pinecone/core-2020-05-10-deduplication huggingface dataset:
Synthesis, structure, and biological activity of des-side Chain analogues of 1α,25-Dihydroxyvitamin D3 with substituents at C18

El pdf es la versión de autor.-- et al.An improved synthetic route to 1α,25-dihydroxyvitamin D3 des-side chain analogues 2a and 2b with substituents at C18 is reported, along with their biological activity. These analogues display significant antiproliferative effects toward MCF-7 breast cancer cells and prodifferentiation activity toward SW480-ADH colon cancer cells; they are also characterized by a greatly decreased calcemic profile. The crystal structure of the human vitaminD receptor (hVDR) complexed to one of these analogues, 20(17→18)-abeo-1α,25-dihydroxy-22-homo-21-norvitamin D3 (2a) reveals that the side chain introduced at position C18 adopts the same orientation in the ligand binding pocket as the side chain of 1α,25-dihydroxyvitamin D3. Vitamin D3 supplements: The synthesis and biological activity of des-side chain analogues of 1α,25-dihydroxyvitamin D3 with substituents at C18 are described. Crystallographic analysis revealed that the new side chain introduced at C18 adopts the same orientation as the natural side chain at C17 in the parent molecule 1α,25-dihydroxyvitamin D3. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.This study was supported by the Spanish Ministry of Education and Science (Grants SAF2004-01885, SAF2007-60341, and SAF2007-67205), the European Union (MRTN-CT-2005-019496, NucSys), the Xunta de Galicia (Projets INCITE08PXIB-209130PR and ACEUIC-2006/XA050), Consolider, Nanobiomed, Fondo de Investigaciones Sanitarias, Fonds voor Wetenschappelijk Onderzoek (FWO) – Vlaanderen (G.553.06 and G.0587.09), CNRS, INSERM,\ud
Universit  de Strasbourg, ANR, and the European Commission Structural Proteomics in Europe SPINE2-Complexes (LSHG-CT-2006-031220).Peer Reviewe
Bis[3,5-bis(benzylidene)-4-oxo-1-piperidinyl]amides: A Novel Class of Potent Cytotoxins

The principal objective of this study was the examination of the theory of cytotoxic synergism. In this exploratory study, we tested the hypothesis that doubling the number of sites available for thiol alkylation in a series of candidate cytotoxins increases potency more than two-fold. This concept was verified in one-third of our comparisons using human Molt 4/C8 and CEM T-lymphocytes and murine L1210 cells. In addition, the significant potencies of various members of our compound series justified further studies. Molecular modeling revealed that relative locations of the amidic groups correlate with cytotoxicity. A potent cytotoxic compound, 1,2-bis(3,5-dibenzylidene-4-oxo-piperidin-1-yl)ethane-1,2-dione (1 a) inhibited the growth of a large number of human tumor cell lines and displayed greater toxicity toward certain non-adherent cells than toward adherent neoplasms or fibroblasts. The mode of action of 1 a includes induction of apoptosis and necrosis.status: publishe
Synthesis and antitumor molecular mechanism of agents based on amino 2-(3',4',5'-trimethoxybenzoyl)benzo[b]furan: inhibition of tubulin and induction of apoptosis

Induction of apoptosis is a promising strategy that could lead to the discovery of new molecules active in cancer chemotherapy. This property is generally observed when cells are treated with agents that target microtubules, dynamic structures that play a crucial role in cell division. Small molecules such as benzo[b]furans are attractive as inhibitors of tubulin polymerization. A new class of inhibitors of tubulin polymerization based on the 2-(3',4',5'-trimethoxybenzoyl)benzo[b]furan molecular skeleton, with the amino group placed at different positions on the benzene ring, were synthesized and evaluated for antiproliferative activity, inhibition of tubulin polymerization, and cell-cycle effects. The methoxy substitution pattern on the benzene portion of the benzo[b]furan moiety played an important role in affecting antiproliferative activity. In the series of 5-amino derivatives, the greatest inhibition of cell growth occurred if the methoxy substituent is placed at the C6 position, whereas C7 substitution decreases potency. The most promising compound in this series is 2-(3',4',5'-trimethoxybenzoyl)-3-methyl-5-amino-6-methoxybenzo[b]furan (3 h), which inhibits cancer cell growth at nanomolar concentrations (IC(50) =16-24 nM), and interacts strongly with tubulin by binding to the colchicine site. Sub-G(1)  apoptotic cells in cultures of HL-60 and U937 cells were observed by flow cytometric analysis after treatment with 3 h in a concentration-dependent manner. We also show that compound 3 h induces apoptosis by activation of caspase-3, -8, and -9, and this is associated with cytochrome c release from mitochondria. The introduction of an α-bromoacryloyl group increased antiproliferative activity with respect to the parent amino derivatives.status: publishe
Dipeptidyl Peptidase IV (DPPIV/CD26)-Based Prodrugs of Hydroxy-Containing Drugs

We previously described a novel prodrug approach in which a di- or tetrapeptide moiety is linked to a wide variety of amine-containing drugs through an amide bond, which is specifically cleaved by dipeptidyl peptidase IV (DPPIV/CD26) activity. Herein we report the application of this prodrug approach to a variety of hydroxy-containing drugs (primary, secondary, tertiary, or aromatic hydroxy groups). We designed and studied tripartite prodrugs containing a dipeptide moiety (cleavable by DPPIV/CD26) and a valine as a hetero-bifunctional connector to link the dipeptide to the hydroxy group of the drug through a metabolically labile ester bond. The hydroxy-containing prodrugs showed various susceptibilities to hydrolysis by DPPIV/CD26 and serum, depending on the nature of the compound. Prodrugs of compounds containing a primary hydroxy group (as in didanosine) or a hydroxy moiety on an aromatic entity (as in acetaminophen) were most efficiently converted. In contrast, a tertiary hydroxy group was much less susceptible to conversion into its parent drug by DPPIV/CD26 or serum. A number of the prodrugs showed remarkable increases in water solubility relative to their parent drugs.status: publishe
Targeted fluorination of a nonsteroidal anti-inflammatory drug to prolong metabolic half-life.

In drug design, one way of improving metabolic stability is to introduce fluorine at a metabolically labile site. In the early stages of drug design, identification of such sites is challenging, and a rapid method of assessing the effect of fluorination on a putative drug’s metabolic stability would be of clear benefit. One approach to this is to employ micro-organisms that are established as models of drug metabolism in parallel with the synthesis of fluorinated drug analogues. In this study, we have used the filamentous fungus Cunninghamella elegans to identify the metabolically labile site of the nonsteroidal anti-inflammatory drug flurbiprofen, to aid in the design of fluorinated derivatives that were subsequently synthesised. The effect of the additional fluorine substitution on cytochrome P450-catalysed oxidation was then determined via incubation with the fungus, and demonstrated that fluorine substitution at the 4′-position rendered the drug inactive to oxidative transformation, whereas substitution of fluorine at either 2′ or 3′ resulted in slower oxidation compared to the original drug. This approach to modulating the metabolic stability of a drug-like compound is widely applicable and can be used to address metabolic issues of otherwise good lead compounds in drug development
SpiroZin1: A Reversible and pH-Insensitive, Reaction-Based, Red-Fluorescent Probe for Imaging Biological Mobile Zinc

A reversible, reaction-based sensor for biological mobile zinc was designed, prepared, and characterized. The sensing mechanism of this probe is based on the zinc-induced, ring-opening reaction of spirobenzopyran to give a cyanine fluorophore that emits in the deep-red region of the electromagnetic spectrum. This probe is not activated by protons and operates efficiently in aqueous solution at pH 7 and high ionic strength. The mechanism of this reaction was studied by using a combination of kinetics experiments and DFT calculations. The biocompatibility of the probe was demonstrated in live HeLa cells.National Institute of General Medical Sciences (U.S.) (Grant GM 65519)Swiss National Science Foundation (Postdoctoral Fellowship)National Institutes of Health (U.S.) (1S0RR13886-01
Chemical modification of a synthetic small molecule boosts its biological efficacy against pluripotency genes in mouse fibroblasts.

A synthetic transcriptional activator encompassing both sequence-specific pyrrole-imidazole polyamides (PIPs) and an epigenetic activator (suberoylanilide hydroxamic acid) was recently shown to induce the endogenous expression of core pluripotency genes in mouse embryonic fibroblasts (MEFs). Microarray data analysis suggested Oct-3/4 as the probable target pathway of the activator. However, the expression levels in MEFs treated with the activator were relatively lower than those in mouse embryonic stem cells. Herein, we report studies carried out to improve the efficacy of the activator and show that the biological activity was significantly (p<0.05) improved against the core pluripotency genes after the incorporation of an isophthalic acid (IPA) at the C terminus. The resultant IPA conjugate dramatically induced Oct-3/4 and demonstrated a new chemical strategy for developing PIP conjugates as next-generation genetic switches
Indolicidin Targets Duplex DNA: Structural and Mechanistic Insight through a Combination of Spectroscopy and Microscopy

Indolicidin (IR13), a 13‐residue antimicrobial peptide from the cathelicidin family, is known to exhibit a broad spectrum of antimicrobial activity against various microorganisms. This peptide inhibits bacterial DNA synthesis resulting in cell filamentation. However, the precise mechanism remains unclear and requires further investigation. The central PWWP motif of IR13 provides a unique structural element that can wrap around, and thus stabilize, duplex B‐type DNA structures. Replacements of the central Trp‐Trp pair with Ala‐Ala, His‐His, or Phe‐Phe residues in the PxxP motif significantly affects the ability of the peptide to stabilize duplex DNA. Results of microscopy studies in conjunction with spectroscopic data confirm that the DNA duplex is stabilized by IR13, thereby inhibiting DNA replication and transcription. In this study we provide high‐resolution structural information on the interaction between indolicidin and DNA, which will be beneficial for the design of novel therapeutic antibiotics based on peptide scaffolds.     That′s a wrap!  The PWWP short peptide derived from indolicidin provides a unique structural element that stabilizes the DNA duplex. Substitution of Trp residues in PWWP with Ala, His, or Phe significantly destabilizes the DNA duplex structure, thereby establishing a strong correlation between the surface area of the residues (decreasing order: Ala<His≤Phe<Trp) present between the PxxP domain and DNA stabilization
Non-natural acetogenin analogues as potent Trypanosoma brucei inhibitors

Neglected tropical diseases remain a serious global health concern. Here, a series of novel bis-tetrahydropyran 1,4-triazole analogues based on the framework of chamuvarinin, a polyketide natural product isolated from the annonaceae plant species are detailed. The analogues synthesized display low micromolar trypanocidal activities towards both bloodstream and insect forms of Trypanosoma brucei, the causative agent of African sleeping sickness, also known as Human African Trypanosomiasis (HAT). A divergent synthetic strategy was adopted for the synthesis of the key tetrahydropyran intermediates to enable rapid access to diastereochemical variation either side of the 1,4-triazole core. The resulting diastereomeric analogues displayed varying degrees of trypanocidal activity and selectivity in structure–activity relationship studies. Together, the biological potency and calculated lipophilicity values indicate that while there is room for improvement, these derivatives may represent a promising novel class of anti-HAT agents.PostprintPeer reviewe
Comparative Cytotoxicity of Artemisinin and Cisplatin and Their Interactions with Chlorogenic Acids in MCF7 Breast Cancer Cells

In parts of Africa and Asia, self-medication with a hot water infusion of Artemisia annua (Artemisia tea) is a common practice for a number of ailments including malaria and cancer. In our earlier work, such an extract showed better potency than artemisinin alone against both chloroquine-sensitive and -resistant parasites. In this study, in vitro tests of the infusion in MCF7 cells showed high IC50 values (>200 μM). The combination of artemisinin and 3-caffeoylquinic acid (3CA), two major components in the extract, was strongly antagonistic and gave a near total loss of cytotoxicity for artemisinin. We observed that the interaction of 3CAs with another cytotoxic compound, cisplatin, showed potentiation of activity by 2.5-fold. The chelation of cellular iron by 3CA is hypothesized as a possible explanation for the loss of artemisinin activity.This study was funded by the Engineering and Physical Sciences
Research Council (EPSRC, UK) and SensaPharm Ltd. via an Industrial
CASE PhD studentship. The award was allocated competitively
by the Chemistry Innovation Knowledge Transfer Network
(CIKTN, UK).This is the final published version. It was originally published by Wiley at http://onlinelibrary.wiley.com/doi/10.1002/cmdc.201402285/abstract
On the Metabolically Active Form of Metaglidasen: Improved Synthesis and Investigation of Its Peculiar Activity on Peroxisome Proliferator-Activated Receptors and Skeletal Muscles

Metaglidasen is a fibrate-like drug reported as a selective modulator of peroxisome proliferator-activated receptorγ (PPARγ), able to lower plasma glucose levels in the absence of the side effects typically observed with thiazolidinedione antidiabetic agents in current use. Herein we report an improved synthesis of metaglidasen′s metabolically active form halofenic acid (R)-2 and that of its enantiomer (S)-2. The activity of the two stereoisomers was carefully examined on PPARα and PPARγ subtypes. As expected, both showed partial agonist activity toward PPARγ; the investigation of PPARα activity, however, led to unexpected results. In particular, (S)-2 was found to act as a partial agonist, whereas (R)-2 behaved as an antagonist. X-ray crystallographic studies with PPARγ were carried out to gain more insight on the molecular-level interactions and to propose a binding mode. Given the adverse effects provoked by fibrate drugs on skeletal muscle function, we also investigated the capacity of (R)-2 and (S)-2 to block conductance of the skeletal muscle membrane chloride channel. The results showed a more beneficial profile for (R)-2, the activity of which on skeletal muscle function, however, should not be overlooked in the ongoing clinical trials studying its long-term effects
Selective Targeting of the TPX2 Site of Importin-α Using Fragment-Based Ligand Design

Protein-protein interactions are difficult therapeutic targets, and inhibiting pathologically relevant interactions without disrupting other essential ones presents an additional challenge. Herein we report how this might be achieved for the potential anticancer target, the TPX2-importin-α interaction. Importin-α is a nuclear transport protein that regulates the spindle assembly protein TPX2. It has two binding sites - major and minor - to which partners bind. Most nuclear transport cargoes use the major site, whereas TPX2 binds principally to the minor site. Fragment-based approaches were used to identify small molecules that bind importin-α, and crystallographic studies identified a lead series that was observed to bind specifically to the minor site, representing the first ligands specific for this site. Structure-guided synthesis informed the elaboration of these fragments to explore the source of ligand selectivity between the minor and major sites. These ligands are starting points for the development of inhibitors of this protein-protein interaction.This work was supported by the University of Cambridge Cancer Research UK Medicinal Chemistry training program and Medical Research Council grant U105178939 (to M.S.).This is the final published version. It first appeared at http://onlinelibrary.wiley.com/doi/10.1002/cmdc.201500014/abstrac
Approaching ‘kit-type’ labelling with 68Ga : the DATA chelators.

The DATA chelators are a novel class of tri-anionic ligands based on 6-amino-1,4-diazepine-triacetic acid, which have been introduced recently for the chelation of 68Ga. Compared with macrocyclic chelators based on the cyclen scaffold (i.e., DOTA, DO3A, and DO2A derivatives), DATA chelators undergo quantitative radiolabelling more rapidly and under milder conditions. In this study, a systematic evaluation of the labelling of four DATA chelators—DATAM, DATAP, DATAPh, and DATAPPh—with 68Ga is presented. The results highlight the extraordinary potential of this new class of chelators for application in molecular imaging using 68Ga positron emission tomography (PET)
4-Alkylated Silver–N-Heterocyclic Carbene (NHC) Complexes with Cytotoxic Effects in Leukemia Cells

Computational chemistry has shown that backbone-alkylated imidazoles ought to be efficient ligands for transition metal catalysts with improved carbene-to-metal donation. In this work, such alkylated imidazoles were synthesized and complexed with silver(I) by means of an eight/nine-step synthetic pathway we devised to access a new class of biologically active silver complexes. The synthesis involves selective iodination of the imidazole backbone, followed by Sonogashira coupling to replace the backbone iodine. The installed alkyne moiety is then subjected to reductive hydrogenation with Pearlman’s catalyst. The imidazole N1 atom is arylated by the palladium-catalyzed Buchwald N-arylation method. The imidazole N3 position was then methylated with methyl iodine, whereupon the synthesis was terminated by complexation of the imidazolium salt with silver(I) oxide. The synthetic pathway provided an overall yield of ≈20 %. The resulting complexes were tested in vitro against HL60 and MOLM-13 leukemic cells, two human-derived cell lines that model acute myeloid leukemia. The most active compounds exhibiting low IC50 values of 14 and 27 μM, against HL60 and MOLM-13 cells, respectively. The imidazole side chain was found to be essential for high cytotoxicity, as the imidazole complex bearing a C7 side chain at the 4-position was four- to sixfold more potent than the corresponding imidazole elaborated with a methyl group
Design, synthesis and in vitro evaluation of indolotacrine analogues as multi-target-directed ligands for the treatment of Alzheimer’s disease

This publication was supported by the project Czech National Institute of Mental Health (NIMH – CZ; no. ED2.1.00/03.0078), Ministry of Education, Youth and Sports of the Czech Republic (no. LD14009), MH CZ - DRO (UHHK, 00179906), the University of Defence of the Czech Republic (long term development plan), MINECO (Government of Spain; Grant SAF2012-33304), the School of Biology at the University of St Andrews, and by COST Action CM1103.In this study, novel indolotacrine analogues have been designed, synthesized and evaluated as potential drugs for the treatment of Alzheimer’s disease. Based on a multi-target-directed ligand approach, novel compounds have been designed to act simultaneously as cholinesterase and monoamine oxidase (MAO) inhibitors. Prepared compounds were also evaluated for their antioxidant, cytotoxic, hepatotoxic and permeability (Blood-Brain Barrier penetration) properties. Indolotacrine 9b (9-methoxy-2,3,4,6-tetrahydro-1H-indolo[2,3-b]quinolin-11-amine) showed the most promising results in the in vitro assessment being a potent inhibitor of acetylcholinesterase (IC50 = 1.5 µM), butyrylcholinesterase (IC50 = 2.4 µM) and monoamine oxidase A (IC50 = 0.49 µM) and a weak inhibitor of monoamine oxidase B (IC50 = 53.9 µM). Although its cytotoxic (IC50 = 5.5 ± 0.4 µM) and hepatotoxic (IC50 = 1.22 ± 0.11 µM) profile is not as good as the standard 7-methoxytacrine (IC50 = 63 ± 4 µM and IC50 = 11.50 ± 0.77 µM respectively), the overall improvement in the inhibitory activities and potential to cross blood-brain barrier make indolotacrine 9b a promising lead compound for further development and investigation.PostprintPeer reviewe
Multitarget Drugs: an Epigenetic Epiphany

Epigenetics refers to changes in a biological phenotype that are not due to an underlying change in genotype. In eukaryotes, epigenetics involves a set of chemical modifications of the DNA and the histone proteins in nucleosomes. These dynamic changes are carried out by enzymes and modulate protein–protein and protein–nucleic acid interactions to determine whether specific genes are expressed or silenced. Both the epigenetic enzymes and recognition domains are currently important drug discovery targets, particularly for the treatment of cancer. This review summarizes the progress of epigenetic targets that have reached a clinical stage: DNA methyltransferases, histone deacetylases, lysine methyltransferases, lysine demethylases, and bromodomains; this is followed by a comprehensive survey of multitarget drugs that have included an epigenetic target as one of their mechanisms of action
Optimization of Inhibitors of Mycobacterium tuberculosis Pantothenate Synthetase Based on Group Efficiency Analysis

Group efficiency analysis is used to systematically improve the potency of inhibitors of Mycobacterium tuberculosis pantothenate synthetase. Binding efficiencies were found to be distributed unevenly within a lead molecule derived using a fragment-based approach. Substitution of the less efficient parts of this molecule allowed systematic development of more potent compounds. This method of dissecting and analyzing different groups within a molecule offers a rational and general way of carrying out lead optimization.Acknowledgements: This research was supported by the Bill & Melinda Gates Foundation[“Integrated Methods for TB Drug Development(IMTB)” Accelerator Grant], the UK Biotechnology and Biological Sciences Research Council (Grant BB/D006104/1), the Fundação para a Ciência e Tecnologia (PhD sponsorship to H.L.S.), and Homerton College (Junior Research Fellowship to A.C.).This is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1002/cmdc.20150041
Combined Use of Oligopeptides, Fragment Libraries, and Natural Compounds: A Comprehensive Approach To Sample the Druggability of Vascular Endothelial Growth Factor

The modulation of protein–protein interactions (PPIs) is emerging as a highly promising tool to fight diseases. However, whereas an increasing number of compounds are able to disrupt peptide-mediated PPIs efficiently, the inhibition of domain–domain PPIs appears to be much more challenging. Herein, we report our results related to the interaction between vascular endothelial growth factor (VEGF) and its receptor (VEGFR). The VEGF–VEGFR interaction is a typical domain–domain PPI that is highly relevant for the treatment of cancer and some retinopathies. Our final goal was to identify ligands able to bind VEGF at the region used by the growth factor to interact with its receptor. We undertook an extensive study, combining a variety of experimental approaches, including NMR-spectroscopy-based screening of small organic fragments, peptide libraries, and medicinal plant extracts. The key feature of the successful ligands that emerged from this study was their capacity to expose hydrophobic functional groups able to interact with the hydrophobic hot spots at the interacting VEGF surface patch.This work was supported by the Ministry of Economy and Competitiveness and the European Fund for Regional Development\ud
(MINECO-FEDER) (Bio2013-40716-R) and the Generalitat de Catalunya (XRB and 2014-SGR-521). We also thank the NMR facility at the Scientific and Technological Centre of the University of Barcelona (CCiT UB) for their technical support.Peer ReviewedPostprint (published version