Class Of Chemotherapeutics Research Articles

Therapeutic use of fluorinated nucleosides - progress in patents.

Fluorinated nucleosides constitute a large class of chemotherapeutics approved for clinical use. The pharmacokinetic and pharmacodynamic properties of a drug can be affected, as a consequence of modulation of electronic, lipophilic and steric parameters, by the introduction of fluorine into the structure of drug-like molecule. Herein, we focus on fluorinated-nucleoside analogs, their therapeutic use and applications based on the patent literature from 2014 to 2018. We briefly discuss the clinical properties of anticancer and antiviral fluorine-containing nucleos(t)ides US FDA-approved or in development, and highlight their resistance mechanisms and limitations in the clinic. We emphasize patent inventions related to improved synthetic methods toward selected nucleos(t)ide analogs including the phosphoramidate sofosbuvir and 18F-labeled nucleosides FLT and FMAU, used as a 18F-PET tracers.

Phenanthridone Alkaloids of the Amaryllidaceae as Activators of the Apoptosis-related Proteolytic Enzymes, Caspases

Apoptosis-inducing anticancer drugs have garnered widespread interest in recent years. Targets which concomitantly also exhibit minimal adverse effects in normal, healthy cells have been particularly well-received. The phenanthridone alkaloids such as pancratistatin and narciclasine exemplify such a class of chemotherapeutics, with potent and selective cytotoxic effects in a wide variety of cancer cells which are manifested via the apoptotic mode of cell death. Caspases are central to the apoptotic process through their key function as effector molecules in apoptosis-related signaling pathways. Any attempt to mediate in such pathways, for example to probe the efficacy or mechanism of action of a drug, would inexorably serve to have a modulatory effect on these proteolytic enzymes. Apoptosis studies of phenanthridone alkaloids of the Amaryllidaceae have only gathered momentum over the past decade, following which caspases have understandably emerged as reliable biochemical markers of the process in an assortment of cancers. This review covers such studies of these alkaloids based on their structural-type, pointing out the various caspases which have been activated in different cancer cells and how structure modification can to a certain extent have a bearing on such activity. Also considered are clues to the apoptosis signaling pathways mediated following phenanthridone-induced activation of caspases.

In vitro assessment of chemotherapy-induced neuronal toxicity

Neurotoxicity is a major concern during drug development, and together with liver and cardio-toxicity, it is one of the main causes of clinical drug attrition. Current pre-clinical models may not sufficiently identify and predict the risk for central or peripheral nervous system toxicity. One such example is clinically dose-limiting neuropathic effects after the administration of chemotherapeutic agents. Thus, the need to establish novel in vitro tools to evaluate the risk of neurotoxicities, such as neuropathy, remains unmet in drug discovery. Though in vitro studies have been conducted using primary and immortalized cell lines, some limitations include the utility for higher throughput methodologies, method reproducibility, and species extrapolation. As a novel alternative, human induced-pluripotent stem cell (iPSC)-derived neurons appear promising for testing new drug candidates. These iPSC-derived neurons are readily available and can be manipulated as required. Here, we describe a novel approach to assess neurotoxicity caused by different classes of chemotherapeutics using kinetic monitoring of neurite dynamic changes and apoptosis in human iPSC-neurons. These studies show promising changes in neurite dynamics in response to clinical inducers of neuropathy, as well as the ability to rank-order and gather mechanistic insight into class-specific compound induced neurotoxicity. This platform can be utilized in early drug development, as part of a weight of evidence approach, to screen drug candidates, and potentially reduce clinical attrition due to neurotoxicity.

Mechanism-informed Repurposing of Minocycline Overcomes Resistance to Topoisomerase Inhibition for Peritoneal Carcinomatosis.

Mechanism-inspired drug repurposing that augments standard treatments offers a cost-effective and rapid route toward addressing the burgeoning problem of plateauing of effective therapeutics for drug-resistant micrometastases. We show that the antibiotic minocycline, by its ability to minimize DNA repair via reduced expression of tyrosyl-DNA phosphodiesterase-1 (Tdp1), removes a key process attenuating the efficacy of irinotecan, a frequently used chemotherapeutic against metastatic disease. Moreover, minocycline and irinotecan cooperatively mitigate each other's undesired cytokine inductions of VEGF and IL8, respectively, thereby reinforcing the benefits of each modality. These mechanistic interactions result in synergistic enhancement of irinotecan-induced platinum-resistant epithelial ovarian cancer cell death, reduced micrometastases in the omenta and mesentery by >75%, and an extended overall survival by 50% in a late-stage peritoneal carcinomatosis mouse model. Economic incentives and easy translatability make the repurposing of minocycline as a reinforcer of the topoisomerase class of chemotherapeutics extremely valuable and merits further investigations. Mol Cancer Ther; 17(2); 508-20. ©2017 AACR.

Discovery and synthesis of the first selective BAG domain modulator of BAG3 as an attractive candidate for the development of a new class of chemotherapeutics.

BAG3 protein has emerged as a key regulator of important cellular processes and its expression is increased in some tumor types; however, despite its potential value for future chemotherapeutics, no selective BAG3 modulators have been yet reported. Here we report the 2,4-thiazolidinedione derivative 28 as the first BAG3 protein modulator.

Exploring Heteroaryl-pyrazole Carboxylic Acids as Human Carbonic Anhydrase XII Inhibitors.

We report the synthesis, biological evaluation, and structural study of a series of substituted heteroaryl-pyrazole carboxylic acid derivatives. These compounds have been developed as inhibitors of specific isoforms of carbonic anhydrase (CA), with potential as prototypes of a new class of chemotherapeutics. Both X-ray crystallography and computational modeling provide insights into the CA inhibition mechanism. Results indicate that this chemotype produces an indirect interference with the zinc ion, thus behaving differently from other related nonclassical inhibitors. Among the tested compounds, 2c with Ki = 0.21 μM toward hCA XII demonstrated significant antiproliferative activity against hypoxic tumor cell lines. Taken together, the results thus provide the basis of structural determinants for the development of novel anticancer agents.

Mechanisms of DNA–protein crosslink repair

Covalent DNA-protein crosslinks (DPCs, also known as protein adducts) of topoisomerases and other proteins with DNA are highly toxic DNA lesions. Of note, chemical agents that induce DPCs include widely used classes of chemotherapeutics. Their bulkiness blocks virtually every chromatin-based process and makes them intractable for repair by canonical repair pathways. Distinct DPC repair pathways employ unique points of attack and are crucial for the maintenance of genome stability. Tyrosyl-DNA phosphodiesterases (TDPs) directly hydrolyse the covalent linkage between protein and DNA. The MRE11-RAD50-NBS1 (MRN) nuclease complex targets the DNA component of DPCs, excising the fragment affected by the lesion, whereas proteases of the spartan (SPRTN)/weak suppressor of SMT3 protein 1 (Wss1) family target the protein component. Loss of these pathways renders cells sensitive to DPC-inducing chemotherapeutics, and DPC repair pathways are thus attractive targets for combination cancer therapy.

Application of stem cell derived neuronal cells to evaluate neurotoxic chemotherapy

The generation of induced pluripotent stem cells (iPSCs) and differentiation to cells composing major organs has opened up the possibility for a new model system to study adverse toxicities associated with chemotherapy. Therefore, we used human iPSC-derived neurons to study peripheral neuropathy, one of the most common adverse effects of chemotherapy and cause for dose reduction. To determine the utility of these neurons in investigating the effects of neurotoxic chemotherapy, we measured morphological differences in neurite outgrowth, cell viability as determined by ATP levels and apoptosis through measures of caspase 3/7 activation following treatment with clinically relevant concentrations of platinating agents (cisplatin, oxaliplatin and carboplatin), taxanes (paclitaxel, docetaxel and nab-paclitaxel), a targeted proteasome inhibitor (bortezomib), an antiangiogenic compound (thalidomide), and 5-fluorouracil, a chemotherapeutic that does not cause neuropathy. We demonstrate differential sensitivity of neurons to mechanistically distinct classes of chemotherapeutics. We also show a dose-dependent reduction of electrical activity as measured by mean firing rate of the neurons following treatment with paclitaxel. We compared neurite outgrowth and cell viability of iPSC-derived cortical (iCell® Neurons) and peripheral (Peri.4U) neurons to cisplatin, paclitaxel and vincristine. Goshajinkigan, a Japanese herbal neuroprotectant medicine, was protective against paclitaxel-induced neurotoxicity but not oxaliplatin as measured by morphological phenotypes. Thus, we have demonstrated the utility of human iPSC-derived neurons as a useful model to distinguish drug class differences and for studies of a potential neuroprotectant for the prevention of chemotherapy-induced peripheral neuropathy.

Chemotherapy and Transplantation: The Role of Immunosuppression in Malignancy and a Review of Antineoplastic Agents in Solid Organ Transplant Recipients.

It is estimated that solid organ transplant recipients have a two- to fourfold greater overall risk of malignancy than the general population. Some of the most common malignancies after transplant include skin cancers and posttransplant lymphoproliferative disorder. In addition to known risk factors such as environmental exposures, genetics, and infection with oncogenic viruses, immunosuppression plays a large role in the development of cancer through the loss of the immunosurveillance process. The purpose of this article is to explain the role of immunosuppression in cancer and to review the classes of chemotherapeutics. The field of anticancer drugs is continually expanding and developing, with limited data on use in transplant recipients. This article aims to provide information on class review, adverse effects, dose adjustments, and drug interactions that are pertinent to the care of transplant recipients.

CHEMOTHERAPY INDUCED CARDIOTOXICITY, ITS PREVENTION, TREATMENT AND RISK FACTORS

Background: Cardiovascular disease is the second leading cause of death among cancer survivors. Chemotherapy is associated with increased risk of non-ischemic cardiomyopathy and heart failure. The incidence of cardiomyopathy is dependent upon the class of chemotherapeutics; there is also a reported

Cisplatin Toxicity in Dorsal Root Ganglion Neurons Is Relieved by Meclizine via Diminution of Mitochondrial Compromise and Improved Clearance of DNA Damage

Chemotherapy-induced neurotoxicity of peripheral nervous system (PNS) hinders efficacy of cancer treatments. Mechanisms initiating PNS injury by anticancer drugs are incompletely understood delaying development of effective management strategies. To understand events triggered in PNS by cancer drugs, we exposed dorsal root ganglion (DRG) neurons to cisplatin, a drug from platinum-based class of chemotherapeutics frequently implicated in peripheral neuropathies. While cisplatin enters cancer cells and forms cisplatin/DNA crosslinks that block cell proliferation, circulating cisplatin can also reach the PNS and produce crosslinks that impede critical DNA transactions in postmitotic neurons. Cisplatin forms crosslinks with both, nuclear and mitochondrial DNA (mtDNA). Crosslinks are repairable primarily via the nucleotide excision repair (NER) pathway, which is present in nuclei but absent from mitochondrial compartment. Hence, high mitochondrial content and limited shielding by blood nerve barrier make DRG neurons particularly vulnerable to mitochondrial injury by cisplatin. We report that in DRG neurons, cisplatin elevates reactive oxygen species, depletes mtDNA, and impairs mitochondrial respiration, whereas concomitant meclizine supplementation preserves redox balance, attenuates mitochondrial compromise, and augments DNA repair. Meclizine is an antihistamine drug recently implicated in neuroprotection via modulation of energy metabolism. Our data demonstrate that in the mitochondria-rich DRG neurons, meclizine mitigates cisplatin-induced mitochondrial compromise via enhancement of pentose phosphate pathway and repletion of nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione stores. The findings suggest that meclizine-mediated preservation of redox balance sustains mitochondrial respiration and supports execution of cellular processes, including timely removal of cisplatin crosslinks from nuclear DNA, thereby attenuating cisplatin toxicity in DRG neurons. Collectively, the findings reveal potential for pharmacologic modulation of dorsal root ganglion neurons metabolism for protection against toxicity of chemotherapeutic drugs.

ProTides of BVdU as potential anticancer agents upon efficient intracellular delivery of their activated metabolites

Nucleosides represent a major chemotherapeutic class for treating cancer, however their limitations in terms of cellular uptake, nucleoside kinase-mediated activation and catabolism are well-documented. The monophosphate pro-nucleotides known as ProTides represents a powerful strategy for bypassing the dependence on active transport and nucleoside kinase-mediated activation. Herein, we report the structural tuning of BVdU ProTides. Forty six phosphoramidates were prepared and biologically evaluated against three different cancer cell lines; murine leukemia (L1210), human CD4+ T-lymphocyte (CEM) and human cervical carcinoma (HeLa). Twenty-fold potency enhancement compared to BVdU was achieved against L1210 cells. Interestingly, a number of ProTides showed low micromolar activity against CEM and HeLa cells compared to the inactive parent BVdU. The ProTides showed poor, if any measurable toxicity to non-tumourigenic human lung fibroblast cell cultures. Separation of four pairs of the diastereoisomeric mixtures and comparison of their spectral properties, biological activities and enzymatic activation rate is reported.

The evolving field of cardio-oncology: beyond anthracyclines and heart failure.

Dr Michael Fradley discusses the cardiac implications beyond anthracyclines and heart failure Over the last several decades, the survival rates for many cancers have increased dramatically, largely driven by improved screening modalities and the development of novel cancer treatments including targeted and immunologic therapies. Despite these advancements, cardiovascular toxicity is a commonly observed complication of many of these treatments. As a result, the field of cardio-oncology has developed at a rapid pace. Cardio-oncology is a multidisciplinary specialty aimed at managing and preventing cardiovascular disease in cancer patients and survivors.1 Initially, cardio-oncology was focused on cardiomyopathy and congestive heart failure associated with anthracyclines, a class of chemotherapeutics used to treat a variety of cancers including breast, sarcoma, leukaemia, and lymphoma.2 As the field of cardio-oncology has grown, there is increased recognition that cardiotoxicity is not limited to just anthracyclines and heart failure; instead novel cancer therapeutics are associated with a variety of cardiac complications including vascular disease, accelerated hypertension, and arrhythmias. It is important for the cardio-oncologist to possess a broad knowledge of these agents and their toxicities in order to provide optimal care to patients. With improved understanding of cancer biology, the landscape of cancer therapeutics has changed dramatically. For example, abnormal cell signalling pathways have been implicated in many different cancers, often due to overexpressed or mutated protein kinases impacting the amino acid tyrosine.3 There is also data demonstrating that certain cancers are particularly dependent on proteasomes (multienzyme complexes that play a key role in protein degradation and homeostasis) for survival and proliferation.4 As such, the development of tyrosine kinase inhibitors (TKIs) and proteasome inhibitors (PIs), have led to significant improvements in the treatment of many liquid and solid tumours. More recently, immunomodulatory drugs (IMiDs) and other immunotherapies that harness the body’s own immune …

Smac mimetic LCL161 supports neuroblastoma chemotherapy in a drug class-dependent manner and synergistically interacts with ALK inhibitor TAE684 in cells with ALK mutation F1174L.

Neuroblastoma is the most common extracranial solid tumor during infancy and childhood.Outcome of high-risk and late-stage disease remains poor despite intensive treatment regimens.Suppressing inhibitor of apoptosis proteins (IAPs) using Smac mimetics (SM) significantly sensitizes neuroblastoma (NB) cells for chemotherapy, however strongly dependent on the cytotoxic drug combined with SM.Therefore, a systematic analysis of the impact of SM in combination with different classes of chemotherapeutics was of crucial importance. Treatment of NB cell lines with SM LCL161 and vinca alkaloids revealed a strong synergistic inhibition of proliferation and significant induction of apoptosis in virtually all established and de novo NB cell lines (n=8).In contrast, combination of anthracyclines or topoisomerase inhibitors with LCL161 showed a synergism for single drugs and/or cell lines only.Furthermore, we could show that insensibility to LCL161-mediated sensitization for chemotherapeutics is associated with aberrant activation of anaplastic lymphoma kinase (ALK) by common mutation F1174L. Inhibition of ALK using TAE684 is able to overcome this resistance in a synergistic fashion, a finding that could be highly relevant for improvement of neuroblastoma therapy.

Abstract 2100: Imputation of drug sensitivity levels in The Cancer Genome Atlas using machine learning identifies novel predictors of chemotherapeutic response

Abstract The Cancer Genome Atlas (TCGA) represents a landmark undertaking that has collected genomic data from tumors of almost 15,000 cancer patients. Most tumors have been assayed using many high-throughput genomics techniques, such as whole-genome DNA copy number, gene expression, mutation status and DNA methylation. The project has also compiled a large set of matching clinical data; however, the utility of TCGA for pharmacogenomic discovery has been severely limited by the lack of cleanly measured drug response data. The absence of such data owes to the difficulty in obtaining this information from cancer patients, because individuals are typically treated with complex multi-drug regimes, which renders the precise measurement of a drug specific response phenotype intractable. However, precisely measured drug response data can be readily obtained in pre-clinical models, such as cell lines. Thus, in this study, we have implemented a machine learning based approach, where gene expression based predictive models of drug response are constructed on approximately 700 cancer cell lines; these models are then applied to nearly 15,000 TCGA tumor samples, for which gene expression data is also available, yielding a predicted drug sensitivity value in each TCGA sample. We used this approach to impute a drug sensitivity estimate for 138 drugs that were treated against the cell lines. Our approach allowed us to transform TCGA into a vast pharmacogenomics dataset, on an unprecedented scale (and thus power), which could be mined for novel associations relevant to chemotherapeutic response. As a proof-of-concept, we first investigated whether the existing small number of known clinically relevant associations could be recapitulated in these imputed data. As an example, we identified the predicted difference in sensitivity to Lapatinib, which interrupts ERBB2, as significantly greater in ERBB2 amplified tumors (P = 6 × 10-12), an association that is drug specific. In ERBB2 amplified tumors, large chunks of chromosome 17, containing many genes, are typically amplified; this recurring phenomenon often renders it impossible to identify the causative genes in genome wide copy number data using conventional approaches. Strikingly however, by interrogating the observed effect size of genes in this amplicon, ERBB2 could be identified as the precise causative drug target in our data, demonstrating the impressive increase in power obtained from this approach. Additionally, the second most significant association for Lapatinib is for EGFR, which is the known secondary target of this drug (P = 5 × 10-4). We also identified many novel associations; e.g. that a copy number amplification in ERLIN2, a gene shown to play a role in stabilizing microtubules, is associated with resistance to a class of chemotherapeutics that interact with the microtubules. This was subsequently validated with follow-up experiments. Citation Format: Paul Geeleher, R. Stephanie Huang, Fan Wang, Gladys Morrison. Imputation of drug sensitivity levels in The Cancer Genome Atlas using machine learning identifies novel predictors of chemotherapeutic response. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2100.

Discovery of selective inhibitors of tyrosyl-DNA phosphodiesterase 2 by targeting the enzyme DNA-binding cleft

Tyrosyl-DNA phosphodiesterase 2 (TDP2) processes protein/DNA adducts resulting from abortive DNA topoisomerase II (Top2) activity. TDP2 inhibition could provide synergism with the Top2 poison class of chemotherapeutics. By virtual screening of the NCI diversity small molecule database, we identified selective TDP2 inhibitors and experimentally verified their selective inhibitory activity. Three inhibitors exhibited low-micromolar IC50 values. Molecular dynamics simulations revealed a common binding mode for these inhibitors, involving association to the TDP2 DNA-binding cleft. MM-PBSA per-residue energy decomposition identified important interactions of the compounds with specific TDP2 residues. These interactions could provide new avenues for synthetic optimization of these scaffolds.

Research progress of histone deacetylase inhibitors in therapy of multiple myeloma

Multiple myeloma (MM) is a clonal B-cell malignant neoplasm. In recent years, higtone deacetylase (HDAC) are dysregulated in MM, and MM patients with high expression of HDAC have significantly poorer prognostic outcomes. Acetylation of proteins influences a diverse range of cellular functions. Moreover, histone acetylation transferase (HAT) and HDAC keep the acetylation status of proteins in dynamic balance. Histone deacetylase inhibitors (HDACI) have emerged as a novel class of chemotherapeutics which are being evaluated in clinical trials. This review discusses the research progress of HDACI in therapy of MM in recent years. Key words: Histone acetyltransferases; Multiple myeloma; Therapy

Sarco"MiR" friend or foe: a perspective on the mechanisms of doxorubicin-induced cardiomyopathy.

Anthracyclines are a class of chemotherapeutics used to treat a variety of human cancers including both solid tumors such as breast, ovarian, and lung, as well as malignancies of the blood including leukemia and lymphoma. Despite being extremely effective anti-cancer agents, the application of these drugs is offset by side effects, most notably cardiotoxicity. Many patients treated with doxorubicin (DOX), one of the most common anthracyclines used in oncology, will develop radiographic signs and/or symptoms of cardiomyopathy. Since more and more patients treated with these drugs are surviving their malignancies and manifesting with heart disease, there is particular interest in understanding the mechanisms of anthracycline-induced injury and developing ways to prevent and treat its most feared complication, heart failure. MicroRNAs (miRNAs) are small noncoding RNAs that regulate the expression of mRNAs. Since miRNAs can regulate many mRNAs in a single network they tend to play a crucial role in the pathogenesis of several diseases, including heart failure. Here we present a perspective on a recent work by Roca-Alonso and colleagues who demonstrate a cardioprotective function of the miR-30 family members following DOX-induced cardiac injury. They provide evidence for direct targeting of these miRNAs on key elements of the β-adrenergic pathway and further show that this interaction regulates cardiac function and apoptosis. These experiments deliver fresh insights into the biology of toxin-induced cardiomyopathy and suggest the potential for novel therapeutic targets.

Valproate as a novel radiosensitizer in selective internal radiation therapy (SIRT) for unresectable hepatocellular carcinoma.

314 Background: A large majority of Hepatocellular Carcinomas (HCC) present in locally advanced or metastatic stages; patients are usually poor candidates for surgical resection. Yttrium-90 Selective Internal Radiation Therapy (SIRT) is employed in both palliative and bridging therapy for unresectable HCCs. Histone Deacetylase Inhibitors (HDACi) are an emerging class of chemotherapeutics which exert their cytotoxicity through epigenetic modification. By maintaining DNA in an open conformation, it increases the surface area exposed for radiation damage- a postulated mechanism of its radiosensitizing effect. It is envisioned that HDACi will greatly augment therapeutic efficacy in brachytherapy. Here, the radiosensitizing effects of valproate, a known HDACi is investigated as potential adjunct with SIRT. Methods: 3 HCC cell lines were studied: HepG2, Hep3B and JNN4. They were first treated at various concentrations of valproate and cell viability was assessed. Next, a Caspase-3/7 assay was carried out to assess cell apoptosis. Westernblot analysis was performed on treated cells to elucidate histone acetylation status with Anti-Acetyl H3/H4 Antibodies. Finally, a clonogenic survival assay compared the effect of Yttrium-90, Lutetium-177, valproate and combination treatment on clonogenic proliferation. Results: Cell viability studies showed that valproate is cytotoxic to all HCC cell lines at concentrations from 10mM. Westernblot analysis demonstrated that valproate treatment maintained histone acetylation across all HCC cell lines validating it’s mechanism of action. Clonogenic Survival demonstrated a significant reduction of cell survival for all HCC cell lines treated with valproate and Isotope as compared to monotherapy. Conclusions: The use of HDACi such as valproate is not only novel in SIRT but showed great promise as an adjunct therapy. Experiments not only demonstrated its cytotoxicity, but also, reduction in clonogenic and proliferative ability of cancer cells. It can be postulated that the co-administration of valproate with SIRT will enhance therapeutic efficacy, allowing more aggressive and efficacious treatment of HCC.

The diterpenoid 7-keto-sempervirol, derived from Lycium chinense, displays anthelmintic activity against both Schistosoma mansoni and Fasciola hepatica.

BackgroundTwo platyhelminths of biomedical and commercial significance are Schistosoma mansoni (blood fluke) and Fasciola hepatica (liver fluke). These related trematodes are responsible for the chronic neglected tropical diseases schistosomiasis and fascioliasis, respectively. As no vaccine is currently available for anti-flukicidal immunoprophylaxis, current treatment is mediated by mono-chemical chemotherapy in the form of mass drug administration (MDA) (praziquantel for schistosomiasis) or drenching (triclabendazole for fascioliasis) programmes. This overreliance on single chemotherapeutic classes has dramatically limited the number of novel chemical entities entering anthelmintic drug discovery pipelines, raising significant concerns for the future of sustainable blood and liver fluke control.Methodology/ Principle FindingsHere we demonstrate that 7-keto-sempervirol, a diterpenoid isolated from Lycium chinense, has dual anthelmintic activity against related S. mansoni and F. hepatica trematodes. Using a microtiter plate-based helminth fluorescent bioassay (HFB), this activity is specific (Therapeutic index = 4.2, when compared to HepG2 cell lines) and moderately potent (LD50 = 19.1 μM) against S. mansoni schistosomula cultured in vitro. This anti-schistosomula effect translates into activity against both adult male and female schistosomes cultured in vitro where 7-keto-sempervirol negatively affects motility/behaviour, surface architecture (inducing tegumental holes, tubercle swelling and spine loss/shortening), oviposition rates and egg morphology. As assessed by the HFB and microscopic phenotypic scoring matrices, 7-keto-sempervirol also effectively kills in vitro cultured F. hepatica newly excysted juveniles (NEJs, LD50 = 17.7 μM). Scanning electron microscopy (SEM) evaluation of adult F. hepatica liver flukes co-cultured in vitro with 7-keto-sempervirol additionally demonstrates phenotypic abnormalities including breaches in tegumental integrity and spine loss.Conclusions/ Significance7-keto-sempervirol negatively affects the viability and phenotype of two related pathogenic trematodes responsible for significant human and animal infectious diseases. This plant-derived, natural product is also active against both larval and adult developmental forms. As such, the data collectively indicate that 7-keto-sempervirol is an important starting point for anthelmintic drug development. Medicinal chemistry optimisation of more potent 7-keto-sempervirol analogues could lead to the identification of novel chemical entities useful for future combinatorial or replacement anthelmintic control.