Interference Compound Research Articles

Sickle Cell Hemoglobin "Drugged" with Cyclic Peptides Is Aggregation Incompetent.

Sickle cell disease (SCD) is a monogenic blood disorder associated with a mutation in the hemoglobin subunit β gene encoding for the β-globin of normal adult hemoglobin (HbA). This mutation transcribes into a Glu-β6 → Val-β6 substitution in the β-globins, inducing the polymerization of this hemoglobin form (HbS) when in the T-state. Despite advances in stem cell and gene therapy, and the recent approval of a new antisickling drug, therapeutic limitations persist. Herein, we demonstrate through molecular dynamics and umbrella sampling, that (unrestrained) blockage of the hydrophobic pocket involved in the lateral contact of the HbS fibers by 5-mer cyclic peptides, recently proposed as SCD aggregation inhibitors (Neto, V.; J. Med. Chem. 2023, 66, 16062-16074), is enough to turn the dimerization of HbS thermodynamically unfavorable. Among these potential drugs, some exhibit an estimated pocket abandonment probability of around 15-20% within the simulations' time frame, and an impressive specificity toward the mutated Val-β6. Additionally, we show that the dimerization can be thermodynamically unfavored by blocking a nearby region while the pocket remains vacant. These results are compared with curcumin, an antisickling molecule and a pan-assay interference compound, with a good binding affinity for different proteins and protein domains. Our results confirm the potential of some of these cyclic peptides as antisickling drug candidates to reduce the concentration of aggregation-competent HbS.

Synthesis of 9-Cinnamyl-9H-purine Derivatives as Novel TLR4/MyD88/NF-κB Pathway Inhibitors for Anti-inflammatory Effects.

The novel 9-cinnamyl-9H-purine skeleton, inspired by resveratrol and curcumin, was developed to avoid a pan-assay interference compound (PAINS) related to invalid metabolic pancreas activity (IMPS). It replaced the phenol group with purine analogues, the building blocks of DNA and RNA. Alterations to the hydroxyl group in the cinnamyl group, such as H, Me, or F substitutions, were made to impede its oxidation to a PAINS-associated quinone. Among the compounds tested, 5e significantly inhibited nitric oxide production in LPS-induced macrophages (IC50: 6.4 vs 26.4 μM for resveratrol). 5e also reduced pro-inflammatory cytokine levels (IL-6, TNF-α, IL-1β) and lowered iNOS and COX-2 protein levels. Mechanistically, 5e disrupted the TLR4-MyD88 protein interaction, leading to the suppression of the NF-κB signaling pathway suppression. In an atopic dermatitis mouse model, 5e reduced ear edema and inflammation. These findings indicate that the novel 9-cinnamyl-9H-purine skeleton provides therapeutic insight into treating various human diseases by regulating inflammation.

Synthesis and cancer cell cytotoxicity of 2-aryl-4-(4-aryl-2-oxobut-3-en-1-ylidene)-substituted benzothiazepanes

Curcumin is a natural product displaying a broad range of biological activities, including anticancer properties. It is, however, poorly absorbed by the human body and, as a so-called pan-assay interference compound, it exhibits non-specific activity leading to false positive results in biological assays. Nonetheless, different structural modifications of the curcumin scaffold have previously shown to lead to an improved biological and specificity profile without losing antiproliferative activity. In that respect, recent research in our group culminated in unprecedented benzothiazepane-based hit molecules with promising biological and drug-like properties. In the present hit expansion study, 14 new 2-aryl-4-(4-aryl-2-oxobut-3-en-1-ylidene)benzothiazepanes were successfully synthesized through the implementation of various aromatic ring modifications and subsequently tested for cancer cell cytotoxicity using eight different cancer cell lines, revealing useful structure-activity relationship insights for this new class of compounds.

Phloretin, as a Potent Anticancer Compound: From Chemistry to Cellular Interactions.

Phloretin is a natural dihydrochalcone found in many fruits and vegetables, especially in apple tree leaves and the Manchurian apricots, exhibiting several therapeutic properties, such as antioxidant, antidiabetic, anti-inflammatory, and antitumor activities. In this review article, the diverse aspects of the anticancer potential of phloretin are addressed, presenting its antiproliferative, proapoptotic, antimetastatic, and antiangiogenic activities in many different preclinical cancer models. The fact that phloretin is a planar lipophilic polyphenol and, thus, a membrane-disrupting Pan-Assay Interference compound (PAIN) compromises the validity of the cell-based anticancer activities. Phloretin significantly reduces membrane dipole potential and, therefore, is expected to be able to activate a number of cellular signaling pathways in a non-specific way. In this way, the effects of this minor flavonoid on Bax and Bcl-2 proteins, caspases and MMPs, cytokines, and inflammatory enzymes are all analyzed in the current review. Moreover, besides the anticancer activities exerted by phloretin alone, its co-effects with conventional anticancer drugs are also under discussion. Therefore, this review presents a thorough overview of the preclinical anticancer potential of phloretin, allowing one to take the next steps in the development of novel drug candidates and move on to clinical trials.

Rotational constriction of curcuminoids impacts 5-lipoxygenase and mPGES-1 inhibition and evokes a lipid mediator class switch in macrophages

Polypharmacological targeting of lipid mediator networks offers potential for efficient and safe anti-inflammatory therapy. Because of the diversity of its biological targets, curcumin (1a) has been viewed as a privileged structure for bioactivity or, alternatively, as a pan-assay interference (PAIN) compound. Curcumin has actually few high-affinity targets, the most remarkable ones being 5-lipoxygenase (5-LOX) and microsomal prostaglandin E2 synthase (mPGES)-1. These enzymes are critical for the production of pro-inflammatory leukotrienes and prostaglandin (PG)E2, and previous structure–activity-relationship studies in this area have focused on the enolized 1,3-diketone motif, the alkyl-linker and the aryl-moieties, neglecting the rotational state of curcumin, which can adopt twisted conformations in solution and at target sites. To explore how the conformation of curcuminoids impacts 5-LOX and mPGES-1 inhibition, we have synthesized rotationally constrained analogues of the natural product and its pyrazole analogue by alkylation of the linker and/or of the ortho aromatic position(s). These modifications strongly impacted 5-LOX and mPGES-1 inhibition and their systematic analysis led to the identification of potent and selective 5-LOX (3b, IC50 = 0.038 µM, 44.7-fold selectivity over mPGES-1) and mPGES-1 inhibitors (2f, IC50 = 0.11 µM, 4.6-fold selectivity over 5-LOX). Molecular docking experiments suggest that the C2-methylated pyrazolocurcuminoid 3b targets an allosteric binding site at the interface between catalytic and regulatory 5-LOX domain, while the o, o'-dimethylated desmethoxycurcumin 2f likely binds between two monomers of the trimeric mPGES-1 structure. Both compounds trigger a lipid mediator class switch from pro-inflammatory leukotrienes to PG and specialized pro-resolving lipid mediators in activated human macrophages.

Enhanced-charge transfer over molecularly imprinted polyaniline modified graphene/TiO2 nanocomposite electrode for highly selective detection of fipronil insecticide

Fipronil contamination in agricultural products and livestock has become a growing concern because its long-term exposure to its toxicity effect on humans may cause the failure of organs, like kidney and liver, and neurological disorders. Early detection of this substance's presence in agricultural and livestock products should be established to minimize its fatal effect. Here, we demonstrate a fabrication of high sensing sensitivity and selectivity electrode for electrochemical detection of fipronil pesticide, i.e. molecularly imprinted polyaniline modified graphene/TiO2 nanocomposite (Gr/TiO2@MIP-PANi). The results show that the composite electrode is extremely sensitive to the fipronil by showing a highly active electron transfer with an oxidation potential as low as 0.21 V. The sensing sensitivity of the composite electrode also exhibits excellent linearity to the fipronil concentration within a range of 1.0 mM–8.0 mM. This gives the limit of detection (LoD) value as low as 0.74 mM. Our analysis also showed that the existence of facile diffusion of fipronil onto the composite electrode is the key factor for the high sensing sensitivity of the composite electrode. In addition, the composite electrode also demonstrate a high selectivity properties as it can detect the presence of 5 mM fipronil in the 5 mM profenofos interference compound. These results signify that the new Gr/TiO2@MIP-PANi nanocomposite electrode should find extensively used for sensitive and selective detection of fipronil in food products.

Facile synthesis of graphene oxide/Fe3O4 nanocomposite for electrochemical sensing on determination of dopamine

Dopamine concentration abnormalities in the body can cause various disorders and diseases such as Parkinson's, Tourette's syndrome, and depression. In this study, graphene oxide (GO) was combined with Fe3O4 to sensitively and selectively detect dopamine. The performance was evaluated by cyclic voltammetry (CV) and differential pulse voltammetry (DPV) methods. The results of testing with CV on the solution [Fe(CN)6] showed that a modification with GO gave a maximum effective surface area value of 0.0127 cm2, proving that GO can increase the effective area and conductivity of the sensor. DPV testing shows that dopamine detection using GO/Fe3O4 has a linear range at a concentration of 1–10 μM with a detection limit of 0.48 μM and a quantification limit of 1.6 μM. GO/Fe3O4 also shows good selectivity where the peak current is separated by 0.245 V with ascorbic acid, which is the closest interference compound.

Norcantharidin promotes cancer radiosensitization through Cullin1 neddylation-mediated CDC6 protein degradation.

Radiotherapy (RT) is a conventional cancer therapeutic modality. However, cancer cells tend to develop radioresistance after a period of treatment. Diagnostic markers and therapeutic targets for radiosensitivity are severely lacking. Our recently published studies demonstrated that the cell division cycle (CDC6) is a critical molecule contributing to radioresistance, and maybe a potential therapeutic target to overcome radioresistance. In the present study, we for the first time reported that Norcantharidin (NCTD), a demethylated form of cantharidin, re-sensitized radioresistant cancer cells to overcome radioresistance, and synergistically promoted irradiation (IR)-induced cell killing and apoptosis by inducing CDC6 protein degradation. Mechanistically, NCTD induced CDC6 protein degradation through the ubiquitin-proteasome pathways. By using small interfering RNA (siRNA) interference or small compound inhibitors, we further determined that NCTD induced CDC6 protein degradation through a neddylation-dependent pathway, but not through Huwe1, Cyclin F, and APC/C-mediated ubiquitin-proteasome pathways. We screened the six most relevant Cullin subunits (CUL1, 2, 3, 4A, 4B, and 5) using siRNAs. The knockdown of Cullin1 but not the other five cullins remarkably elevated CDC6 protein levels. NCTD promoted the binding of Cullin1 to CDC6, thereby promoting CDC6 protein degradation through a Cullin1 neddylation-mediated ubiquitin-proteasome pathway. NCTD can be used in combination with radiotherapy to achieve better anticancer efficacy, or work as a radiosensitizer to overcome cancer radioresistance.

Highly Synergistic Sensor of Graphene Electrode Functionalized with Rutile TiO<sub>2</sub> Microstructures to Detect L-Tryptophan Compound

Electrochemical processes are an effective method for detecting dangerous food ingredients. The synergetic between the reduction-oxidation (redox) processes inspired several papers and spurred research towards studying the new materials that can further adapt to optimize the rapid detection of chemical compounds. In this study, we report the eco-synthesis using graphene/TiO2 rutile (G/TiO2) electrode microstructures easily prepared through the physical method by mixing graphene and TiO2 powder and its application for sensing L-tryptophan (Trp) compound. The material characterization results show that the graphene surface is smoother than the G/TiO2 material. Graphene has been detected using X-ray diffraction (XRD) at a value of 2 thetas 26.39° and TiO2 forms rutile crystals (110). The FTIR spectrum exhibits the functional groups from graphene of -OH, C-H, C=C, C-O, and TiO2 identified with Ti-O bonds. The electrochemical test against G/TiO2 electrode microstructures for Trp compound shows that 0.5 g TiO2 rutile was the best composition functionalized with graphene material under 0.1M K3[Fe(CN)6] + 0.1M NaNO3 electrolyte with a scan rate of 0.1 V/s. Determination of the detection limit was obtained at 0.005 mg/L with a HorRat value of 1.05%. The stability test was carried out for 25 days, and the addition of Pb(NO3)2 as an interference compound had a significant effect on the decrease in electrode performance.

Discovery of Natural Compounds as Potential Inhibitors of Human Carbonic Anhydrase II: An Integrated Virtual Screening, Docking, and Molecular Dynamics Simulation Study

Carbonic anhydrase II (CAII) is one of the zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide, leading to the formation of bicarbonate and proton. CAII plays a significant role in health and disease. For example, CAII helps to maintain eye pressure while regulating the pH of the tumor microenvironment, and by extension, contributing to cancer progression. Owing to its remarkable role in cancer, visual health, and other human diseases, CAII can serve as an attractive therapeutic target. We report an original study based on high-throughput virtual screening of natural compounds from the ZINC database in search of potential inhibitors of CAII. We selected the hits based on the physicochemical, absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties, pan-assay interference compound (PAINS) patterns, and interaction analysis. Importantly, two natural compounds were identified, ZINC08918123 and ZINC00952700, bearing considerable affinity and specific interactions to the residues of the CAII-binding pocket with well-organized conformational fitting compatibility. We investigated the conformational dynamics of CAII in complex with the identified compounds through molecular dynamics simulation, which revealed the formation of a stable complex preserved throughout the 100 ns trajectories. The stability of the protein/ligand complexes is maintained by significant numbers of noncovalent interactions throughout the simulations. In conclusion, natural compounds identified in the present study specifically and computer-assisted drug design broadly offer a reliable resource and strategy to discover potential promising therapeutic inhibitors of CAII to cure various cancers and glaucoma after further experimental validation and clinical studies.

Remodelin Is a Cryptic Assay Interference Chemotype That Does Not Inhibit NAT10-Dependent Cytidine Acetylation.

Remodelin is a putative small molecule inhibitor of the RNA acetyltransferase NAT10 which has shown preclinical efficacy in models of the premature aging disease Hutchinson-Gilford Progeria Syndrome (HGPS). Here we evaluate remodelin's assay interference characteristics and effects on NAT10-catalyzed RNA cytidine acetylation. We find the remodelin chemotype constitutes a cryptic assay interference compound, which does not react with small molecule thiols but demonstrates protein reactivity in ALARM NMR and proteome-wide affinity profiling assays. Biophysical analyses find no direct evidence for interaction of remodelin with the NAT10 acetyltransferase active site. Cellular studies verify that N4-acetylcytidine (ac4C) is a nonredundant target of NAT10 activity in human cell lines and find that this RNA modification is not affected by remodelin treatment in several orthogonal assays. These studies display the potential for remodelin's chemotype to interact with multiple protein targets in cells and indicate remodelin should not be applied as a specific chemical inhibitor of NAT10-catalyzed RNA acetylation.

Quantitative structure activity relationship and molecular simulations for the exploration of natural potent VEGFR-2 inhibitors: an in silico anti-angiogenic study

VEGFR-2 has recently become an eye-catching molecular target for the novel therapeutic designs against cancer for its well known role in persuading angiogenesis in tumor cells. The current study set sights on the exploration of novel potent natural compound targeting VEGFR-2 via computational ligand-based modeling and database screening followed by binding pattern analysis, reactivity site prediction and MD simulation studies. The known 53 VEGFR-2 inhibitors (with IC50 ranging from 0.7 nM to 9700 nM) were headed for development of Ligand based pharmacophore model using 3 D QSAR pharmacophore generation module of DS Client. Training set inhibitors (23 compounds) were exploited to create pharmacophore model based on their chemical features. The model was validated through 30 test set inhibitors and exploited further for screening of 62,082 natural compounds from InterBioscreen natural compound database. Screened compounds further went through Drug-Likeliness study, ADMET prediction, Binding pattern analysis, In silico prediction of reactivity sites, Biological activity spectra prediction, pan assay interference compound identification and MD simulation analysis. Out of 5 screened compounds, Compound A and Compound B exhibited highest binding energy judged against the standard drug “Sorafenib”. On further conducting reactivity site prediction, BAS prediction, and pan assay interference compound identification, Compound B exhibited better result which was carried forward for MD simulation study for 50 ns. MD simulation results suggested that Compound B exhibited more stable binding to the active site of VEGFR-2 without causing any conformational changes in protein-ligand complex. Thereby, the investigation proposes Compound B to hold potent antiangiogenic potential targeting VEGFR-2. Communicated by Ramaswamy H. Sarma

Antitrypanosomal butanolides from Aiouea trinervis.

In a search for new antitrypanosomal agents in the Brazilian flora, the ethanol extract of the xylopodium from Aiouea trinervis (Lauraceae) exhibited in vitro activity against the epimastigote forms of Trypanosoma cruzi, the etiological agent of Chagas disease. Bioassay-guided chromatographic fractionation of the ethanol extract afforded three butanolides, isoobtusilactone A (1), epilitsenolide C2 (2), and epilitsenolide C1 (3). Butanolides 1 and 3 were more active against T. cruzi epimastigotes than the reference drug benznidazole (by 8.9-fold and 3.2-fold, respectively), while 2 proved inactive. Compounds 1 and 3 showed low cytotoxicity in mammalian Vero cells (CC50> 156 μmol L-1) and high selectivity index (SI) values for epimastigotes (SI = 56.8 and 28.6, respectively), and 1 was more selective than benznidazole (SI = 46.5). Butanolide 1 at 24 μmol L-1 also led to cell cycle alterations in epimastigote forms, and inhibited the growth of amastigote cells in more than 70 %. In silico ADMET properties of 1 were also analyzed and predicted favorable drug-like characteristics. This butanolide also complied with Lipinski's rule of five and was not predicted as interference compound (PAINS). This is the first report on the isolation of these bioactive butanolides under the guidance of in vitro trypanocidal activity against T. cruzi.

Nostotrebin 6 Related Cyclopentenediones and δ-Lactones with Broad Activity Spectrum Isolated from the Cultivation Medium of the Cyanobacterium Nostoc sp. CBT1153

Cyanobacteria are an interesting source of biologically active natural products, especially chemically diverse and potent protease inhibitors. On our search for inhibitors of the trypanosomal cysteine protease rhodesain, we identified the homodimeric cyclopentenedione (CPD) nostotrebin 6 (1) and new related monomeric, dimeric, and higher oligomeric compounds as the active substances in the medium extract of Nostoc sp. CBT1153. The oligomeric compounds are composed of two core monomeric structures, a trisubstituted CPD or a trisubstituted unsaturated δ-lactone. Nostotrebin 6 thus far has been the only known cyanobacterial CPD. It has been found to be active in a broad variety of assays, indicating that it might be a pan-assay interference compound (PAIN). Thus, we compared the antibacterial and cytotoxic activities as well as the rhodesain inhibition of selected compounds. Because a compound with a δ-lactone instead of a CPD core structure was equally active as nostotrebin 6, the bioactivities of these compounds seem to be based on the phenolic substructures rather than the CPD moiety. While the dimers were roughly equally potent, the monomer displayed slightly weaker activity, suggesting that the compounds show unspecific activity depending upon the number of free phenolic hydroxy groups per molecule.

Trace level analyses of selected perfluoroalkyl acids in food: Method development and data generation

To comprise the future requirements to detect low levels of perfluoroalkyl acids (PFAAs) including branched and linear perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), and perfluorohexane sulfonic acid (PFHxS) in food items, analytical methods for their determination in five different food matrices (cow milk, butter, chicken meat, beef, and fish) were developed and validated. Analytical method for eggs was only validated for PFOS and PFOA because of interfering substance appeared in some samples. The method applied on foods of animal origin includes alkaline digestion, extraction, and clean-up with solid phase extraction and adsorption on granular carbon where necessary. The method was shown effective to eliminate taurodeoxycholic acid (TDC), a bile acid that is an endogenous interference compound in egg samples causing ionization suppression and false positive result for PFOS when 499 > 80 transition was used for quantification. The validation was performed and resulted in recoveries >70% for all three PFAAs, the limits of quantification (LOQs) in all matrices were 3.1 pg g−1, 3.4 pg g−1, and 4.9 pg g−1 for PFHxS, PFOA, and L-PFOS, respectively. The optimized method was successfully applied to 53 food samples from the Swedish market and from developing countries. PFOS and PFOA were detected in all samples. PFHxS was detected in 76% of the samples. Further method development on separating interfering substance from PFHxS in egg is warranted due to relatively high detection of this compound in other food items. With this method, concentrations in the low pg g−1 range in food samples of animal origin were quantified including the branched PFOS isomers. This method can be applied to enforce potential future limit values for PFOS and PFOA as a consequence of the recent European Food Safety Authority (EFSA) recommendation where the tolerable intakes have been drastically lowered. Further method development is needed for foods of plant origin such as vegetables, flour, nuts, or bread.

Curcumin is an APE1 redox inhibitor and exhibits an antiviral activity against KSHV replication and pathogenesis

Curcumin, a polyphenol, is the main bioactive compound in dietary spice turmeric curcuma longa. It possesses anti-inflammatory, anti-oxidant and anti-neoplastic properties and shows potentials in treating or preventing particular diseases such as oxidative and inflammatory conditions, metabolic syndrome, arthritis, anxiety, hyperlipidemia and cancers. The diverse range and potential health beneficial effects has generated enthusiasm leading to intensive investigation into the phytochemical. However, a concern has been also raised if curcumin has a promiscuous bioassay profile and is a Pan-Assay INterference compound (PAINS). Here we present evidence indicating that curcumin is not a PAINS, but an inhibitor to APE1 redox function that affects many genes and pathways. This discovery explains the wide range of effects of curcumin on diverse human diseases and predicts a potential application in treatment of viral infection and virus-associated cancer. As a proof-of-concept, we demonstrated that curcumin is able to efficiently block Kaposi's sarcoma-associated herpesvirus replication and inhibit the pathogenic processes of angiogenesis and cell invasion.

Molecular dynamics insights for PI3K-δ inhibition & structure guided identification of novel PI3K-δ inhibitors

Conjugated structure based and ligand based drug design techinques have been used previously to unearth putative binding ligands for kinase inhibition. PI3K-δ is a lipid kinase and it has been found abberant in diseases such as cancer,inflammation etc. Preliminarily, protein crystal structure analysis suggest avaibility of two crystal structures with varying degree of root mean square de throughtion in protein back bone and root mean square fluctuation in side chain geometry. Therefore, PI3K-δ crystal structure was selected based on charactristic reciever operating characterstic curve and % enrichment of actives analysis. Active site analysis through molecular dynamics simulations provided insights about four residues Ile910, Asp911, Met752, Lys755, which act as flap. These residues fecilitate ligand binding in a unique manner.Thereafter, a validated designed protocol has been used to screen asinex ligand database using molecular docking and binding energy calculations. Based on binding affinity & energy scores and interaction pattern analysis total top 50 ligands were selected for PI3K-δ inhibition studies. Moreover, two molecules ethyl 2-(2-((4-chloro-1-methyl-1H-pyrazole-3-carbonyl) oxy)acetamido) benzo[1]thiazole-6-carboxylate and 1,6,7-trimethyl-8-((tetrahydrofuran-2-yl) methyl)-1H-imidazo [1',2':1,5] pyrrolo[3,2-d]pyrimidine-2,4(3H,8H)-dione have been identified, which could be potential hits for PI3K-δ using insights provided by molecular modelling studies. The identified compunds were subjected to pan assay interference compound filter and were found to be compliant. Quantum mechanical calculations were perfromed for identified hits. The above strategy could be implemented as a strategy for rational drug design.Communicated by Ramaswamy H. Sarma

Enzymatic formation of curcumin in vitro and in vivo

The recent classification of curcumin (Cur) as a pan-assay interference compound (PAINS) and an invalid metabolic panaceas (IMPS) candidate demonstrated the controversial nature of Cur as a drug lead owing to its aggregation in aqueous phase and inherent instability in vivo. Here, we report a simple prodrug approach to generate nanoparticles of Curin situ that allow it to function reproducibly as an anticancer and an anti-inflammatory agent. Diphosphorylated curcumin (Cur-2p), a precursor of Cur and a substrate of alkaline phosphatase (ALP), exhibited drastically improved chemical stability and low aggregation in water. After conversion to curcumin around or inside cancer cells by ALP, Cur-2p selectively inhibited cancer cells that overexpressed ALP, but did not affect normal cells. Moreover, the intravitreal injection of Cur-2p resulted in excellent intraocular biocompatibility with no apparent damage to the morphology and visual function of retina, as shown by fundus imaging, optical coherence tomography (OCT), and histological observation. A rodent model of uveitis showed that Cur-2p significantly suppressed the inflammation response compared with Cur. As a rational approach to investigate and apply PAINS and IMPS candidates, this work presents a straightforward method to maximize the potential of drug leads and ultimately fulfil the promises and potential clinical benefits of PAINS and IMPS candidates.

Effectiveness of Curcumin for Treating Cancer During Chemotherapy

Abstract Oncologists tend to avoid the use of supplements during chemotherapy. To understand the safety issue, a literature review was conducted to evaluate safety and possible benefits of taking curcumin during chemotherapy. Curcumin was chosen because of its wide use in the public and because of the availability of clinical trials utilizing curcumin during chemotherapy. Curcumin is considered a “pan-assay interference compound,” creating false leads in drug discovery assays. The pharmacodynamics of curcumin presents many challenges for a therapeutic agent, including poor bioavailability and rapid metabolism and excretion. The proposed molecular targets for curcumin include inhibition of nuclear factor kappa B and inhibition of cyclooxygenase-2. Clinical trials investigating the efficacy of curcumin treatment for cancer have been conducted in patients with colorectal cancer (CRC), pancreatic cancer, breast cancer, prostate cancer, multiple myeloma, lung cancer, and head and neck cancer. Outcomes revealed...

I9 IUPHAR: Immunology, metabolism and natural products

IUPHAR brings together two different worlds by creating synergies between them, rather than independent research, and increasing mechanistic research of NPs: Natural/traditional products (NPs): • Plant, Microbial, Animal, Marine-based • Sometimes Mixtures • Chinese, Indian, African-based research • Benefits from centuries of natural practice • Natural, biological synthesis. New Molecular Chemical Entities (NMEs): • Synthetic chemistry-based • Frequently multiple metabolites • USA and European-based research • Benefits from molecular research • Synthesis often with lipid/aqueous separation. There is insufficient clinical evidence for NP efficacy or if/how they work. Agents such as curcumin have been claimed to have multiple beneficial effects ( > 9000 PubMed references), yet Nelson et al. [1] propose that curcumin is a PAIN (pan-assay interference compound): unstable, reactive and non-bioavailable 1 . WHO have issued guidelines for the use/research of natural products and traditional medicines. However, both disease and drug targets need defining, because both NMEs and NPs need re-evaluating based on recent genetic data. IUIS (immunology) and IUPHAR are collaborating on inflammation and immune system research as immunopharmacological drug targets are crucial for new drug discovery, particularly in cancer, but immunological targets and protocols are poorly defined for NPs. Scientific education to the developing (and developed) world via our publicly available web sites backed up by expert subcommittees (example: www.guidetopharmacology.org for all drug targets is supported by > 90 subcommittees of scientists) will help in a unique cooperative international initiative. We are also establishing industry and clinical priorities to help progress.