Design, synthesis, and in vitro and in vivo biological evaluation of dihydroartemisinin derivatives as potent anti-cancer agents with ferroptosis-inducing and apoptosis-activating properties.

Natural products play a pivotal role in drug development, including their direct use as pharmaceuticals and their structural modification, yielding molecules with enhanced therapeutic potential. The discovery of bioactive molecules, lead compounds, and novel drugs is intrinsically linked to the structural optimization of natural products. In this study, forty-one derivatives of dihydroartemisinin (DHA) were synthesized by incorporating fragments with anti-tumour activity via molecular hybridization, and assessed for their anti-proliferative activity against human cancer cell lines (A549, Bel-7402, HCT-116, and SW620) and normal human liver cells (LO2). Most derivatives exhibited superior anti-proliferative activity compared to DHA. Notably, compound A3, featuring a 4-Cl phenyl carbamate moiety, demonstrated significant anti-proliferative activity against HCT-116 cells with an IC50 of 0.31 µM, making it 16-fold more potent than DHA (IC50 = 5.10 µM). The anti-proliferative mechanism did not involve cytotoxicity (SI = 54.13), indicating its superior safety profile compared to DHA (SI = 1.65). Further mechanistic studies revealed that compound A3 inhibits HCT-116 cell proliferation by modulating the expression of PI3K/AKT/mTOR and STAT3 proteins. STAT3 downregulation represses the expression of the critical ferroptosis protein glutathione peroxidase 4 (GPX4), aggravating the accumulation of reactive oxygen species (ROS) and depletion of glutathione (GSH). This redox imbalance triggers and accelerates ferroptosis. Additionally, A3 also induces apoptosis by damaging mitochondria and influencing MAPK signaling. Compound A3 arrested cells in the G2/M phase by regulating p53 expression. In an HCT-116 xenograft mouse model, compound A3 exhibited significant anti-cancer efficacy, with a tumor growth inhibition rate of 58.7 %. Therefore, compound A3 thus has the potential to serve as a lead compound for the development of new anti-tumor drugs.

Design, synthesis, and evaluation of antitumor activity in Pseudolaric acid B Azole derivatives: Novel and potent angiogenesis inhibitor via regulation of the PI3K/AKT and MAPK mediated HIF-1/VEGF signaling pathway.

Tumor proliferation and metastasis are intricately linked to blood vessel formation, with vascular endothelial growth factor (VEGF) playing a pivotal role in orchestrating angiogenesis throughout tumor progression. Pseudolaric acid B (PAB) has emerged as a potent inhibitor of tumor cell proliferation, migration, and angiogenesis. In efforts to enhance its efficacy, 37 derivatives of PAB were synthesized and assessed for their capacity to suppress VEGF secretion in SiHa cells under hypoxic conditions. Notably, majority of these derivatives exhibited significant inhibition of VEGF protein secretion without inducing cytotoxicity. Among them, compound M2 displayed the most potent inhibitory activity, with an IC50 value of 0.68 µM, outperforming the lead compound PAB (IC50 = 5.44 µM). Compound M2 not only curbed the migration and angiogenesis of HUVECs under hypoxic conditions but also hindered the invasion of SiHa cells. Mechanistic investigations unveiled that compound M2 may impede the accumulation and nuclear translocation of hypoxia-inducible factor 1α (HIF-1α) in SiHa cells, thereby downregulating VEGF expression. This inhibitory effect on HIF-1α was corroborated by experiments utilizing the protease inhibitor MG-132 and protein synthesis inhibitor CHX, indicating that compound M2 diminishes HIF-1α levels by reducing its synthesis. Furthermore, compound M2 was observed to modulate the PI3K/AKT/mTOR and MAPK signaling pathways in tumor cells, thereby regulating HIF-1α translation and synthesis. In vivo studies demonstrated that compound M2 exhibited low toxicity and effectively curbed tumor growth. Immunohistochemistry analyses validated that compound M2 effectively suppressed the expression of HIF-1α and VEGF in tumor tissues, underscoring its potential as a promising therapeutic agent for targeting tumor angiogenesis.

Design, synthesis, and in vivo and in vitro biological screening of pseudolaric acid B derivatives as potential anti-tumor agents.

Pseudolaric Acid B (PAB), a natural product with remarkable anti-tumor activity, is a starting point for new anticancer therapeutics. We designed and synthesized 27 PAB derivatives and evaluated their anti-proliferative activities against four cancer cell lines: MCF-7, HCT-116, HepG2, and A549. Compared with unmodified PAB, the PAB derivatives showed stronger anti-proliferative activity. The ability of compound D3 (IC50 = 0.21 µM) to inhibit HCT-116 cells was approximately 5.3 times that of PAB (IC50 = 1.11 µM) and the antiproliferative action was unrelated to cytotoxicity (SI=20.38), indicating its superior safety profile (PAB; SI=0.95). Compound D3 effectively suppressed the EdU-positive rate and reduced colony formation, arrested HCT-116 cells in the S and G2/M phases and induced apoptosis. In vivo experiments further demonstrated low toxicity of compound D3 while suppressing tumor growth in mice. In summary, given its strong anti-proliferative effect and relative safety, further development of compound D3 is warranted.

Design and synthesis of forsythin derivatives as anti-inflammatory agents for acute lung injury.

Acute lung injury (ALI) is a clinically high mortality disease, which has not yet been effectively treated. The development of anti-ALI drugs is imminent. ALI can be effectively treated by inhibiting the inflammatory cascade and reducing the inflammatory response in the lung. Forsythia suspense is a common Chinese herbal medicine with significant anti-inflammatory activity. Using forsythin as the parent, 27 Forsythin derivatives were designed and synthesized, and the anti-AIL activity of these compounds was evaluated. Among them, compound B5 has the best activity to inhibit the release of IL-6, and the inhibition rate reaches 91.79% at 25 µM, which was 7.5 times that of the parent forsythin. In addition, most of the compounds have no significant cytotoxicity in vitro. Further studies showed that compound B5 had a concentration-dependent inhibitory effect on NO, IL-6 and TNF-α. And the IC50 values of compound B5 for NO and IL-6 are 10.88 µM and 4.93 µM, respectively. We also found that B5 could significantly inhibit the expression of some immune-related cytotoxic factors, including inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). In addition, B5 inhibits NF-κB/MAPK signaling pathway. In vivo experiments showed that B5 could alleviate lung inflammation in LPS-induced ALI mice and inhibit IL-6, TNF-α, COX-2 and iNOS. In summary, B5 has anti-inflammatory effects and alleviates ALI by regulating inflammatory mediators and inhibiting MAPK and NF-κB signaling pathways.

Bioactivities and Structure-Activity Relationships of Usnic Acid Derivatives: A Review.

Usnic acid has a variety of biological activities, and has been widely studied in the fields of antibacterial, immune stimulation, antiviral, antifungal, anti-inflammatory and antiparasitic. Based on this, usnic acid is used as the lead compound for structural modification. In order to enhance the biological activity and solubility of usnic acid, scholars have carried out a large number of structural modifications, and found some usnic acid derivatives to be of more potential research value. In this paper, the structural modification, biological activity and structure-activity relationship of usnic acid were reviewed to provide reference for the development of usnic acid derivatives.

Panaxadiol carbamate derivatives: Synthesis and biological evaluation as potential multifunctional anti-Alzheimer agents.

It is reported that panaxadiol has neuroprotective effects. Previous studies have found that compound with carbamate structure introduced at the 3-OH position of 20 (R) -panaxadiol showed the most effective neuroprotective activity with an EC50 of 13.17 µM. Therefore, we designed and synthesized a series of ginseng diol carbamate derivatives with ginseng diol as the lead compound, and tested their anti-AD activity. It was found that the protective effect of compound Q4 on adrenal pheochromocytoma was 80.6 ±â€¯10.85 % (15 µM), and the EC50 was 4.32 µM. According to the ELISA results, Q4 reduced the expression of Aß25-35 by decreasing ß-secretase production. Molecular docking studies revealed that the binding affinity of Q4 to ß-secretase was -49.67 kcal/mol, indicating a strong binding affinity of Q4 to ß-secretase. Western blotting showed that compound Q4 decreased IL-1ß levels, which may contribute to its anti-inflammatory effect. Furthermore, compound Q4 exhibits anti-AD activities by reducing abnormal phosphorylation of tau protein and activation of the mitogen activated protein kinase pathway. The learning and memory deficits in mice treated with Q4in vivo were significantly alleviated. Therefore, Q4 may be a promising multifunctional drug for the treatment of AD, providing a new way for anti-AD drugs.

Bioactivities and Structure-Activity Relationships of Maslinic Acid Derivatives: A Review.

Maslinic acid has a variety of biological activities, such as anti-tumor, hypoglycemic, anti-inflammatory, and anti-parasitic. In order to enhance the biological activity of maslinic acid, scholars have carried out a lot of structural modifications, and found some more valuable maslinic acid derivatives. In this paper, the structural modification, biological activity, and structure-activity relationship of maslinic acid were reviewed, providing references for the development of maslinic acid.

Research status of indole-modified natural products.

Indole is a heterocyclic compound formed by the fusion of a benzene ring and pyrrole ring, which has rich biological activity. Many indole-containing compounds have been sold on the market due to their excellent pharmacological activity. For example, vincristine and reserpine have been widely used in clinical practice. The diverse structures and biological activities of natural products provide abundant resources for the development of new drugs. Therefore, this review classifies natural products by structure, and summarizes the research progress of indole-containing natural product derivatives, their biological activities, structure-activity relationship and research mechanism which has been studied in the past 13 years, so as to provide a basis for the development of new drug development.

Natural Products-Pyrazine Hybrids: A Review of Developments in Medicinal Chemistry.

Pyrazine is a six-membered heterocyclic ring containing nitrogen, and many of its derivatives are biologically active compounds. References have been downloaded through Web of Science, PubMed, Science Direct, and SciFinder Scholar. The structure, biological activity, and mechanism of natural product derivatives containing pyrazine fragments reported from 2000 to September 2023 were reviewed. Publications reporting only the chemistry of pyrazine derivatives are beyond the scope of this review and have not been included. The results of research work show that pyrazine-modified natural product derivatives have a wide range of biological activities, including anti-inflammatory, anticancer, antibacterial, antiparasitic, and antioxidant activities. Many of these derivatives exhibit stronger pharmacodynamic activity and less toxicity than their parent compounds. This review has a certain reference value for the development of heterocyclic compounds, especially pyrazine natural product derivatives.

Synthesis and structure-activity relationship studies of fusidic acid derivatives as anti-inflammatory agents for acute lung injury.

Acute lung injury (ALI) are severe forms of diffuse lung disease that impose a substantial health burden all over the world. In the United States, approximately 190,000 cases per year of ALI each year, with an associated 74,500 deaths per year. Anti-inflammatory therapy has become a reasonable approach for the treatment of patients with ALI. In this study, fusidic acid derivatives were used to design new anti-inflammatory compounds with high pharmacological activity and low toxicity. A total of 30 new fusidic acid derivatives were discovered, synthesized, and screened for their anti-inflammatory activity against lipopolysaccharide (LPS)-treated RAW264.7 cells. Of them, b2 was found to be the most active, with a higher efficiency compared with fusidic acid and celecoxib in 10 µM. In vitro, we further measured b2 inhibited inflammatory factor NO (IC50 = 5.382 ± 0.655 µM), IL-6 (IC50 = 7.767 ± 0.871 µM), and TNF-α (IC50 = 7.089 ± 0.775 µM) and b2 inhibited inflammatory cytokines COX-2 and iNOS, ROS production, NF-κB/MAPK and Bax/Bcl-2 signaling pathway pathway. In vivo,b2 attenuated ALI pathological changes and inhibited inflammatory cytokines COX-2 and iNOS in lung tissue and NF-κB/MAPK and Bax/Bcl-2 signaling pathway. In conclusion, b2 may be a promising anti-inflammatory lead compound.

Pharmacological overview of hederagenin and its derivatives.

Hederagenin is a pentacyclic triterpenoid isolated from plants and widely distributed in a variety of medicinal plants. By integrating and analyzing external related literature reports, the latest research progress on the pharmacological effects and structural modification of hederagenin was reviewed. Hederagenin has a wide range of pharmacological activities, including antitumor, anti-inflammatory, antidepressant, anti-neurodegenerative, antihyperlipidemic, antidiabetic, anti-leishmaniasis, and antiviral activities. Among them, it shows high potential in the field of anti-tumor treatment. This paper also reviews the structural modifications of hederagenin, including carboxyl group modifications and two hydroxyl group modifications. Future research on hederagenin will focus on prolonging its half-life, improving its bioavailability and structural modification to enhance its pharmacological activity, accelerating the preclinical research stage of hederagenin for it to enter the clinical research stage as soon as possible.

Discovery of Triazolyl Derivatives of Cucurbitacin B Targeting IGF2BP1 against Non-Small Cell Lung Cancer.

Cucurbitacin B (CuB) is a potent but toxic anticancer natural product. Herein, we designed and synthesized 2-OH- and 16-OH-modified CuB derivatives to improve their antitumor efficacy and reduce toxicity. Among them, derivative A11 had the most potent antiproliferative activity against A549 lung cancer cells (IC50 = 0.009 µM) and was approximately 10-fold more potent than CuB, while the cytotoxicity of A11 toward normal L02 cells was about 10-fold less potent, indicating a much wider therapeutic window than CuB. Derivative A11 directly binds to the insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) protein with a KD value of 2.88 nM, which is about 23-fold more potent than CuB, leading to the decreased expression of downstream apoptosis- and cell cycle-related proteins. More importantly, A11 exhibited much more potent anticancer efficacy in an A549 xenograft mouse model with a TGI rate of 80% and a superior in vivo safety profile than that of CuB.

Application of Quinoline Ring in Structural Modification of Natural Products.

Natural compounds are rich in pharmacological properties that are a hot topic in pharmaceutical research. The quinoline ring plays important roles in many biological processes in heterocycles. Many pharmacological compounds, including saquinavir and chloroquine, have been marketed as quinoline molecules with good anti-viral and anti-parasitic properties. Therefore, in this review, we summarize the medicinal chemistry of quinoline-modified natural product quinoline derivatives that were developed by several research teams in the past 10 years and find that these compounds have inhibitory effects on bacteria, viruses, parasites, inflammation, cancer, Alzheimer's disease, and others.

Design, synthesis fusidic acid derivatives alleviate acute lung injury via inhibiting MAPK/NF-κB/NLRP3 pathway.

Acute lung injury (ALI) refers to a series of lung lesions resulting from multiple lung injuries, even leading to morbidity and death, abundant previous reports have showed that anti-inflammatory as a key to treatment of ALI. Fusidic acid (FA) as an antibiotic has significant anti-bacterial activity and anti-inflammatory effects. In this study, we designed and synthesized 34 FA derivatives to identify new anti-inflammatory drugs. The anti-inflammatory activities of the derivatives were screened using lipopolysaccharide (LPS)-induced RAW264.7 cells to evaluate the anti-inflammatory activity of the compounds, we measured nitric oxide (NO) and interleukin-6 (IL-6). Most of compounds showed inhibitory effects on inflammatory NO and IL-6 in LPS-induced RAW264.7 cells. Based on the screening results, compound a1 showed the strongest anti-inflammatory activity. Compared with FA, the inhibition rate NO and IL-6 of compound a1 increased 3.08 and 2.09 times at 10 µM, respectively. We further measured a1 inhibited inflammatory factor NO (IC50 = 3.26 ± 0.42 µM), IL-6 (IC50 = 1.85 ± 0.21 µM) and TNF-α (IC50 = 3.88 ± 0.55 µM). We also demonstrated that a1 markedly inhibits the expression of certain immune-related cytotoxic factors, including cyclooxygenase-2 (COX-2) and inducible nitric-oxide synthase (iNOS). In vivo results indicate that a1 can reduce lung inflammation and NO, IL-6, TNF-α, COX-2 and iNOS in LPS-induced ALI mice. On the one hand, we demonstrated a1 inhibits the mitogen-activated protein kinase (MAPK) signaling pathway by down-regulating the phosphorylation of p38 MAPK, c-Jun N-terminal kinase (c-JNK) and extracellular signal-regulated kinase (ERK). Moreover, a1 also suppressing the phosphorylation of inhibitory NF-κB inhibitor α (IκBα) inhibits the activation of the nuclear factor-κB (NF-κB) signaling pathway. On the other hand, we demonstrated a1 also role in anti-inflammatory by inhibits nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome and further inhibits Caspase-1 and inflammatory factor interleukin-1ß (IL-1ß). In conclusion, our study demonstrates that a1 has an anti-inflammatory effect and alleviates ALI by regulating inflammatory mediators and suppressing the MAPK, NF-κB and NLRP3 inflammasome signaling pathways.

Application of the Mannich reaction in the structural modification of natural products.

The Mannich reaction is commonly used to introduce N atoms into compound molecules and is thus widely applied in drug synthesis. The Mannich reaction accounts for a certain proportion of structural modifications of natural products. The introduction of Mannich bases can significantly improve the activity, hydrophilicity, and medicinal properties of compounds; therefore, the Mannich reaction is widely used for the structural modification of natural products. In this paper, the application of the Mannich reaction to the structural modification of natural products is reviewed, providing a method for the structural modification of natural products.

Research progress of natural products and their derivatives against Alzheimer's disease.

Alzheimer's disease (AD), a persistent neurological dysfunction, has an increasing prevalence with the aging of the world and seriously threatens the health of the elderly. Although there is currently no effective treatment for AD, researchers have not given up, and are committed to exploring the pathogenesis of AD and possible therapeutic drugs. Natural products have attracted considerable attention owing to their unique advantages. One molecule can interact with multiple AD-related targets, thus having the potential to be developed in a multi-target drug. In addition, they are amenable to structural modifications to increase interaction and decrease toxicity. Therefore, natural products and their derivatives that ameliorate pathological changes in AD should be intensively and extensively studied. This review mainly presents research on natural products and their derivatives for the treatment of AD.

Application of cinnamic acid in the structural modification of natural products: A review.

Natural products can generally exhibit a variety of biological activities, but most show mediocre performance in preliminary activity evaluation. Natural products often require structural modification to obtain promising lead compounds. Cinnamic acid (CA) is readily available and has diverse biological activities and low cytotoxicity. Introducing CA into natural products may improve their performance, enhance biological activity, and reduce toxic side effect. Herein, we aimed to discuss related applications of CA in the structural modification of natural products and provide a theoretical basis for future derivatization and drug development of natural products. Published articles, web databases (PubMed, Science Direct, SCI Finder, and CNKI), and clinical trial websites (https://clinicaltrials.gov/) related to natural products and CA derivatives were included in the discussion. Based on the inclusion criteria, 128 studies were selected and discussed herein. Screening natural products of CA derivatives allowed for classification by their biological activities. The full text is organized according to the biological activities of the derivatives, with the following categories: anti-tumor, neuroprotective, anti-diabetic, anti-microbial, anti-parasitic, anti-oxidative, anti-inflammatory, and other activities. The biological activity of each CA derivative is discussed in detail. Notably, most derivatives exhibited enhanced biological activity and reduced cytotoxicity compared with the lead compound. CA has various advantages and can be widely used in the synthesis of natural product derivatives to enhance the properties of drug candidates or lead compounds.

Synthesis and evaluation of in vitro and in vivo anti-Toxoplasma gondii activity of tetraoxane-substituted ursolic acid derivatives.

A series of derivatives of ursolic acid (UA) were synthesised, the anti-Toxoplasma gondii activity was tested, and the selectivity index (SI) of these compounds was calculated to determine the derivative with the best anti-Toxoplasma gondii activity. Compound A7 showed the best activity against the Toxoplasma gondii (IC50 in T. gondii infected GES-1 cells: 9.1 ± 7.2 µM), better than the lead compound UA and the positive control drug Spiramycin. Compound A7 was selected for further in vivo research: A7 was tested for its effect on the inhibition rate of tachyzoites in mice and its biochemical parameters, such as alanine aminotransferase, aspartate aminotransferase, glutathione, and malondialdehyde were determined. Compound A7 was evaluated for its anti-Toxoplasma activity and partial damage to the liver. Therefore, the results show that compound A7 could be a potential lead compound for developing a novel anti-Toxoplasma gondii molecule.

In vitro and in vivo biological evaluation of newly synthesized multi-target 20(R)-panaxadiol derivatives for treating Alzheimer's disease.

An extensive study was performed to discover a series of novel 20(R)-panaxadiol derivatives with various substituents at the 3-OH position as nontoxic, brain-permeable, multi-target leads for treating Alzheimer's disease. In vitro analysis revealed that a compound bearing benzyl-substituted carbamate, which we denoted compound 14a, exhibited the most potent neuroprotective activity, with an EC50 of 13.17 µM. The neuroprotective effect of compound 14a was slightly more potent than that of donepezil and much more potent than that of 20(R)-panaxadiol. Compound 14a at 7.5-120 µM exhibited low toxicity in various cell lines. In addition, compound 14a exhibited a wide range of biological activities, including inhibiting apoptosis; inducing tau hyperphosphorylation; affecting beta-amyloid (Aß), ß-secretase, reactive oxygen species, tumor necrosis factor-α, cyclooxygenase-2, and interleukin-1ß production; and promoting Aß25-35 disaggregation. The effective permeability of compound 14a across the blood-brain barrier was 26.13 × 10-6 cm/s, indicating that it can provide adequate exposure in the central nervous system. Further, compound 14a improved learning, memory, and novel object recognition in mice, and in vivo toxicity experiments confirmed a good therapeutic safety range. Thus, compound 14a is a promising multifunctional lead for treating Alzheimer's disease and offers new avenues for natural product-derived anti-Alzheimer's disease drugs.

Study on the vasodilatory activity of lotus leaf extract and its representative substance nuciferine on thoracic aorta in rats.

Lotus (Nelumbo nucifera) leaves are widely used for both edible and medicinal applications. For its further utilization, we studied the vasodilatory activity of lotus leaf extract for the first time. In this study, we obtained the extracts using different ratios of water and ethanol, which was followed by polarity-dependent extraction. We found that the CH2Cl2 layer exhibited better vasodilatory activity (EC50 = 1.21 ± 0.10 µg/ml). HPLC and ESI-HRMS analysis of the CH2Cl2 layer using the standard product as a control revealed that nuciferine (Emax = 97.95 ± 0.76%, EC50 = 0.36 ± 0.02 µM) was the main component in this layer. Further research revealed that nuciferine exerts a multi-target synergistic effect to promote vasodilation, via the NO signaling pathway, K+ channel, Ca2+ channel, intracellular Ca2+ release, α and ß receptors, etc. Nuciferine exhibits good vasodilatory activity, and it exhibits the potential to be utilized as a lead compound.