Semisynthetic Compounds Research Articles

Classification and microbes involved in Plastic biodegradation: A review

Plastic is composed of synthetic and semi-synthetic compounds with immense applications. While Plastics are dangerous and harm the environment, their practice is causing their ingesting to grow. Outdated methods of plastic degradation through physical and chemical means like landfill, incineration, and recycling are expensive and perilous and release hazardous chemical substances to the environment. Thus, proper approaches are required to overcome this trick. Biodegradation through microbes on the other hand offers a hopeful solution. Presently, numerous categories of bacteria and other microbial species degrade plastic materials. Several steps are required in plastic biodegradation like biodeterioration, depolymerization, assimilation and mineralization. These processes will result in secretion of enzymes that degrade plastics and converts it into gasses and biomass along other biproducts.

Discovery of benzo[c]phenanthridine derivatives with potent activity against multidrug-resistant Mycobacterium tuberculosis.

Mycobacterium tuberculosis (Mtb), the pathogen responsible for tuberculosis (TB), is the leading cause of bacterial disease-related death worldwide. Current antibiotic regimens for the treatment of TB remain dated and suffer from long treatment times as well as the development of drug resistance. As such, the search for novel chemical modalities that have selective or potent anti-Mtb properties remains an urgent priority, particularly against multidrug-resistant (MDR) Mtb strains. Herein, we design and synthesize 35 novel benzo[c]phenanthridine derivatives (BPDs). The two most potent compounds, BPD-6 and BPD-9, accumulated within the bacterial cell and exhibited strong inhibitory activity (MIC90 ~2 to 10 µM) against multiple Mycobacterium strains while remaining inactive against a range of other Gram-negative and Gram-positive bacteria. BPD-6 and BPD-9 were also effective in reducing Mtb survival within infected macrophages, and BPD-9 reduced the burden of Mycobacterium bovis BCG in the lungs of infected mice. The two BPD compounds displayed comparable efficacy to rifampicin (RIF) against non-replicating Mtb (NR-Mtb). Importantly, BPD-6 and BPD-9 inhibited the growth of multiple MDR Mtb clinical isolates. Generation of BPD-9-resistant mutants identified the involvement of the Mmr efflux pump as an indirect resistance mechanism. The unique specificity of BPDs to Mycobacterium spp. and their efficacy against MDR Mtb isolates suggest a potential novel mechanism of action. The discovery of BPDs provides novel chemical scaffolds for anti-TB drug discovery.IMPORTANCEThe emergence of drug-resistant tuberculosis (TB) is a serious global health threat. There remains an urgent need to discover new antibiotics with unique mechanisms of action that are effective against drug-resistant Mycobacterium tuberculosis (Mtb). This study shows that novel semi-synthetic compounds can be derived from natural compounds to produce potent activity against Mtb. Importantly, the identified compounds have narrow spectrum activity against Mycobacterium species, including clinical multidrug-resistant (MDR) strains, are effective in infected macrophages and against non-replicating Mtb (NR-Mtb), and show anti-mycobacterial activity in mice. These new compounds provide promising chemical scaffolds to develop potent anti-Mtb drugs of the future.

The Alternatives of Antibiotics in Poultry Production for Reducing Antimicrobial Resistance

Antibiotics are natural, semi-synthetic, or chemical compounds that have anti-microbial activity and are used in livestock and poultry production for a variety of reasons, including therapeutic and growth promotion. The use of antibiotics in poultry production has been associated with the development of resistant bacteria. The present study attempted to explain the role of antibiotics as poultry growth promoters, bacterial resistance, and risks for human health, with a special focus on some selected bacterial species isolated from poultry farms and products. Furthermore, the manuscript reviewed the literature on alternative feed additives to reduce the reliance on antibiotics. Microbial resistance is a significant global health concern that has been a top global threat in the 21st century. The use of antibiotics in poultry production as non-therapeutic or growth promoters is at low doses and continuously, associated with developing resistant bacteria. Meanwhile, antibiotic-resistant genes in humans may have their roots in the diets of animals treated with antibiotics. Developing bacterial resistance has encouraged researchers to reduce the reliance on antibiotics by identifying potential feed additives, such as essential oils, bacteriophages, antimicrobial peptides, probiotics, prebiotics, organic acid, and enzymes that improve the immune system functions, reduce morbidity and mortality, improve the growth performances of poultry, and preserve consumer health.

Novel meriolin derivatives potently inhibit cell cycle progression and transcription in leukemia and lymphoma cells via inhibition of cyclin-dependent kinases (CDKs)

A key feature of cancer is the disruption of cell cycle regulation, which is characterized by the selective and abnormal activation of cyclin-dependent kinases (CDKs). Consequently, targeting CDKs via meriolins represents an attractive therapeutic approach for cancer therapy. Meriolins represent a semisynthetic compound class derived from meridianins and variolins with a known CDK inhibitory potential. Here, we analyzed the two novel derivatives meriolin 16 and meriolin 36 in comparison to other potent CDK inhibitors and could show that they displayed a high cytotoxic potential in different lymphoma and leukemia cell lines as well as in primary patient-derived lymphoma and leukemia cells. In a kinome screen, we showed that meriolin 16 and 36 prevalently inhibited most of the CDKs (such as CDK1, 2, 3, 5, 7, 8, 9, 12, 13, 16, 17, 18, 19, 20). In drug-to-target modeling studies, we predicted a common binding mode of meriolin 16 and 36 to the ATP-pocket of CDK2 and an additional flipped binding for meriolin 36. We could show that cell cycle progression and proliferation were blocked by abolishing phosphorylation of retinoblastoma protein (a major target of CDK2) at Ser612 and Thr82. Moreover, meriolin 16 prevented the CDK9-mediated phosphorylation of RNA polymerase II at Ser2 which is crucial for transcription initiation. This renders both meriolin derivatives as valuable anticancer drugs as they target three different Achilles’ heels of the tumor: (1) inhibition of cell cycle progression and proliferation, (2) prevention of transcription, and (3) induction of cell death.

Semisynthetic compounds for controlling Colletotrichum lindemuthianum on bean seeds

Anthracnose caused by Colletotrichum lindemuthianum is one of the main diseases that affect the bean crop. The use of semisynthetic compounds for controlling anthracnose aims at providing a higher balance to the ecosystem and a lower environmental impact. Based on this context, the objective of this work was: a) to carry out the prospection of compounds such as Phenyl S Citral, Phenyl Se Citronellal, and Citral at concentrations of 1, 0.5, 0.25, 0.125, 0.0625, 0.0312, 0.0156, 0.0078, and 0.0039%, which were modified from the essential oil of citronella and lemongrass, for controlling C. lindemuthianum; b) to evaluate the initial performance of seedlings and treat the incidence of C. lindemuthianum in bean seeds with Phenyl S Citral and Phenyl Se Citronellal at concentrations of 0.125 and 0.0625%. Phenyl Se Citronellal at 0.5% controlled 100% of mycelial growth and Phenyl S Citral at 0.5 and 1% controlled more than 50% of mycelial growth of C. lindemuthianum. The treatment with Phenyl S Citral and Phenyl Se Citronellal did not affect the physiological quality of bean seeds while increasing seedling development when using the 0.0625% concentration of Phenyl Se Citronellal. Treatment with Phenyl Se Citronellal at both concentrations decreased the incidence of C. lindemuthianum infection.

Structure and Ligand Based Virtual Screening and MPO Topological Analysis of Triazolo Thiadiazepine-fused Coumarin Derivatives as Anti-Parkinson Drug Candidates.

Parkinson's disease (PD) is a debilitating condition that can cause locomotor problems in affected patients, such as tremors and body rigidity. PD therapy often includes the use of monoamine oxidase B (MAOB) inhibitors, particularly phenylhalogen compounds and coumarin-based semi-synthetic compounds. The objective of this study was to analyze the structural, pharmacokinetic, and pharmacodynamic profile of a series of Triazolo Thiadiazepine-fused Coumarin Derivatives (TDCDs) against MAOB, in comparison with the inhibitor safinamide. To achieve this goal, we utilized structure-based virtual screening techniques, including target prediction and absorption, distribution, metabolism, and excretion (ADME) prediction based on multi-parameter optimization (MPO) topological analysis, as well as ligand-based virtual screening techniques, such as docking and molecular dynamics. The findings indicate that the TDCDs exhibit structural similarity to other bioactive compounds containing coumarin and MAOB-binding azoles, which are present in the ChEMBL database. The topological analyses suggest that TDCD3 has the best ADME profile, particularly due to the alignment between low lipophilicity and high polarity. The coumarin and triazole portions make a strong contribution to this profile, resulting in a permeability with Papp estimated at 2.15 × 10-5cm/s, indicating high cell viability. The substance is predicted to be metabolically stable. It is important to note that this is an objective evaluation based on the available data. Molecular docking simulations showed that the ligand has an affinity energy of -8.075kcal/mol with MAOB and interacts with biological substrate residues such as Pro102 and Phe103. The results suggest that the compound has a safe profile in relation to the MAOB model, making it a promising active ingredient for the treatment of PD.

Natural and Synthetic Phosphodiesterase Inhibitors in 2023: an Update on the Impact on Neurological and Psychiatric Conditions.

This Perspective provides an updated overview on the involvement of phosphodiesterase (PDE) isoforms and of the corresponding inhibitors in neurological disorders, including dementia, Parkinson's disease, multiple sclerosis, neuropsychiatric conditions and cerebral ischemia. Particular attention has been dedicated to natural and semi-synthetic compounds. Translation into the clinic of preclinical results, toxicity profile and bioavailability represent the challenging aspects in the development of PDE inhibitors. With the aim of providing the latest updates to the reader, the 2023 contributions in the field were considered for the preparation of this Perspective.

Caspase-driven cancer therapies: Navigating the bridge between lab discoveries and clinical applications.

Apoptosis is the cell's natural intrinsic regulatory mechanism of normal cells for programmed cell death, which plays an important role in cancer as a classical mechanism of tumor cell death causing minimal inflammation without causing damage to other cells in the vicinity. Induction of apoptosis by activation of caspases is one of the primary targets for cancer treatment. Over the years, a diverse range of natural, synthetic, and semisynthetic compounds and their derivatives have been investigated for their caspase-mediated apoptosis-induced anticancer activities. The review aims to compile the preclinical evidence and highlight the critical mechanistic pathways related to caspase-induced cell apoptosis in cancer treatment. The focus is placed on the key components of the mechanisms, including their chemical nature, and specific attention is given to phytochemicals derived from natural sources and synthetic and semisynthetic compounds. 180+ compounds from the past two decades with potential as anticancer agents are discussed in this review article. By summarizing the current knowledge and advancements in this field, this review provides a comprehensive overview of potential therapeutic strategies targeting apoptosis in cancer cells. The findings presented herein contribute to the ongoing efforts to combat cancer and stimulate further research into the development of effective and targeted anticancer therapies.

Semisynthesis and Cytotoxic Evaluation of an Ether Analogue Library Based on a Polyhalogenated Diphenyl Ether Scaffold Isolated from a Lamellodysidea Sponge.

The known oxygenated polyhalogenated diphenyl ether, 2-(2',4'-dibromophenoxy)-3,5-dibromophenol (1), with previously reported activity in multiple cytotoxicity assays was isolated from the sponge Lamellodysidea sp. and proved to be an amenable scaffold for semisynthetic library generation. The phenol group of 1 was targeted to generate 12 ether analogues in low-to-excellent yields, and the new library was fully characterized by NMR, UV, and MS analyses. The chemical structures for 2, 8, and 9 were additionally determined via single-crystal X-ray diffraction analysis. All natural and semisynthetic compounds were evaluated for their ability to inhibit the growth of DU145, LNCaP, MCF-7, and MDA-MB-231 cancer cell lines. Compound 3 was shown to have near-equivalent activity compared to scaffold 1 in two in vitro assays, and the activity of the compounds with an additional benzyl ring appeared to be reliant on the presence and position of additional halogens.

Isolation and Identification of Bioactive Compounds from Leaf and Flower Extracts of Firmiana colorata

Background Firmiana colorata is notable for its use in traditional medicine. Isolation structural elucidation of its bioactive compounds and scientific reasoning for its traditional use renders authenticity to the plant and corroborate the search for novel semi-synthetic compounds with potent medicinal properties. Objective The current study aimed to report the isolation structural elucidation and identification of two bioactive compounds from leaf and flower extracts of F. colorata using chromatographic and spectroscopic methods.Methodology Pure compounds were isolated from leaf and flower extracts respectively through column chromatography using n-hexane ethyl acetate and methanol mixture.Results Two pure compounds one isolated from a leaf extract Compound 1 and the other from a flower extract Compound 2 were successfully obtained using column chromatography. Based on a comparison of the spectral data of F. colorata with literature references Compound 1 from the leaf extract was identified as stearic acid and Compound 2 from the flower extract was identified as p-Coumaric acid.Conclusion Leaves of F. colorata are a good source of stearic acid which may find application in the food cosmetic and pharmaceutical industries. p-Coumaric acid is considered the contributor to the anti-inflammatory and antimicrobial properties exhibited by the flower extracts of F. colorata.

Chlorophyllin attenuates the effects of benzo[a]pyrene in human hepatoma HepG2/C3A cells

Chlorophyllin, a semisynthetic compound derived from chlorophyll, has been a focus in cancer prevention because it exerts important biological activities, such as antigenotoxic, antioxidative and anticarcinogenic activities. The aim of this study was to evaluate the effect of chlorophyllin against benzo[a]pyrene toxicity in HepG2/C3A cells. Cells were co-treated (chlorophyllin plus benzo[a]pyrene) and the cell viability, cell growth kinetics, cell cycle, and apoptosis were evaluated. The mRNA levels of cell cycle and apoptotic genes were analyzed. Our results showed that chlorophyllin reduce the antiproliferative effects of benzo[a]pyrene in a multi-specific manner, restoring the normal distribution of the cell cycle and inhibiting the cell death induced by the xenobiotic. Gene expression analysis showed that benzo[a]pyrene decreased the mRNA levels of genes involved in cell cycle control (cyclins and cyclin-dependent kinases) and apoptosis. Cells co-treated with 200 µM of chlorophyllin and benzo[a]pyrene also showed a downregulation of mRNA levels of the genes, but the expression levels of the gene that encodes to tumor protein p53 were maintained near to control. Thus, chlorophyllin is a good candidate as a chemoprotective agent that mitigates the cytotoxic effects benzo[a]pyrene and, thus, might be a promising tool to prevent liver cancer.

Pterostilbene-Isothiocyanate Inhibits Proliferation of Human MG-63 Osteosarcoma Cells via Abrogating β-Catenin/TCF-4 Interaction-A Mechanistic Insight.

Osteosarcoma, a highly metastasizing bone neoplasm, is a leading cause of death and disability in children and adolescents worldwide. Osteosarcoma is only suboptimally responsive to surgery and radio- and chemotherapy, that too with adverse side effects. Hence, there is a necessary need for safer alternative therapeutic approaches. This study evaluated the anticancer effects of the semi-synthetic compound, pterostilbene-isothiocyanate (PTER-ITC), on human osteosarcoma MG-63 cells through cytotoxicity, wound-healing, and transwell-migration assays. Results showed that PTER-ITC specifically inhibited the survival, proliferation, and migration of osteosarcoma cells. PTER-ITC induced apoptosis in MG-63 cells by disrupting mitochondrial membrane potential, as evident from the outcomes of different cytological staining. The antimetastatic potential of PTER-ITC was evaluated through immunostaining, RT-qPCR, and immunoblotting. In silico (molecular docking and dynamic simulation) and, subsequently, biochemical [co-immunoprecipitation (Co-IP) and luciferase reporter] assays deciphered the underlying mode-of-action of this compound. PTER-ITC increased E-cadherin and reduced N-cadherin levels, thereby facilitating the reversal of epithelial-mesenchymal transition (EMT). It also modulated the expressions of proliferative cell nuclear antigen (PCNA), caspase-3, poly [ADP-ribose] polymerase (PARP-1) and matrix metalloproteinase-2/9 (MMPs-2/9) at transcriptional and translational levels. PTER-ITC interfered with the β-catenin/transcription factor-4 (TCF-4) interaction in silico by occupying the β-catenin binding site on TCF-4, confirmed by their reduced physical interactions (Co-IP assay). This inhibited transcriptional activation of TCF-4 by β-catenin (as shown by luciferase reporter assay). In conclusion, PTER-ITC exhibited potent anticancer effects in vitro against human osteosarcoma cells by abrogating the β-catenin/TCF-4 interaction. Altogether, this study suggests that PTER-ITC may be regarded as a new approach for osteosarcoma treatment.

In Vitro and In Vivo Effects of Synthesis Novel Phenoxyacetamide Derivatives as Potent Apoptotic Inducer against HepG2 Cells through PARP-1 Inhibition.

To discover potential cytotoxic agents, new semi-synthetic phenoxy acetamide derivatives, compound I and compound II, were synthesized, characterized, and screened for their cytotoxic activity against breast cancer (MCF-7) and liver cancer (HepG2) cell lines. The two compounds were more promising against HepG2 than the MCF-7 cell line according to IC50 values. When tested against the HepG2 cell line, compound I, and compound II both had significantly increased cytotoxic activity when compared to the reference medication 5-Fluorouracil (5-FU), with IC50 values of 1.43 M, 5.32 M, and 6.52 M for compound 1, 5-FU and compound II, respectively. Also, compound I displayed a degree of selectivity towards cancer cells compared to normal cells. Compound I significantly enhanced HepG2 total apoptotic cell death by about a 24.51-fold increase. According to cell cycle analysis, compound I induced the arrest of the cell cycle phases G1/S and blocked the progression of the HepG2 cells. Applying the RT-PCR technique achieved a highly significant upregulation in pro-apoptotic genes. The anti-apoptotic gene was significantly downregulated. There was an intrinsic and extrinsic pathway, but the intrinsic pathway was the dominant one. Tumor growth suppression as measured by tumor weight and volume and other hematological, biochemical, and histopathological analyses confirmed the efficacy of compound I as an anticancer agent in vivo examination. Finally, the molecular docking study revealed that compound I was properly docked inside the binding site of PARP-1 protein with stable binding energies and interactive binding modes. Therefore, compound I shows promise as a selective anti-cancer derivative for the treatment of liver cancer after more investigations and clinical studies. This selectivity is a favorable characteristic in the developing cytotoxic agents for cancer treatment, as it indicates a potential for reduced harm to health tissues.

Anti-breast cancer potential of a new xanthine derivative: In silico, antiproliferative, selectivity, VEGFR-2 inhibition, apoptosis induction and migration inhibition studies

BackgroundThe overexpression of VEGFR-2 receptors in breast cancer provides a valuable approach to anticancer strategies. Targeting VEGFR-2, a new semisynthetic compound (T-1-MCPAB) has been designed. MethodsComputational methods (ADMET, toxicity, DFT, Molecular Docking, Molecular Dynamics Simulations, MM-GBSA, PLIP, and PCAT) were conducted. In addition to the semi-synthesis, in vitro studies (anti-VEGFR-2, anti-proliferative, flow cytometry, and wound scratch assay) were employed. ResultsADME and toxicity profiles of T-1-MCPAB studies indicated its overall drug-likeness showing results much better than Sorafenib. Then, T-1-MCPAB’s exact 3D structure, stability, and reactivity were evoked by the DFT calculations. Molecular docking, molecular dynamics simulations, MM-GPSA, PLIP, and PCAT studies denoted the correct binding and inhibiting potential of T-1-MCPAB, towards VEGFR-2 protein. After the semisynthesis, T-1-MCPAB inhibited VEGFR-2 with an IC50 of 0.135 µM, which was comparable to sorafenib's IC50 of 0.0591 µM. T-1-MCPAB also showed a notable performance against MCF7 and T47D breast cancer cell lines with IC50 values of 30.95 µM and 63.64 µM, respectively, and had high selectivity index values of 3.7 and 1.8, respectively. Furthermore, T-1-MCPAB influenced early and late apoptosis and significantly decreased the potential of MCF7 cells to heal and migrate. ConclusionT-1-MCPAB is a promising VEGFR-2 inhibitor with potential for breast cancer treatment. Further chemical and biological studies are needed to explore its potential as a therapeutic agent.

An Investigation of Structure-Activity Relationships and Cell Death Mechanisms of the Marine Alkaloids Discorhabdins in Merkel Cell Carcinoma Cells.

A library of naturally occurring and semi-synthetic discorhabdins was assessed for their effects on Merkel cell carcinoma (MCC) cell viability. The set included five new natural products and semi-synthetic compounds whose structures were elucidated with NMR, HRMS, and ECD techniques. Several discorhabdins averaged sub-micromolar potency against the MCC cell lines tested and most of the active compounds showed selectivity towards virus-positive MCC cell lines. An investigation of structure-activity relationships resulted in an expanded understanding of the crucial structural features of the discorhabdin scaffold. Mechanistic cell death assays suggested that discorhabdins, unlike many other MCC-active small molecules, do not induce apoptosis, as shown by the lack of caspase activation, annexin V staining, and response to caspase inhibition. Similarly, discorhabdin treatment failed to increase MCC intracellular calcium and ROS levels. In contrast, the rapid loss of cellular reducing potential and mitochondrial membrane potential suggested that discorhabdins induce mitochondrial dysfunction leading to non-apoptotic cell death.

Molecular Docking Analysis of Embelia ribes for Selected Constituents as Spodoptera frugiperda (Fall Armyworm) Beta Glycosidase and Caspase-1 Inhibitors

Insect pest control is one of the major issues facing the agriculture sector because of the need for new agrochemicals and biocontrol agents that are environmentally friendly, economically affordable, and safe for human health. Spodoptera frugiperda (fall armyworm) is one of the insect pests that causes huge damage to various crops around the globe due to its generalist nature. In the present study, three selected Embelia ribes Burm F (Myrsinaceae) constituents, which include embelin, 5-O-methylembelin, and vilangin; one semi-synthetic compound (potassium embelate); three synthetic compounds, namely coenzyme Q10, dopaquinone, and idebenone; and two reference compounds (azadirachtin and amitraz) were assessed on the docking behavior of S. frugiperda (beta glycosidase and caspase-1. The docking studies showed that coenzyme Q10 exhibited the highest binding energies (-130.61 and -434.56 kcal.mol-1) for the target enzymes S. frugiperda (beta glycosidase and caspase-1, respectively). Thus, the present investigation provides new knowledge in understanding Embelia ribes Burm F (Myrsinaceae) constituents as possible inhibitors against S. frugiperda (beta glycosidase and caspase-1) enzyme activities. Furthermore, the present work can help to develop new insecticides and pesticides against S. frugiperda and other related insect pests.

Synthetic and Semisynthetic Compounds as Antibacterials Targeting Virulence Traits in Resistant Strains: A Narrative Updated Review.

This narrative review paper provides an up-to-date overview of the potential of novel synthetic and semisynthetic compounds as antibacterials that target virulence traits in resistant strains. The review focused on research conducted in the last five years and investigated a range of compounds including azoles, indoles, thiophenes, glycopeptides, pleuromutilin derivatives, lactone derivatives, and chalcones. The emergence and spread of antibiotic-resistant bacterial strains is a growing public health concern, and new approaches are urgently needed to combat this threat. One promising approach is to target virulence factors, which are essential for bacterial survival and pathogenesis, but not for bacterial growth. By targeting virulence factors, it may be possible to reduce the severity of bacterial infections without promoting the development of resistance. We discuss the mechanisms of action of the various compounds investigated and their potential as antibacterials. The review highlights the potential of targeting virulence factors as a promising strategy to combat antibiotic resistance and suggests that further research is needed to identify new compounds and optimize their efficacy. The findings of this review suggest that novel synthetic and semisynthetic compounds that target virulence factors have great potential as antibacterials in the fight against antibiotic resistance.

An ongoing journey of chalcone analogues as single and multi-target ligands in the field of Alzheimer's disease: A review with structural aspects.

Alzheimer's disease (AD) is a chronic and irreversible neurodegenerative disorder with progressive dementia and cognitive impairment. AD poses severe health challenge in elderly people and become one of the leading causes of death worldwide. It possesses complex pathophysiology with several hypotheses (cholinergic hypothesis, amyloid hypothesis, tau hypothesis, oxidative stress, mitochondrial dysfunction etc.). Several attempts have been made for the management of multifactorial AD. Acetylcholinesterase is the only target has been widely explored in the management of AD to the date. The current review set forth the chalcone based natural, semi-synthetic and synthetic compounds in the search of potential anti-Alzheimer's agents. The main highlights of current review emphasizes on chalcone target different enzymes and pathways like Acetylcholinesterase, β-secretase (BACE1), tau proteins, MAO, free radicals, Advanced glycation end Products (AGEs) etc. and their structure activity relationships contributing in the inhibition of above mentioned various targets of AD.

Chalcone Derivative CX258 Suppresses Colorectal Cancer via Inhibiting the TOP2A/Wnt/β-Catenin Signaling

The deregulation in the Wnt/β-catenin signaling pathway is associated with many human cancers, particularly colorectal cancer (CRC) and, therefore, represents a promising target for drug development. We have screened over 300 semisynthetic and natural compounds using a Wnt reporter assay and identified a family of novel chalcone derivatives (CXs) that inhibited Wnt signaling and CRC cell proliferation. Among them, we selected CX258 for further in vitro and in vivo study to investigate the molecular mechanisms. We found that CX258 significantly inhibited β-catenin expression and nuclear translocation, inducing cell cycle arrest at the G2/M phase in CRC cells. Additionally, CX258 reduced the expression of DNA Topoisomerase II alpha (TOP2A) in CRC cells. Moreover, knocking down TOP2A by siRNAs inhibited the Wnt/β-catenin signaling pathway, a finding suggesting that CX258 inhibited Wnt/β-catenin signaling and CRC cell proliferation at least partially by modulating TOP2A. Further studies showed that CDK1 that interacts with TOP2A was significantly reduced after TOP2A knockdown. We demonstrated that CX258 significantly inhibited DLD-1 CRC cell xenografts in SCID mice. In summary, we identified CX258 as a promising candidate for colorectal cancer treatment by targeting the TOP2A/Wnt/β-catenin signaling pathway.

Isolation, Characterization of Undescribed Alkaloids, and Semisynthetic Modifications of Cytotoxic Pyranoacridone Alkaloids from Glycosmis pentaphylla.

Two undescribed alkaloids (10 and 11), along with nine known alkaloids (1-9), have been isolated from the stem and root bark of Glycosmis pentaphylla. Among them are carbocristine (11), a carbazole alkaloid first time isolated from a natural source, and acridocristine (10), a pyranoacridone alkaloid first time isolated from the genus "Glycosmis". In vitro cytotoxicity of isolated compounds has been analyzed on breast cancer (MCF-7), lung cancer (CALU-3), and squamous cell carcinoma cell lines (SCC-25). The results demonstrated that compounds are moderately active. In order to study the structural activity relationship of majorly isolated compounds, semisynthetic modifications have been done on majorly isolated compounds such as des-N-methylacronycine (4) and noracronycine (1) to synthesize 11 semisynthetic derivatives (12-22) on functionalizable -NH and -OH groups of the pyranoacridone scaffold at 12th and 6th positions. Semisynthetic derivatives are explored on the same cell lines as isolated compounds, and the results exhibit that semisynthetic compounds showed potent cytotoxic activity compared with naturally isolated compounds. In the case of CALU-3, the dimer at -OH position of noracronycine (1), i.e., compound 22, showed 24-fold better activity with an IC50 of 4.49 μM compared with noracronycine (1) with IC50 97.5 μM. In MCF-7, the dimer at -OH position of noracronycine (1), i.e., compound 22, showed 14-fold better activity with an IC50 of 13.2 μM compared with noracronycine (1) with IC50 187 μM.