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In the past two decades, targeted anti‐cancer therapeutics have achieved remarkable success due to their exceptional advantages of selectivity towards cancer cells and safety. Targeted small molecule anti‐cancer therapies persisted in many barriers; majorly poor response to drug therapy. Piperidine, a heterocyclic moiety, exceeds twenty instances of other pharmaceutical classes and natural compounds in the form of alkaloids effective in anti‐cancer treatment. The current review focuses on recent advancements, mainly from 2017–2023, of piperidine‐containing small molecule development as anti‐cancer agents. Total 10 piperidine containing anti‐cancer drugs have been approved by USFDA since 2017 to till date and around 15 small molecule anti‐cancer inhibitors containing piperidine scaffold which are in their early discovery phase have been reviewed which are classified according to their biological target. It highlights the structural contribution of piperidine ring towards the enhancement of activity or pharmacokinetic properties of diverse biological target‐specific anti‐cancer inhibitors of angiogenesis, EGFR, VEGFR, ALK, AKT1, topoisomerase, CDK2 etc. The role of the piperidine ring in enhancing potency, selectivity and bioavailability of novel molecules has been discussed. This review will be helpful to researchers, especially medicinal chemists, for the designing of piperidine‐containing potent drugs for specific biological targets for cancer. [ABSTRACT FROM AUTHOR]

Cancer poses a serious threat to health globally, with millions diagnosed every year. According to Global Cancer Statistics 2024, about 20 million new cases were reported in 2022, and 9.7 million people worldwide died of this condition. Advanced therapies include combination of one or more treatment procedures, depending on the type, stage, and particular genetic constitution of the cancer, which may include surgery, radiotherapy, chemotherapy, immunotherapy, hormone therapy, targeted therapy, and stem cell transplant. Also, awareness about lifestyle changes, preventive measures and screening at early stages has reduced the incidence of the disease; still, there is a major failure in controlling the incidence of cancer because of its complex and multifaceted nature. With increasing interest in bacterial metabolites as possible novel and effective treatment options in cancer therapy, their main benefits include not only direct anticancer effects but also the modulation of the immune system and potential for targeted and combination therapies. They can therefore be used in combination with chemotherapy, radiotherapy, or immunotherapy to improve outcomes or reduce side effects. Furthermore, nanoparticle-based delivery systems have the potential to enhance the potency and safety of anticancer drugs by providing improved stability, targeted release, and controlled delivery. [ABSTRACT FROM AUTHOR]

MDA-9/Syntenin, a key scaffolding protein and a molecular hub involved in a diverse range of cell signaling responses, has proved to be a challenging target for the design and discovery of small molecule probes. In this paper, we report on the design and synthesis of small molecule ligands of this key protein. Genetic algorithm-based computational design and the five–eight step synthesis of three molecules led to ligands with affinities in the range of 1–3 µM, a 20–60-fold improvement over literature reports. The design and synthesis strategies, coupled with the structure-dependent gain or loss in affinity, afford the deduction of principles that should guide the design of advanced probes of MDA-9/Syntenin. [ABSTRACT FROM AUTHOR]

Discovery research is the starting point for the development of more effective anti‐cancer treatments. It requires an interdisciplinary research environment with first‐class infrastructural support in which curiosity‐driven research can lead to new concepts for treating cancer. Translating such research findings to clinical practice requires complementary skills and infrastructures, including high‐quality clinical facilities, access to patient cohorts and participation of pharma. This complex ecosystem has yielded many new but also “me too” treatment regimens, especially in immuno‐oncology resulting in an extremely high pricing of anti‐cancer agents. The costs of antibodies, vaccines, and cell therapies charged by pharma stand out although the concepts and methodologies have been largely developed in academia, financed from public funds. Comprehensive Cancer Centres (CCCs) covering a coherent stretch of the cancer research continuum are well‐positioned to make these personalized treatments more affordable, but this will require restructuring of the way the translational cancer research continuum is funded.

Cancer is the second leading cause of death today and remains a threat to human health. The advent of multi‐drug resistance and adverse effects make the current first‐line anti‐cancer medicines inadequate, despite the fact that numerous efforts have been made in the field of cancer therapy and significant progress has been made in the diagnosis and treatment of cancer. Consequently, the development of novel anticancer drugs with high activity and minimal toxicity is imperative. The benzimidazole ring has attracted the attention of medicinal chemists due to its medicinal and pharmacological properties. The heterocyclic pharmacophore of benzimidazole is a crucial scaffold for developing pharmaceuticals and drugs. In this review, we summarized the recent progress of benzimidazole as a privileged scaffold for the discovery of anti‐cancer agents based on biological targets, such as VEGFR (Vascular Endothelial Growth Factor), PI3 K inhibitors (Phosphoinositide 3‐kinase), EGFR kinase inhibitors (Epidermal Growth Factor Receptor), PARPs (Poly ADP‐ribose polymerases), Tubulin Polymerization, HAT/HDAC (histone acetylase/histone deacetylase), SphK1 (Sphingosine kinase‐1 inhibitors), aromatase, carbonic anhydrase, and topoisomerase inhibitors. The last 5 years of literature have been reviewed and relevant studies have been summarized in this review. [ABSTRACT FROM AUTHOR]

A range of new fluorinated derivatives of benzophenone analogs were developed and assessed on the human MDA‐MB‐231 triple‐negative breast cancer cell line and human cervical carcinoma cell line KB‐3‐1 for cytotoxic and anti‐proliferative effects. Synthesized derivatives were characterized by 1H NMR, 13C NMR, FTIR, HRMS, and XRD spectroscopy. Compounds 6 a and 7 a had ~2.1 and ~13‐fold more cytotoxic activity against the KB‐3‐1 cell line than the positive control, gemcitabine. Malononitrile‐modified fluorinated benzophenone derivatives 6 b and 7 b exhibited outstanding cytotoxicity against the KB‐3‐1 cell line, outperforming the standard reference by ~3.6 and ~13.5 times, respectively. Similarly, compounds 6 a, and 7 a exhibited ~1.2 and ~2.5 fold accurate cytotoxic activity against the MDA‐MB‐231 breast cancer cell line compared to a standard reference. Whereas, compounds 6 b and 7 b exhibited ~2.2 and ~2.8 fold accurate cytotoxic activity compared to a reference standard. The experimental results demonstrated that out of eight novel compounds, compound 7 b had greater cytotoxic activity than the standard reference against the cervical cancer cell line KB‐3‐1 and the breast cancer MDA‐MB‐231. Molecular docking investigation was used to examine the expected binding affinity and potential binding poses of the produced compounds. [ABSTRACT FROM AUTHOR]

Discovery research is the starting point for the development of more effective anti‐cancer treatments. It requires an interdisciplinary research environment with first‐class infrastructural support in which curiosity‐driven research can lead to new concepts for treating cancer. Translating such research findings to clinical practice requires complementary skills and infrastructures, including high‐quality clinical facilities, access to patient cohorts and participation of pharma. This complex ecosystem has yielded many new but also "me too" treatment regimens, especially in immuno‐oncology resulting in an extremely high pricing of anti‐cancer agents. The costs of antibodies, vaccines, and cell therapies charged by pharma stand out although the concepts and methodologies have been largely developed in academia, financed from public funds. Comprehensive Cancer Centres (CCCs) covering a coherent stretch of the cancer research continuum are well‐positioned to make these personalized treatments more affordable, but this will require restructuring of the way the translational cancer research continuum is funded. [ABSTRACT FROM AUTHOR]

Cancer remains a significant global health challenge, claiming nearly 10 million lives in 2020 according to the World Health Organization. In the quest for novel treatments, fungi, especially Aspergillus species, have emerged as a valuable source of bioactive compounds with promising anticancer properties. This study conducts a comprehensive bibliometric analysis to map the research landscape of Aspergillus in oncology, examining publications from 1982 to the present. We observed a marked increase in research activity starting in 2000, with a notable peak from 2005 onwards. The analysis identifies key contributors, including Mohamed GG, who has authored 15 papers with 322 citations, and El-Sayed Asa, with 14 papers and 264 citations. Leading countries in this research field include India, Egypt, and China, with King Saud University and Cairo University as the leading institutions. Prominent research themes identified are "endophyte," "green synthesis," "antimicrobial," "anti-cancer," and "biological activities," indicating a shift towards environmentally sustainable drug development. Our findings highlight the considerable potential of Aspergillus for developing new anticancer therapies and underscore the necessity for further research to harness these natural compounds for clinical use. [ABSTRACT FROM AUTHOR]

Hypoxia-inducible Factor 1 (HIF-1) is a transcriptional activator that intervenes in versatile reactions to hypoxia. Natural drugs, widely distributed in plants, comprise many metabolites, possessing their potential as anti-cancer agents. Studies have highlighted HIF-1 as a potential pharmacological target for cancer therapy. Secondary metabolites derived from natural products (plant-derived or marine organisms) with unique chemical structures have demonstrated HIF-1 inhibition. Ganetespib, topotecan, PX-478, aminoflavone, fluorine-19-fluoroded xyglucose, etc. have entered clinical phases of evaluation for different types of cancer. The present work describes role of HIF-1 in tumor progression, summarizes plant based inhibitors such as berberine, rohitukine, harringtonine, acronycin, nuciferine, evodiamine, matrine, etc. Some of the major categories with HIF-1 inhibitory potential are alkaloids, flavonoids, steroids, etc. The manuscript aims to benefit the discovery and development of anti-cancer therapeutics from natural compounds. [ABSTRACT FROM AUTHOR]

A new series of thieno[2,3-d][1,2,4]triazolo[1,5-a]pyrimidines was designed and synthesized using readily available starting materials, specifically, β-enaminoester. Their cytotoxicity was screened against three cancer cell lines, namely, MCF-7, HCT-116, and PC-3. 2-(4-bromophenyl)triazole 10b and 2-(anthracen-9-yl)triazole 10e afforded excellent potency against MCF-7 cell lines (IC50 = 19.4 ± 0.22 and 14.5 ± 0.30 μM, respectively) compared with doxorubicin (IC50 = 40.0 ± 3.9 μM). The latter derivatives 10b and 10e were further subjected to in silico ADME and docking simulation studies against EGFR and PI3K and could serve as ideal leads for additional modification in the field of anticancer research. [ABSTRACT FROM AUTHOR]

Cancer cell line is commonly used for discovery and development of anti-cancer drugs. It is generally considered that drug response remains constant for a certain cell line due to the identity of genetics thus protein patterns. Here, we demonstrated that cancer cells continued dividing even after reaching confluence, in that the proteomics was changed continuously and dramatically with strong relevance to cell division, cell adhesion and cell metabolism, indicating time-dependent intrinsically reprogramming of cells during expansion. Of note, the inhibition effect of most anti-cancer drugs was strikingly attenuated in culture cells along with cell expansion, with the strongest change at the third day when cells were still expanding. Profiling of an FDA-approved drug library revealed that attenuation of response with cell expansion is common for most drugs, an exception was TAK165 that was a selective inhibitor of mitochondrial respiratory chain complex I. Finally, we screened a panel of natural products and identified four pentacyclic triterpenes as selective inhibitors of cancer cells under prolonged growth. Taken together, our findings underscore that caution should be taken in evaluation of anti-cancer drugs using culture cells, and provide agents selectively targeting overgrowth cancer cells.

Abstract Background Previous studies by our group have shown that oxidative phosphorylation (OXPHOS) is the main pathway by which pancreatic cancer stem cells (CSCs) meet their energetic requirements; therefore, OXPHOS represents an Achille’s heel of these highly tumorigenic cells. Unfortunately, therapies that target OXPHOS in CSCs are lacking. Methods The safety and anti-CSC activity of a ruthenium complex featuring bipyridine and terpyridine ligands and one coordination labile position (Ru1) were evaluated across primary pancreatic cancer cultures and in vivo, using 8 patient-derived xenografts (PDXs). RNAseq analysis followed by mitochondria-specific molecular assays were used to determine the mechanism of action. Results We show that Ru1 is capable of inhibiting CSC OXPHOS function in vitro, and more importantly, it presents excellent anti-cancer activity, with low toxicity, across a large panel of human pancreatic PDXs, as well as in colorectal cancer and osteosarcoma PDXs. Mechanistic studies suggest that this activity stems from Ru1 binding to the D-loop region of the mitochondrial DNA of CSCs, inhibiting OXPHOS complex-associated transcription, leading to reduced mitochondrial oxygen consumption, membrane potential, and ATP production, all of which are necessary for CSCs, which heavily depend on mitochondrial respiration. Conclusions Overall, the coordination complex Ru1 represents not only an exciting new anti-cancer agent, but also a molecular tool to dissect the role of OXPHOS in CSCs. Results indicating that the compound is safe, non-toxic and highly effective in vivo are extremely exciting, and have allowed us to uncover unprecedented mechanistic possibilities to fight different cancer types based on targeting CSC OXPHOS.

Cancer remains a significant global health challenge, claiming nearly 10 million lives in 2020 according to the World Health Organization. In the quest for novel treatments, fungi, especially Aspergillus species, have emerged as a valuable source of bioactive compounds with promising anticancer properties. This study conducts a comprehensive bibliometric analysis to map the research landscape of Aspergillus in oncology, examining publications from 1982 to the present. We observed a marked increase in research activity starting in 2000, with a notable peak from 2005 onwards. The analysis identifies key contributors, including Mohamed GG, who has authored 15 papers with 322 citations, and El-Sayed Asa, with 14 papers and 264 citations. Leading countries in this research field include India, Egypt, and China, with King Saud University and Cairo University as the leading institutions. Prominent research themes identified are “endophyte,” “green synthesis,” “antimicrobial,” “anti-cancer,” and “biological activities,” indicating a shift towards environmentally sustainable drug development. Our findings highlight the considerable potential of Aspergillus for developing new anticancer therapies and underscore the necessity for further research to harness these natural compounds for clinical use.

Background: Previous studies by our group have shown that oxidative phosphorylation (OXPHOS) is the main pathway by which pancreatic cancer stem cells (CSCs) meet their energetic requirements; therefore, OXPHOS represents an Achille's heel of these highly tumorigenic cells. Unfortunately, therapies that target OXPHOS in CSCs are lacking. Methods: The safety and anti-CSC activity of a ruthenium complex featuring bipyridine and terpyridine ligands and one coordination labile position (Ru1) were evaluated across primary pancreatic cancer cultures and in vivo, using 8 patient-derived xenografts (PDXs). RNAseq analysis followed by mitochondria-specific molecular assays were used to determine the mechanism of action. Results: We show that Ru1 is capable of inhibiting CSC OXPHOS function in vitro, and more importantly, it presents excellent anti-cancer activity, with low toxicity, across a large panel of human pancreatic PDXs, as well as in colorectal cancer and osteosarcoma PDXs. Mechanistic studies suggest that this activity stems from Ru1 binding to the D-loop region of the mitochondrial DNA of CSCs, inhibiting OXPHOS complex-associated transcription, leading to reduced mitochondrial oxygen consumption, membrane potential, and ATP production, all of which are necessary for CSCs, which heavily depend on mitochondrial respiration. Conclusions: Overall, the coordination complex Ru1 represents not only an exciting new anti-cancer agent, but also a molecular tool to dissect the role of OXPHOS in CSCs. Results indicating that the compound is safe, non-toxic and highly effective in vivo are extremely exciting, and have allowed us to uncover unprecedented mechanistic possibilities to fight different cancer types based on targeting CSC OXPHOS. [ABSTRACT FROM AUTHOR]

The increasing resistance of cancers to common treatments has caused researchers to make more efforts to discover and identify new anticancer agents. Excessive use of chemical drugs increases the resistance of cancer cells, and as a result, treatment measures fail due to a decrease in the response level of these cells to the drug. Therefore, it is extremely important to study drugs that are more effective and have fewer side effects. Angiogenesis is a new treatment method that has been studied recently due to the high importance of this treatment method and the efficiency of this method in the treatment of some diseases, including all types of tumors. There are many hopes for the use of this method. It has created an effective method. Among the most important potential advantages of this method in cancer treatment, we can mention the absence of cell resistance problems, easy access to intravascular targets, as well as the wide scope of using this type of strategy to treat many types of diseases related to angiogenesis. Therefore, the use of different angiogenesis models and the development of these models can be very important for the treatment of all types of cancer and other diseases. In this review article, various dimensions of the angiogenesis process and the mechanisms and factors related to it, as well as the studies surrounding them, have been discussed. [ABSTRACT FROM AUTHOR]

Targeting the VEGFR-2 signaling pathway is an inveterate approach toward combating pancreatic and hepatocellular cancers. Based on Sunitinib, the FDA-approved VEGFR-2 inhibitor, novel indolin-2-one-triazole hybrids were designed and synthesized as anti-hepatocellular and anti-pancreatic cancer agents with VEGFR-2 inhibitory activity. All the targeted compounds were assessed for their anti-cancer activity, revealing IC50 values extending from 0.17 to 4.29 µM for PANC1 and 0.58 to 4.49 µM for HepG2 cell lines. An extensive SAR study was conducted to explore the effect of different substituents along with N-alkylation. The potent anti-cancer analogs 11d, 11e, 11g, 11k and 14c were evaluated for their VEGFR-2 inhibitory actions, where their IC50 values ranged from 16.3 to 119.6 nM compared to Sorafenib, which revealed an IC50 of 29.7 nM, having compound 11d as the most active analog. An in silico ADME study was performed to confirm the drug-likeness of the synthesized compounds. Finally, molecular docking simulation was conducted for the most potent VEGFR-2 inhibitor (11d), demonstrating the strong binding with the vital amino acid residues of the VEGFR-2 ATP binding site. [ABSTRACT FROM AUTHOR]

Despite the exceptional progress in breast cancer pathogenesis, prognosis, diagnosis, and treatment strategies, it remains a prominent cause of female mortality worldwide. Additionally, although chemotherapies are effective, they are associated with critical limitations, most notably their lack of specificity resulting in systemic toxicity and the eventual development of multi-drug resistance (MDR) cancer cells. Liposomes have proven to be an invaluable drug delivery system but of the multitudes of liposomal systems developed every year only a few have been approved for clinical use, none of which employ active targeting. In this review, we summarize the most recent strategies in development for actively targeted liposomal drug delivery systems for surface, transmembrane and internal cell receptors, enzymes, direct cell targeting and dual-targeting of breast cancer and breast cancer-associated cells, e.g., cancer stem cells, cells associated with the tumor microenvironment, etc.

Extracellular Vesicles (EVs) encompasses a diverse array of vesicles generated by cells, with exosomes constituting the most prominent subset within this classification. Exosomes facilitate intercellular communication by transporting various biologics derived from donor or parental cells and delivering them to recipient cells. The potential of their distinctive ability to transport cargo has recently been investigated for its application to provide anti-cancer medications and imaging agents. Exosomes, which are endogenously generated, possess numerous advantages compared to the presently employed synthetic lipid-based nanoparticles for clinical applications in cancer treatment and other medical conditions. Identifying exosomes' involvement in human diseases has prompted extensive preclinical and clinical investigations into their potential as a viable means of Drug Delivery (DD) and as a theranostic tool for cancer diagnosis and treatment. Nevertheless, it is crucial to acknowledge that exosomes possess certain limitations, with one of the primary concerns revolving around the choice of the biological source utilized to generate exosomes that are both highly biocompatible and capable of being produced in large quantities. This paper examines the diverse origins of medically feasible exosomes that can be extracted to serve as drug carriers in the context of cancer therapy. The synthesis of nanosomes for anti-cancer DD has been presented in this paper. Nanosomes have been obtained by integrating Doxorubicin-conjugated Gold Nanoparticles (DOX-GNP) and organic exosomes. The precise delivery of "armed" exosomes to tumor masses can be achieved through either "passive" targeting, which relies on the inherent tropism of exosomes, or "active" targeting, which involves modifying the surface of exosomal membranes. Despite the numerous advantages of exosomes compared to synthetic nanoparticles, there are still obstacles to overcome to improve the efficiency of loading anti-cancer agents into exosomes. Additionally, there is a need to develop quantitative and qualitative analytical techniques for monitoring the delivery of exosomes and exosome-incorporated anticancer agents to the tumor parenchyma in vivo. [ABSTRACT FROM AUTHOR]

This document is a compilation of research articles and studies on the pharmacognosy and medicinal properties of mangrove plants. The articles discuss the chemical constituents, biological activities, and potential anticancer effects of different mangrove species. The studies highlight the antimicrobial, antioxidant, and antiproliferative properties of mangrove extracts, as well as their potential as a source of natural products for cancer treatment. The document provides a comprehensive overview of the research conducted on mangrove plants and their potential medicinal applications. [Extracted from the article]

Cancer was the world's second major cause of death. Several treatments were available, including chemotherapy, radiotherapy, immunotherapy, and surgery. However, they are restricted due to their risk to normal cells, their ability to destroy the immune system, and conferring increased risk of secondary cancer development. Nanotechnology was extensively researched and used in cancer treatment because nanoparticles could play an essential role in drug delivery. Furthermore, nanoparticle drug delivery systems have been shown to help overcome cancer-related drug resistance. Gold nanoparticles have unique physical, chemical, and biological properties, making them suitable candidates for non-toxic drug carriers. Because of their nanorange size, surface modifications of gold nanoparticles could improve their stability, minimize nanoparticle aggregation, and enhance attachment to anti-cancer agents and target cells, further increasing their ability to penetrate cell membranes and reduce toxicity. This review aims to discuss the current research in targeting drug delivery for anti-cancer agents using gold nanoparticles. By conducting a literature search through the PubMed and Scopus database up to April 2022 using the term gold nanoparticles, targeted drug delivery, chemotherapy, gene therapy, and cancer, this review summarized report on the implementation of gold nanoparticles for targeted drug-delivery systems for cancer therapeutics. The targeting ligands included folic acid, aptamers, hyaluronic acid, glutathione, peptides, and antibodies. According to the findings of studies, implementing gold nanoparticles as nanocarriers significantly improves drug delivery of anti-cancer agents to cancer cells without affecting other untargeted cells. Enhanced cell uptake, increase in drug toxicity, inhibition of tumor growth, and selective drug target are also reported to be the advantages of gold nanoparticle-based targeted drug delivery carriers. [ABSTRACT FROM AUTHOR]

Urological cancers have obtained much attention in recent years due to their mortality and morbidity. The most common and malignant tumor of urological cancers is prostate cancer that imposes high socioeconomic costs on public life and androgen-deprivation therapy, surgery, and combination of chemotherapy and radiotherapy are employed in its treatment. PI3K/Akt signaling is an oncogenic pathway responsible for migration, proliferation and drug resistance in various cancers. In the present review, the role of PI3K/Akt signaling in prostate cancer progression is highlighted. The activation of PI3K/Akt signaling occurs in prostate cancer, while PTEN as inhibitor of PI3K/Akt shows down-regulation. Stimulation of PI3K/Akt signaling promotes survival of prostate tumor cells and prevents apoptosis. The cell cycle progression and proliferation rate of prostate tumor cells increase by PI3K/Akt signaling induction. PI3K/Akt signaling stimulates EMT and enhances metastasis of prostate tumor cells. Silencing PI3K/Akt signaling impairs growth and metastasis of prostate tumor cells. Activation of PI3K/Akt signaling mediates drug resistance and reduces radio-sensitivity of prostate tumor cells. Anti-tumor compounds suppress PI3K/Akt signaling in impairing prostate tumor progression. Furthermore, upstream regulators such as miRNAs, lncRNAs and circRNAs regulate PI3K/Akt signaling and it has clinical implications for prostate cancer patients. [ABSTRACT FROM AUTHOR]

Mitochondrial Complex I plays a crucial role in the proliferation, chemoresistance, and metastasis of breast cancer (BC) cells. This highlights it as an attractive target for anti-cancer drugs. Using submitochondrial particles, we identified FRV–1, an ortho-carbonyl quinone, which inhibits NADH:duroquinone activity in D-active conformation and reduces the 3ADP state respiration dependent on Complex I, causing mitochondrial depolarization, ATP drop, increased superoxide levels, and metabolic remodeling towards glycolysis in BC cells. Introducing methyl groups at FRV–1 structure produced analogs that acted as electron acceptors at the Complex I level or increased the inhibitory effect of FCCP-stimulated oxygen consumption rate, which correlated with their redox potential, but increased toxicity on RMF-621 human breast fibroblasts was observed. FRV–1 was inactive in the naphthoquinone oxidoreductase 1 (NOQ1)-positive BC cell line, MCF7, but the sensitivity was recovered by dicoumarol, a NOQ1 inhibitor, suggesting that FRV–1 is a NOQ1 substrate. Importantly, FRV–1 selectively inhibited the proliferation, migration, and invasion of NQO1 negative BC cell, MDA-MB-231, in an OXPHOS- and ROS-dependent manner and sensitized it to the BH3 mimetic drug venetoclax. Overall, FRV–1 is a novel Complex I inhibitor in D-active conformation, blocking possibly the re-activation to A-state, producing selective anti-cancer effects in NQO1-negative BC cell lines. [ABSTRACT FROM AUTHOR]

Background & Objectives: Accurate identification of molecular and toxicological functions of potential drug candidates is crucial for drug discovery and development. This may aid in the evaluation of the risks of genotoxicity and carcinogenesis. In addition, in silico characterization of existing and new drugs might offer clues for future investigations and aid in the development of anticancer treatments. Using next-generation knowledge discovery (NGKD) methodology, we endeavored to establish a risk assessment of anticancer drugs for their molecular mechanism(s) and genotoxicity. Methods: This study was performed at the Faculty of Applied Medical Sciences, King Abdulaziz University (KAU), Jeddah, Saudi Arabia, in November 2022. Using innovative in silico model systems, we assessed the molecular mechanism of action and toxicity of around 20 distinct substances such as Deguelin, Etoposide, Camptothecin, Cytarabine (Ara-C), Cisplatin, Hydroxyurea, Trichostain A, Antimycin, Colchicine, 2-deoxyglucose, Tunicamycin, Thapsigargin, Vinblastin, Docetaxel, Oxaliplatin, Methotrexate, 5-flurouracil, Bleomycin, Taxol (Paclitaxel), and Apicidin. Using the Ingenuity Pathway Analysis (IPA) knowledge base, the number of targets for each compound was determined in silico. Subsequently, they were examined using Fisher's exact test and Benjamini Hochberg Multiple Testing Correction (P<0.05) and submitted to core analysis with IPA to decode the biological and toxicological activities differently controlled by these drugs. In addition, a multiple comparison module in IPA was used to compare the core analyses of each molecule. In addition, we obtained the top 100 protein targets of Etoposide, Camptothecin, and Ara-C using SwissTargetPrediction, as well as the key pathways and gene ontologies affected by these drugs and disease associations using the WebGestalt tool. Results: We identified distinct toxicological signatures and canonical signaling pathways in tumor cell lines regulated by these 20 anticancer drugs. These signaling pathways included cell death and apoptosis in addition to molecular processes, p53 signaling, and aryl hydrocarbon receptor signaling. The TP53 signaling pathway is utilized by these agents to effectively trigger cell death and apoptosis, and p53 functions as a master regulator in a variety of cellular stress responses, including genotoxic stress. Conclusion: Our research has laid the groundwork for the discovery of additional biomarkers that assess both the safety and effectiveness of treatment. Our mechanism based "NGKD" tools have more relevance for the identification of safer therapies and has the potential to lead to the rational screening of drug candidates targeting specific molecular networks and canonical pathways implicated in cancer and genotoxicity. In addition, the combination of protein, microRNA and metabolome profiles may be essential for the development of translatable biomarkers for the safety and efficacy of pharmacotherapeutic agents. Our research has laid the groundwork for the discovery of additional biomarkers that assess both the safety and the effectiveness of a treatment. [ABSTRACT FROM AUTHOR]

The second-most common reason for death globally and a significant issue for human health is cancer. The focus of the current review is to discuss cancer treatment and issues with anticancer medications. Nearly all cell types can develop cancer, a very varied group of approximately 200 illnesses with at least one factor in common "uncontrolled cellular development" that results in aberrant cell proliferation. In solid tumors, cancerous cells may remain localized or in situ at the location of the initial lesion, or they may become locally progressed or metastatic to distant site. Ninety percent of all cancer-related fatalities are due to by metastasis. It is the primary determinant of whether malignancy is high-risk, requiring aggressive treatment, or low-risk, curable by active surveillance, surgical removal, or adjuvant therapy. Recent advancements in computational drug discovery methodologies have not only produced important insights into the field of cancer therapy but have also had a significant and impact on the development of novel anticancer medications. Within the scope of this review, we investigated potential therapeutic targets for anti-cancer drugs. [ABSTRACT FROM AUTHOR]

Herein, we report an efficient and eco-friendly, ultrasound assisted synthetic strategy for the construction of diversified pyrrolobenzodiazepine-triazole hybrids, which are potentially pharmaceutically important scaffolds, via a domino reaction involving intermolecular electrophilic substitution followed by intramolecular Huisgen 1,3-dipolar azide-alkyne cycloaddition. The USP of the reported protocol is the use of benign and inexpensive, recyclable molecular iodine-ionic liquid synergistic catalytic system cum reaction media for achieving the synthesis. The other salient features of this method are the use of mild reaction conditions, high yield and atom economy, operational simplicity, broad substrate scope and easy workup and purification. All the synthesized compounds were evaluated for in vitro anti-proliferative activity against various cancer cell lines. From among the synthesized title compounds, 9,9-dimethyl-8-phenyl-9Hbenzo [b]pyrrolo [1,2-d][1,2,3]triazolo[5,1-g][1,4]diazepine (7) was found most to be the most active compound exhibiting IC50 value of 6.60, 5.45, 7.85, 11.21, 12.24, 10.12, and 11.32 µM against MCF-7, MDA-MB-231, HeLa, SKOV-3, A549, HCT-116 and DLD-1 cell lines, respectively. Further the compounds were found to be nontoxic against normal human embryonic kidney (HEK-293) cell line. [ABSTRACT FROM AUTHOR]

Lung cancer is one of the most lethal malignancies in the world. However, current curative approaches for treating this type of cancer have some weaknesses. Therefore, scientists are attempting to discover new anti-lung cancer agents. Sea cucumber is a marine-derived source for discovering biologically active compounds with anti-lung cancer properties. To explore the anti-lung cancer properties of sea cucumber, we analyzed surveys using VOSviewer software and identified the most frequently used keywords. We then searched the Google Scholar database for compounds with anti-lung cancer properties within that keyword family. Finally, we used AutoDock 4 to identify the compounds with the highest affinity for apoptotic receptors in lung cancer cells. The results showed that triterpene glucosides were the most frequently identified compounds in studies examining the anti-cancer properties of sea cucumbers. Intercedenside C, Scabraside A, and Scabraside B were the three triterpene glycosides with the highest affinity for apoptotic receptors in lung cancer cells. To the best of our knowledge, this is the first time that anti-lung cancer properties of sea cucumber-derived compounds have been examined in in silico conditions. Ultimately, these three components displayed anti-lung cancer properties in in silico conditions and may be used for the manufacture of anti-lung cancer agents in the near future. [ABSTRACT FROM AUTHOR]

We chemically linked corosolic and asiatic acids and a synthetic polyoxygenated analogue of ursolic acid via an alkyl linker to the cationic mitochondrial targeting compound F16 (4-(1H-indole-3-ylvinyl)-N-methylpyridinium iodide). The conjugates were tested for cytotoxic activity against two human lung adenocarcinoma cell lines, H1299 and A549, and non-cancerous mouse embryonic fibroblast cells. The results showed that conjugation of polyoxygenated triterpene acids with the terminal cationic fragment F16 in the C-28 side chain enhanced cytotoxicity (30–35 fold) compared to the original natural ursolic acid. However, the presence of hydroxyl or acetyl functions in the A-ring of F16 conjugates of corosolic or asiatic acids resulted in a significant decrease in cytotoxicity compared to their structural analogue, the F16 derivative of ursolic acid. [ABSTRACT FROM AUTHOR]

Background: With widespread therapeutic advancement, targeted anticancer therapeutics are taking over traditional treatment protocols. Nevertheless, the resistance to targeted therapeutics has halted the enthusiastic treatment response. An example of targeted therapy is Lapatinib. Lapatinib is a tyrosine kinase inhibitor used in HER2-positive breast cancer. It is widely used in HER2-positive metastatic breast cancer in combination with other drugs. Methods: This study's main objective was to provide a plausible mechanistic insight into lapatinib’s resistance in two HER2 positive breast cancer cell lines, SKBR3 and BT-474. We performed gene set analysis to identify the differentially expressed genes (DEG) in response to treatment with lapatinib from the gene expression profiles obtained from GSE38376 and GSE16179. The DEG was then analyzed by Ingenuity Pathway Analysis (IPA). Results: The IPA analysis showed that the increased expression of Hypoxia-inducible factor-1 alpha (HIF-1α) and Wnt/β-catenin and their related networks were associated with resistance and poor prognosis in SKBR3 and BT-474 cell lines, respectively. Although both cell lines are categorized as HER2 positive cell lines and in some reports were used interchangeably, in our hands, the two cell lines exhibited different biological pathways underlying resistance to lapatinib. In addition, among the other top canonical pathways, TNF was identified as the top upstream regulator in SKBR3 cell lines, whereas the Microphthalmia-associated transcription factor (MITF) was predicted as a top regulator in BT-474 cell lines. Conclusions: This study highlights the relevance of HIF-1α and Wnt/β-catenin compensatory networks in resistance toward lapatinib. Our findings outline the activation of angiogenesis and invasion processes in resistant cells with differential underlining gene networks in two different HER2 positive cell lines. The two cell lines reflect two different types of breast cancer, and hence the treatment strategy to avoid resistance should be planned differently.

Abstract Background Secondary metabolites have played a key role as starting points for drug development programs due to their often unique features compared with synthetically derived molecules. However, limitations related to the discovery and supply of these molecules by biotechnological means led to the retraction of big pharmaceutical companies from this field. The reasons included problems associated with strain culturing, screening, re-discovery, purification and characterization of novel molecules from natural sources. Nevertheless, recent reports have described technical developments that tackle such issues. While many of these reports focus on the identification and characterization of such molecules to enable subsequent chemical synthesis, a biotechnological supply strategy is rarely reported. This may be because production processes usually fall under proprietary research and/or few processes may meet the requirements of a pharmaceutical development campaign. We aimed to bridge this gap for illudin M—a fungal sesquiterpene used for the development of anticancer agents—with the intention to show that biotechnology can be a vital alternative to synthetic processes dealing with small molecules. Results We used µL-scale models to develop an adsorption and extraction strategy for illudin M recovery from culture supernatant of Omphalotus nidiformis and these findings were successfully transferred into lab-scale. By adsorbing and eluting the product using a fixed resin-bed we reduced the working volume by ~ 90% and removed the aqueous phase from the process. After a washing step, a highly concentrated illudin M fraction was obtained by isocratic elution with 80% methanol. The fraction was dried and extracted using a water/heptane mixture, enriching illudin M in the heptane phase. From heptane illudin M could be instantly crystalized by concentrating the solution, achieving a final purity > 95%. Conclusion We have developed a robust, scalable and low-cost downstream process to obtain highly pure illudin M. By using solid phase extraction we reduced the production of solvent waste. Heptane from the final purification step could be recycled. The reduced amounts of solvents required, and the short purification time render this method a very economic and ecologic alternative to published processes.

• Synthesis of small molecules have been carried out. • COX-2 inhibition up regulates the functioning of p53 and controls the cancer growth. • Molecular docking of potent compounds with 6COX, 1RV1 and 4ZXF. • DFT studies of potent COX-2 and MDM 2 inhibitors. The tumor suppressor p53 plays a vital role in gene expression, autophagy, and apoptosis. However, p53 negatively controlled by MDM 2, mouse double protein, and cyclooxygenase-2 enzyme (COX-2) can cause dysregulation of p53 and tumor development. The p53 activation can be triggered by inhibition of COX-2. Also, p53-MDM2 interaction can be inhibited by small molecules derived from natural and synthetic routes. Given the importance of this, we herein report the design, and synthesis of small molecules embelin, quinazoline and isatin analogs as p53-mdm2 protein-protein interaction and COX-2 dual inhibitors. Among these small molecules, molecular docking studies of compound 8 have displayed almost the same binding affinity for COX-2 (PDB-6COX) compared to celecoxib (-8.8 kcal/mol). With MDM 2 protein {(PDB-1RV1) and (PDB-5ZXF)}, only compounds 4a (-8.2 and -8.0 kcal/mol) , 11a (-8.2 and -7.9 kcal/mol) have shown comparable binding score of potent MDM-2 inhibitor Nutlin-3a (-9.8 and -7.8 kcal/mol). These data suggest that the binding of these molecules with COX-2, and the active site of MDM-2 results in the down-regulation of these two proteins and no degradation of p53. In silico ADME studies suggest that most compounds displayed promising drug-likeness without violating Lipinski's rule of five. For DFT studies, the molecular structures of 8 and 11a were optimized using the Gaussian software with the B3LYP hybrid functional and the 6–31 G (d, p) basis set to determine their chemical behavior and reactivity. Finally, the potent molecules 4a, 8 , and 11a that target COX-2 and MDM 2 can be developed as anti-inflammatory and anticancer therapeutic. [Display omitted] [ABSTRACT FROM AUTHOR]

• Highlighted the chemistry of Indole, Thiophene, Traiazole, Piperizine, Chalcone, Pyrazole and Oxazole based benzofuran derivatives. • A total of 211 compounds have been described across 42 schemes. • The synthesis and anticancer activities of all final products are thoroughly discussed, including detailed methodologies, reaction conditions, and biological assays. • This comprehensive analysis provides valuable insights into the chemical processes and potential therapeutic applications of benzofuran derivatives, highlighting their significance in medicinal chemistry. Benzofuran serves as the primary active pharmaceutical ingredient (API) in a plethora of both naturally occurring and synthetic drugs known for their potent biological activities. The diverse array of biological effects demonstrated by benzofuran and its analogues encompasses anticancer, anti-microbial, anti-inflammatory, anti-fungal, analgesic, anti-parasitic, anti-hyperglycemic, anti-hyperlipidemic, anti-convulsant, antipyretic, anti-tubercular, anti-Alzheimer, and antioxidant properties, among others. Given this extensive range of therapeutic potentials, benzofuran and its derivatives have garnered significant attention and are extensively utilized in pharmaceutical research and development. This review article focuses specifically on the anti-cancer properties of benzofuran and its derivatives, underscoring the pivotal role of benzofuran as a prominent and versatile scaffold for designing and developing novel therapeutic agents. [ABSTRACT FROM AUTHOR]

Abstract Background The fungal sesquiterpenes Illudin M and S are important base molecules for the development of new anticancer agents due to their strong activity against some resistant tumor cell lines. Due to nonspecific toxicity of the natural compounds, improvement of the pharmacophore is required. A semisynthetic derivative of illudin S (Irofulven) entered phase II clinical trials for the treatment of castration-resistant metastatic prostate cancer. Several semisynthetic illudin M derivatives showed increased in vitro selectivity and improved therapeutic index against certain tumor cell lines, encouraging further investigation. This requires a sustainable supply of the natural compound, which is produced by Basidiomycota of the genus Omphalotus. We aimed to develop a robust biotechnological process to deliver illudin M in quantities sufficient to support medicinal chemistry studies and future preclinical and clinical development. In this study, we report the initial steps towards this goal. Results After establishing analytical workflows, different culture media and commercially available Omphalotus strains were screened for the production of illudin M.Omphalotus nidiformis cultivated in a medium containing corn steep solids reached ~ 38 mg L−1 setting the starting point for optimization. Improved seed preparation in combination with a simplified medium (glucose 13.5 g L−1; corn steep solids 7.0 g L− 1; Dox broth modified 35 mL), reduced cultivation time and enhanced titers significantly (~ 400 mg L−1). Based on a reproducible cultivation method, a feeding strategy was developed considering potential biosynthetic bottlenecks. Acetate and glucose were fed at 96 h (8.0 g L−1) and 120 h (6.0 g L−1) respectively, which resulted in final illudin M titer of ~ 940 mg L−1 after eight days. This is a 25 fold increase compared to the initial titer. Conclusion After strict standardization of seed-preparation and cultivation parameters, a combination of experimental design, empirical trials and additional supply of limiting biosynthetic precursors, led to a highly reproducible process in shake flasks with high titers of illudin M. These findings are the base for further work towards a scalable biotechnological process for a stable illudin M supply.

Herein, we report an efficient and eco-friendly, ultrasound assisted synthetic strategy for the construction of diversified pyrrolobenzodiazepine-triazole hybrids, which are potentially pharmaceutically important scaffolds, via a domino reaction involving intermolecular electrophilic substitution followed by intramolecular Huisgen 1,3-dipolar azide-alkyne cycloaddition. The USP of the reported protocol is the use of benign and inexpensive, recyclable molecular iodine-ionic liquid synergistic catalytic system cum reaction media for achieving the synthesis. The other salient features of this method are the use of mild reaction conditions, high yield and atom economy, operational simplicity, broad substrate scope and easy workup and purification. All the synthesized compounds were evaluated for in vitro anti-proliferative activity against various cancer cell lines. From among the synthesized title compounds, 9,9-dimethyl-8-phenyl-9H-benzo [b]pyrrolo [1,2-d][1,2,3]triazolo[5,1-g][1,4]diazepine (7) was found most to be the most active compound exhibiting IC50 value of 6.60, 5.45, 7.85, 11.21, 12.24, 10.12, and 11.32 µM against MCF-7, MDA-MB-231, HeLa, SKOV-3, A549, HCT-116 and DLD-1 cell lines, respectively. Further the compounds were found to be non-toxic against normal human embryonic kidney (HEK-293) cell line.

Inhibiting the interaction between the p53 tumor suppressor and its negative regulator murine double minute 2 (MDM2) is a promising therapeutic opportunity in cancer drug research. Herein, we describe the design, synthesis, and in vitro screening of phenyl chroman‐based derivatives 7 a–l as MDM2 inhibitors. Among target compounds, 7 e, 7 h, and 7 j had considerable cytotoxicity activity at concentrations of 50 μM and 100 μM against MCF7 and HCT‐116 cell lines. Designed compounds that demonstrated good toxicity, were selected for enzyme inhibition assay. The most potent MDM2 inhibitor in this series is compound 7 h, which showed a Ki value of 13.66 μM. Moreover, compound 7 h with acceptable safety profiles in normal cells was found the least effective compound against human umbilical vein endothelial cells (HUVECs). In addition, cell cycle analysis was also investigated for representative compound 7 h. Also, the docking study was done to predict the possible interaction between the synthesized compound and both MDM2 and murine double minute x (MDMX) proteins. Interestingly, the docking results were in good agreement with the experimental assay. [ABSTRACT FROM AUTHOR]

There is huge potential in the phyto-chemical compounds obtained from the seaweeds naming brown (Phaeophyta), red (Rhodophyta) and green (Chlorophyta) macroalgae. These seaweeds are abundant in anti-cancer and anti-HIV agents. Chlorophyta are polydisperse heteropolysaccharides and Phaeophyta are fucoidans which are wither fucose containing sulfated polysaccharides. Brown seaweeds are rich in fucoidans, alginic acids and laminarans which possess anti-cancer activity by inhibiting growth, proliferation of cancer cells and target various molecular and signaling pathways to prevent the growth and proliferation of cancer cell lines. The phytochemicals like phlorotannins, lectins, sulfated polysaccharides and diterpenes possess activity against HIV infection. The most effective method of preventing HIV infection is to inhibit the virus attachment and virus penetration on the host cell by preventing the binding of receptors to cell membrane surface. The properties of macroalgae can be explored more prominently to combat cancer and HIV-infection medically and professionally. Most of them are only included for traditional or local medicinal therapy and these species are mostly included in the dietary food and supplements of society. To fully grasp their depth capability and promise for the future, more research into these marine macroalgae and their phytocompounds is required. • Anti-cancer bioactive compounds obtained from marine macroalgae. • Anti-HIV bioactive compounds obtained from marine macroalgae. • Bioactive compounds inhibitory effect on cancer growths and prompt of cancer cell death by stimulating apoptosis. • Affecting virus attachment and replication to prevent HIV infection. [ABSTRACT FROM AUTHOR]

Pancreatic cancer remains as global health challenge, ranking as the seventh leading cause of cancer-related deaths worldwide with high mortality rates and a low five-year survival rate. Despite advancements in conventional therapies, including surgery, chemotherapy, and radiation, the overall survival rates for pancreatic cancer patients have shown minimal improvement. Consequently, there is an urgent need for alternative therapeutic strategies. The search for effective treatments has increasingly turned towards natural products, which offer a diverse array of bioactive compounds with potential anticancer properties. All the natural products, derived from plants, marine organisms, and microorganisms, have emerged as promising candidates in cancer treatment. The review explores the potential role of various natural compounds such as polyphenols, alkaloids, terpenoids, and flavonoids in pancreatic cancer management. With over 60% of cancer medications in clinical trials having natural origins, the review underscores the importance of exploring these compounds for their chemopreventive potential. It covers the epidemiological, molecular pathways influenced by these natural products (such as apoptosis, cell cycle regulation and signaling pathways) and therapeutic aspects aims to contribute to the ongoing efforts in understanding and addressing the complexities of pancreatic cancer. Overall, this review highlights the urgency of developing novel therapeutic strategies and incorporating natural compounds into current treatment modalities to improve outcomes for pancreatic cancer patients., Competing Interests: Declarations. Ethical approval: Not Applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Nature B.V.)

The escalating prevalence of lifestyle and microbial diseases poses a significant threat to human well-being, necessitating the discovery and development of novel drugs with distinct modes of action. Addressing this challenge involves employing innovative strategies, and one current approach involves utilizing heterocyclic compounds to synthesize hybrid molecules. These hybrids have resulted from the fusion of two or more bioactive heterocyclic moieties into a single molecule. The focus of this review revolves around the strategic incorporation of heterocycles, particularly thiazole derivatives. Thiazole derivatives, due to their unique structural features, are explored in depth within this review paper. The paper comprehensively outlines diverse hybridization strategies of thiazole derivatives, highlighting their vibrant biological activities mainly in the last decade, 2014-2024. By presenting an extensive overview, the review aims to provide valuable insights into the potential of thiazole derivatives as promising candidates for drug development. The insights garnered from this paper are expected to offer valuable guidance for future drug design endeavors, providing a foundation for developing novel and effective drugs to combat lifestyle diseases and microbial resistance., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

We chemically linked corosolic and asiatic acids and a synthetic polyoxygenated analogue of ursolic acid via an alkyl linker to the cationic mitochondrial targeting compound F16 (4-(1H-indole-3-ylvinyl)-N-methylpyridinium iodide). The conjugates were tested for cytotoxic activity against two human lung adenocarcinoma cell lines, H1299 and A549, and non-cancerous mouse embryonic fibroblast cells. The results showed that conjugation of polyoxygenated triterpene acids with the terminal cationic fragment F16 in the C-28 side chain enhanced cytotoxicity (30–35 fold) compared to the original natural ursolic acid. However, the presence of hydroxyl or acetyl functions in the A-ring of F16 conjugates of corosolic or asiatic acids resulted in a significant decrease in cytotoxicity compared to their structural analogue, the F16 derivative of ursolic acid.

Mitochondrial Complex I plays a crucial role in the proliferation, chemoresistance, and metastasis of breast cancer (BC) cells. This highlights it as an attractive target for anti-cancer drugs. Using submitochondrial particles, we identified FRV–1, an ortho-carbonyl quinone, which inhibits NADH:duroquinone activity in D-active conformation and reduces the 3ADP state respiration dependent on Complex I, causing mitochondrial depolarization, ATP drop, increased superoxide levels, and metabolic remodeling towards glycolysis in BC cells. Introducing methyl groups at FRV–1 structure produced analogs that acted as electron acceptors at the Complex I level or increased the inhibitory effect of FCCP-stimulated oxygen consumption rate, which correlated with their redox potential, but increased toxicity on RMF-621 human breast fibroblasts was observed. FRV–1 was inactive in the naphthoquinone oxidoreductase 1 (NOQ1)-positive BC cell line, MCF7, but the sensitivity was recovered by dicoumarol, a NOQ1 inhibitor, suggesting that FRV–1 is a NOQ1 substrate. Importantly, FRV–1 selectively inhibited the proliferation, migration, and invasion of NQO1 negative BC cell, MDA-MB-231, in an OXPHOS- and ROS-dependent manner and sensitized it to the BH3 mimetic drug venetoclax. Overall, FRV–1 is a novel Complex I inhibitor in D-active conformation, blocking possibly the re-activation to A-state, producing selective anti-cancer effects in NQO1-negative BC cell lines.

[Display omitted] • A series of naphthyl amide derivatives were designed and synthesized as a another type of reversible MAGL inhibitors. • The naphthyl amide derivative ± 34 , were identified as potent reversible MAGL inhibitor. • Compound ± 34 showed appreciable antiproliferative activities against several cancer cells, including H460, HT29, CT-26, Huh7 and HCCLM-3. Monoacylglycerol lipase (MAGL) is a key enzyme responsible for the metabolism of the endocannabinoid 2-arachidonoylglycerol (2-AG), and has attracted great interest due to its involvement in various physiological and pathological processes, such as cancer progression. In the past, a number of covalent irreversible inhibitors have been reported for MAGL, however, experimental evidence highlighted some drawbacks associated with the use of these irreversible agents. Therefore, efforts were mainly focused on the development of reversible MAGL inhibitor in recent years. Here, we designed and synthesized a series of naphthyl amide derivatives (12 – 39) as another type of reversible MAGL inhibitors, exemplified by ± 34 , which displayed good MAGL inhibition with a pIC 50 of 7.1, and the potency and selectivity against endogenous MAGL were further demonstrated by competitive ABPP. Moreover, the compound showed appreciable antiproliferative activities against several cancer cells, including H460, HT29, CT-26, Huh7 and HCCLM-3. The investigations culminated in the discovery of the naphthyl amide derivative ± 34 , and it may represent as a new scaffold for MAGL inhibitor development, particularly for the reversible ones. [ABSTRACT FROM AUTHOR]

Background: Secondary metabolites have played a key role as starting points for drug development programs due to their often unique features compared with synthetically derived molecules. However, limitations related to the discovery and supply of these molecules by biotechnological means led to the retraction of big pharmaceutical companies from this field. The reasons included problems associated with strain culturing, screening, re-discovery, purification and characterization of novel molecules from natural sources. Nevertheless, recent reports have described technical developments that tackle such issues. While many of these reports focus on the identification and characterization of such molecules to enable subsequent chemical synthesis, a biotechnological supply strategy is rarely reported. This may be because production processes usually fall under proprietary research and/or few processes may meet the requirements of a pharmaceutical development campaign. We aimed to bridge this gap for illudin M—a fungal sesquiterpene used for the development of anticancer agents—with the intention to show that biotechnology can be a vital alternative to synthetic processes dealing with small molecules. Results: We used µL-scale models to develop an adsorption and extraction strategy for illudin M recovery from culture supernatant of Omphalotus nidiformis and these findings were successfully transferred into lab-scale. By adsorbing and eluting the product using a fixed resin-bed we reduced the working volume by ~ 90% and removed the aqueous phase from the process. After a washing step, a highly concentrated illudin M fraction was obtained by isocratic elution with 80% methanol. The fraction was dried and extracted using a water/heptane mixture, enriching illudin M in the heptane phase. From heptane illudin M could be instantly crystalized by concentrating the solution, achieving a final purity > 95%. Conclusion: We have developed a robust, scalable and low-cost downstream process to obtain highly pure illudin M. By using solid phase extraction we reduced the production of solvent waste. Heptane from the final purification step could be recycled. The reduced amounts of solvents required, and the short purification time render this method a very economic and ecologic alternative to published processes. [ABSTRACT FROM AUTHOR]

Depriving cancer cells of sufficient NAD levels, mainly through interfering with their NAD-producing capacity, has been conceived as a promising anti-cancer strategy. Numerous inhibitors of the NAD-producing enzyme, nicotinamide phosphoribosyltransferase (NAMPT), have been developed over the past two decades. However, their limited anti-cancer activity in clinical trials raised the possibility that cancer cells may also exploit alternative NAD-producing enzymes. Recent studies show the relevance of nicotinic acid phosphoribosyltransferase (NAPRT), the rate-limiting enzyme of the Preiss–Handler NAD-production pathway for a large group of human cancers. We demonstrated that the NAPRT inhibitor 2-hydroxynicotinic acid (2-HNA) cooperates with the NAMPT inhibitor FK866 in killing NAPRT-proficient cancer cells that were otherwise insensitive to FK866 alone. Despite this emerging relevance of NAPRT as a potential target in cancer therapy, very few NAPRT inhibitors exist. Starting from a high-throughput virtual screening approach, we were able to identify and annotate two additional chemical scaffolds that function as NAPRT inhibitors. These compounds show comparable anti-cancer activity to 2-HNA and improved predicted aqueous solubility, in addition to demonstrating favorable drug-like profiles. [ABSTRACT FROM AUTHOR]