent and multifunctional nanoparticles should be investigated and further converted into clinical applications in the future.

A Review on the Mechanism and Structure-activity Relationship of Resveratrol Heteroaryl Analogues.

Resveratrol is one of the most interesting naturally-occurring nonflavonoid phenolic compounds with various biological activities, such as anticancer, neuroprotection, antibacterial, and anti-inflammatory. However, there is no clinical usage of resveratrol due to either its poor activity or poor pharmacokinetic properties. Heteroarenes-modified resveratrol is one pathway to improve its biological activities and bioavailability, and form more modification sites. In this review, we present the progress of heteroaryl analogues of resveratrol with promising biological activities in the latest five years, ranging from the synthesis to the structure-activity relationship and mechanism of actions. Finally, introducing heteroarenes into resveratrol is an effective strategy, which focuses on the selectivity of structure-activity relationship in vivo.

Design, Synthesis, and Biological Evaluation of Novel Arylomycins against Multidrug-Resistant Gram-Negative Bacteria.

G0775, an arylomycin-type SPase I inhibitor that is being evaluated in a preclinical study, exhibited potent antibacterial activities against some Gram-negative bacteria but meanwhile suffered defects such as a narrow antibacterial spectrum and poor pharmacokinetic properties. Herein, systematic structural modifications were carried out, including optimization of the macrocyclic skeleton, warheads, and lipophilic regions. The optimization culminated in the discovery of 138f, which showed more potent activity and a broader spectrum against clinically isolated carbapenem-resistant Gram-negative bacteria, especially against Acinetobacter baumannii and Pseudomonas aeruginosa. 162, the free amine of 138f, exhibited an excellent pharmacokinetic profile in rats. In a neutropenic mouse thigh model of infection with multidrug-resistant P. aeruginosa, the potent in vivo antibacterial efficacy of 162 was confirmed and superior to that of G0775 (3.5-log decrease vs 1.1-log decrease in colony-forming unit (CFU)). These results support 162 as a potential antimicrobial agent for further research.

Abstract 4479: Design, synthesis, and evaluation of amino acid conjugated niclosamide prodrugs as a PepT1 substrate

Abstract The anthelmintic drug, Niclosamide, has a multitude of promising anticancer properties including inhibition of key signaling pathways involved in tumorigenesis, disruption of mitochondrial function, degradation of the overexpressed androgen receptor, and more. However, a key limitation of the clinical use of Niclosamide in cancer treatment is its low solubility and cellular uptake, which result in poor pharmacokinetic properties and dose-limiting GI toxicities at concentrations lower than the therapeutic threshold of the drug. To overcome this, we hypothesized that we could use amino acid conjugated niclosamide prodrugs to improve cellular uptake by creating a substrate of the PepT1 transport protein. The overexpression of the PepT1 transport protein that is involved in many hormonal cancers is being used to our advantage. Our study involved first synthesizing a group of niclosamide and niclosamide analogs conjugated with polar or nonpolar amino acids. Next, we conducted a Glycine-Sarcosine assay measuring changes in the uptake of the dipeptide glycyl-sarcosine (Gly-Sar). Our initial step was to examine if our conjugates could disrupt the absorption of Gly-Sar. The active conjugate will be tested whether they are substrates or inhibitors of the transporter. For the future, we have plans to determine the half-maximal inhibitory concentration (IC50) of niclosamide conjugates in various cancer cell lines and to quantify cleavage of the prodrugs intracellularly. Citation Format: Alaina C. McDonough, Jeffery Y. Cheng, Shabber Mohammed, Pui-Kai Li, Yangzom Bhutia. Design, synthesis, and evaluation of amino acid conjugated niclosamide prodrugs as a PepT1 substrate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4479.

Abstract 5817: pH responsive delivery of gemcitabine/pirarubicin co-loaded biodegradable polymeric nanoparticles for synergistic anti-cancer therapy

Abstract Gemcitabine, a nucleoside antimetabolite, is a widely known chemotherapeutic agent being used as a first line treatment alone or in combination with other chemo drugs for different types of cancer. However, due to its extremely short half-life in the body caused by enzymatic degradation and poor pharmacokinetics, the I.V. dosage of administration is quite high i.e., >1000 mg/m2 for metastatic breast cancer treatment. Moreover, gemcitabine in combination with anthracyclines imparts synergy but free anthracyclines are reported to be associated with long term cardiac toxicity. Nanoparticle-based drug delivery systems have provided a befitted solution for improving the poor pharmacokinetic properties and systemic toxicity caused by the chemo drugs because of their ability to improve bioavailability of the drugs at the desired site as well as overcoming multi-drug resistance (MDR).In the present work, PLA-based biodegradable block copolymeric nanoparticles have been employed to co-load Gemcitabine and Pirarubicin for improved anti-cancer activity. Gemcitabine and Pirarubicin have been chemically conjugated to the amphiphilic block copolymer mPEG PLA via a pH responsive Schiff’s Base linkage using a linker molecule Levulinic acid. The prepared PIRA/GEM co-loaded nanoparticles exhibited an optimum size, zeta potential and polydispersity index i.e., 187 ± 3.5 nm, -10 ± 2.0 and < 0.1 PDI respectively. Further, in the drug release experiments, these Nps displayed sustained and higher drug release in lysosomal pH (pH 5.0) than in the physiological buffer environment (pH 7.4) attributed to the pH sensitive bonding. The co-loaded Nps were prepared in multiple ratios (Pira: Gem - 1:1, 1:3, and 3:1) and investigated for in-vitro cellular inhibition studies in comparison to singly loaded drug Nps and corresponding free drug formulations in various breast cancer cell lines. Additionally, apoptotic studies revealed significant enhancement in synergistic activity in the case of PIRA/GEM co-loaded Nps in comparison to conventional free drug formulations. In conclusion, this nano-formulation demonstrated excellent anti-cancer activity against breast cancer cells therefore it may be used as a potential candidate for therapeutic use. Citation Format: Priya Gupta, Surender M. Kharbanda, Harpal Singh. pH responsive delivery of gemcitabine/pirarubicin co-loaded biodegradable polymeric nanoparticles for synergistic anti-cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5817.

Unleashing the Potential of Camptothecin: Exploring Innovative Strategies for Structural Modification and Therapeutic Advancements.

Camptothecin (CPT) is a potent anti-cancer agent targeting topoisomerase I (TOP1). However, CPT has poor pharmacokinetic properties, causes toxicities, and leads to drug resistance, which limit its clinical use. In this paper, to review the current state of CPT research. We first briefly explain CPT's TOP1 inhibition mechanism and the key hurdles in CPT drug development. Then we examine strategies to overcome CPT's limitations through structural modifications and advanced delivery systems. Though modifications alone seem insufficient to fully enhance CPT's therapeutic potential, structure-activity relationship analysis provides insights to guide optimization of CPT analogs. In comparison, advanced delivery systems integrating controlled release, imaging capabilities, and combination therapies via stimulus-responsive linkers and targeting moieties show great promise for improving CPT's pharmacological profile. Looking forward, multifaceted approaches combining selective CPT derivatives with advanced delivery systems, informed by emerging biological insights, hold promise for fully unleashing CPT's anti-cancer potential.

In silico Toxicity and Pharmaceutical Properties to Get Candidates for Antitumor Drug

Background: Drug metabolism is a crucial aspect of medical practice and pharmacology, involving the transformation of drugs by various bodily systems to create compounds that are more easily eliminated from the body. Sorafenib was reported as a useful adjuvant treatment in patients with hepatocellular carcinoma who underwent surgical resection. However, poor pharmacokinetic properties such as limited water solubility, rapid elimination and metabolism lead to low bioavailability, restricting its further clinical application. Rosmarinic acid, soluble in ethanol and found in Rosemary leaves, has demonstrated therapeutic benefits in conditions such as cancer, diabetes, inflammatory disorders, neurodegenerative disorders, and liver disease. 
 Method: In silico is a term for experiments or tests carried out using computer simulation methods. In silico testing has emerged as a valuable approach for initiating the exploration of novel drug compounds or enhancing the efficacy of existing ones. This method involves predicting, generating hypotheses, and uncovering potential breakthroughs in medicine and therapy through virtual simulations.
 Results: Caco2 value of Sorafenib ligand as a comparison, namely 0.762. The highest Caco2 value is owned by Betulinic Acid and the value The lowest Caco2 is owned by Rosmarinic Acid. The highest sample HIA value was owned by Ursolic Acid and the lowest was owned by Rosmarinic Acid. Meanwhile, Sorafenib's HIA value is 85,494. ligands such as Carnosol and rosmanol have a high distribution volume, while the Sama carnosic league, ursolic acid and betulinic acid have a low distribution volume. The Rosmarinic acid ligand has a good distribution volume of 0.393, while the distribution volume value of Sorafenib is -0.009. The highest BBB sample value was owned by Carnosol and the lowest was owned by Rosmarinic acid. Meanwhile, the comparison ligand has a value of -1.473 and is considered less distributed in the brain. all ligands such as Carnosic Acid, Carnosol, Rosmanol, Ursolic Acid, Betulinic Acid, Rosmarinic acid do not have mutagenicity and Cytotoxic effects, but have an effect on immunity. The comparison ligand Sorafenib turned out to have effects on hepatotoxicity, immunity and cytotoxicity.
 Conclusion: In pharmacokinetic research, the six phenolic acid compounds in Rosemary exhibited superior properties compared to the reference ligand Sorafenib.

Synergism of non-thermal plasma and low concentration RSL3 triggers ferroptosis via promoting xCT lysosomal degradation through ROS/AMPK/mTOR axis in lung cancer cells

BackgroundThough (1S, 3R)-RSL3 has been used widely in basic research as a small molecular inducer of ferroptosis, the toxicity on normal cells and poor pharmacokinetic properties of RSL3 limited its clinical application. Here, we investigated the synergism of non-thermal plasma (NTP) and low-concentration RSL3 and attempted to rise the sensitivity of NSCLC cells on RSL3.MethodsCCK-8 assay was employed to detect the change of cell viability. Microscopy and flowcytometry were applied to identify lipid peroxidation, cell death and reactive oxygen species (ROS) level respectively. The molecular mechanism was inspected with western blot and RT-qPCR. A xenograft mice model was adopted to investigate the effect of NTP and RSL3.ResultsWe found the synergism of NTP and low-concentration RSL3 triggered severe mitochondria damage, more cell death and rapid ferroptosis occurrence in vitro and in vivo. NTP and RSL3 synergistically induced xCT lysosomal degradation through ROS/AMPK/mTOR signaling. Furthermore, we revealed mitochondrial ROS was the main executor for ferroptosis induced by the combined treatment.ConclusionOur research shows NTP treatment promoted the toxic effect of RSL3 by inducing more ferroptosis rapidly and provided possibility of RSL3 clinical application.Graphical DeK3en8zu4Ed_UHNNMi2cXVideo

Advances, opportunities, and challenges in methods for interrogating the structure activity relationships of natural products.

Time span in literature: 1985-early 2024Natural products play a key role in drug discovery, both as a direct source of drugs and as a starting point for the development of synthetic compounds. Most natural products are not suitable to be used as drugs without further modification due to insufficient activity or poor pharmacokinetic properties. Choosing what modifications to make requires an understanding of the compound's structure-activity relationships. Use of structure-activity relationships is commonplace and essential in medicinal chemistry campaigns applied to human-designed synthetic compounds. Structure-activity relationships have also been used to improve the properties of natural products, but several challenges still limit these efforts. Here, we review methods for studying the structure-activity relationships of natural products and their limitations. Specifically, we will discuss how synthesis, including total synthesis, late-stage derivatization, chemoenzymatic synthetic pathways, and engineering and genome mining of biosynthetic pathways can be used to produce natural product analogs and discuss the challenges of each of these approaches. Finally, we will discuss computational methods including machine learning methods for analyzing the relationship between biosynthetic genes and product activity, computer aided drug design techniques, and interpretable artificial intelligence approaches towards elucidating structure-activity relationships from models trained to predict bioactivity from chemical structure. Our focus will be on these latter topics as their applications for natural products have not been extensively reviewed. We suggest that these methods are all complementary to each other, and that only collaborative efforts using a combination of these techniques will result in a full understanding of the structure-activity relationships of natural products.

Inhibition of protein-protein interactions using biodegradable depsipeptide nanoassemblies

Although peptides notoriously have poor intrinsic pharmacokinetic properties, it is well-known that nanostructures with excellent pharmacokinetic properties can be designed. Noticing that peptide inhibitors are generally nonpolar, here, we consolidate the peptide inhibitor targeting intracellular protein–protein interactions (PPIs) as an integral part of biodegradable self-assembled depsipeptide nanostructures (SdPNs). Because the peptide inhibitor has the dual role of PPI inhibition and self-assembly in this design, problems associated with the poor pharmacokinetics of peptides and encapsulation/entrapment processes can be overcome. Optimized SdPNs displayed better tumor targeting and PPI inhibition properties than the comparable small molecule inhibitor in vivo. Kinetics of PPI inhibition for SdPNs were gradual and controllable in contrast to the rapid inhibition kinetics of the small molecule. Because SdPN is modular, any appropriate peptide inhibitor can be incorporated into the platform without concern for the poor pharmacokinetic properties of the peptide.

Recombinant human endostatin as a potential anti-angiogenic agent: therapeutic perspective and current status.

Angiogenesis is the physiological process that results in the formation of new blood vessels develop from pre-existing vasculature and plays a significant role in several physiological and pathological processes. Inhibiting angiogenesis, a crucial mechanism in the growth and metastasis of cancer, has been proposed as a potential anticancer therapy. Different studies showed the beneficial effects of angiogenesis inhibitors either in patients suffering from different cancers, alone or in combination with conventional therapies. Even though there are currently a number of efficient anti-angiogenic drugs, including monoclonal antibodies and kinase inhibitors, the associated toxicity profile and theiraffordability constraints are prompting researchers to search for a safe and affordable angiostatic agent for cancer treatment. Endostatin is one of the endogenous anti-angiogenic candidates that have been extensively pursued for the treatment of cancer, but even over three decades after its discovery, we have not made much advancement in employing it as an anticancer therapeutic despite of its remarkable anti-angiogenic effect with low toxicity profile. A recombinant human endostatin (rh-Es) variant for non-small cell lung cancer was approved by China in 2006 and has since been used effectively. Several other successful clinical trials related to endostatin for various malignancies are either ongoing or have already been completed with promising results. Thus, in this review, we have provided an overview of existing anti-angiogenic drugs developed for cancer therapy, with a summary of tumour angiogenesis in the context of Endostatin, and clinical status of rh-Es in cancer treatment. Furthermore, we briefly discuss the various strategies to improve endostatin features (poor pharmacokinetic properties) for developing rh-Es as a safe and effective agent for cancer treatment.