Assessment of CYP2C9 structural models for site of metabolism prediction.
In this study, we systematically evaluated the effects of protein crystal structural models, scoring functions, heme forms, conserved active site water molecule, and protein flexibility on SOMs prediction of CYP2C9 substrates. Our results demonstrated that ChemScore and GlideScore outperformed four other scoring functions including Vina, GoldScore, ChemPLP, and ASP on average. The performance of the crystal structural models with the pentacoordinated heme was generally superior to that of the hexacoordinated iron-oxo heme (referred to as Compound I) models. The inclusion of the conserved active site water molecule imp...
Source: ChemMedChem - February 18, 2021 Category: Chemistry Authors: Zhang X, Xu M, Wu Z, Liu G, Tang Y, Li W Tags: ChemMedChem Source Type: research

Synthesis and Assessment of fused β-carboline derivatives as Kappa Opioid Receptor agonist.
Synthesis and Assessment of fused β-carboline derivatives as Kappa Opioid Receptor agonist. ChemMedChem. 2021 Feb 17;: Authors: Batra S, Yadav VD, Kumar L, Kumari P, Kumar S, Singh M, Siddiqi MI, Yadav PN Abstract The synthesis of 5-formyl-6-aryl-6H-indolo[3,2,1-de][1,5] naphthyridine-2-carboxylates via reaction between 1-formyl-9H-b-carbolines and cinnamaldehydes in the presence of pyrrolidine in water under microwave irradiation is described. Pharmacophoric modification of the formyl group offered several new fused-b-carboline derivatives which were investigated for their k-opioid receptor (KOR...
Source: ChemMedChem - February 17, 2021 Category: Chemistry Authors: Batra S, Yadav VD, Kumar L, Kumari P, Kumar S, Singh M, Siddiqi MI, Yadav PN Tags: ChemMedChem Source Type: research

Corrigendum: Kiss1R Identification and Biodistribution Analysis Employing a Western Ligand Blot and Ligand-Derivative Stain with a FITC-Kisspeptin Derivative.
PMID: 33594770 [PubMed] (Source: ChemMedChem)
Source: ChemMedChem - February 17, 2021 Category: Chemistry Authors: Hasegawa K, Maedomari R, Sato Y, Gotoh K, Kudoh S, Kojima A, Okada S, Ito T Tags: ChemMedChem Source Type: research

Development of a high-affinity antibody-binding peptide for site-specific modification.
We report the design and synthesis of a novel unnatural amino acid, 4-(2-aminoethylcarbamoyl)leucine (Aecl), which possesses both the γ-dimethyl fragment and a primary amino group. A peptide containing Aecl8 (15-Lys8Aecl) was synthesized and showed a binding affinity 10-fold higher (Kd = 24.3 nM) than that of 15-IgBP (Kd = 267 nM). Fluorescein isothiocyanate (FITC)-labeled 15-Lys8Aecl with an N-hydroxy succinimide ester at the side chain of Aecl8 (FITC-15-Lys8Aecl(OSu)) successfully labeled an antibody (Trastuzumab, Herceptin®) with the fluorophore. This peptide scaffold has both strong binding affinity and cross...
Source: ChemMedChem - February 17, 2021 Category: Chemistry Authors: Muguruma K, Osawa R, Fukuda A, Ishikawa N, Fujita K, Taguchi A, Takayama K, Taniguchi A, Ito Y, Hayashi Y Tags: ChemMedChem Source Type: research

Virus-Based Nanoreactors with GALT Activity for Classic Galactosemia Therapy.
alt R Abstract Enzymatic nanoreactors were obtained by galactose-1-phosphate uridylyl-transferase (GALT) encapsulation into plant virus capsids by a molecular self-assembly strategy. The aim of this work was to produce virus-like nanoparticles containing GALT for an enzyme-replacement therapy for classic galactosemia. The encapsulation efficiency and the catalytic constants of bio-nanoreactors were determined by using different GALT and virus coat protein ratios. The substrate affinity of nanoreactors was slightly lower than that of the free enzyme; the activity rate was 16 % of the GALT free enzyme. The en...
Source: ChemMedChem - February 17, 2021 Category: Chemistry Authors: Gama P, Cadena-Nava RD, Juarez-Moreno K, Pérez-Robles J, Vazquez-Duhalt R Tags: ChemMedChem Source Type: research

Plasmid DNA based bioluminescence-activated system for photodynamic therapy in cancer treatment.
This study provides a new strategy for the application of bioluminescence in PDT treatment. PMID: 33594787 [PubMed - as supplied by publisher] (Source: ChemMedChem)
Source: ChemMedChem - February 16, 2021 Category: Chemistry Authors: Fan D, Wang T, Hu J, Zhou L, Zhou J, Wei S Tags: ChemMedChem Source Type: research

The Acid/Base Characterization of Molecules with Epigenetic Activity.
Medina-Franco JL Abstract The acidic and basic functional groups in a molecule strongly influence its physicochemical properties, affinity for a macromolecule, pharmacokinetics, and toxicity. For instance, basicity has been correlated with molecular promiscuity, hERG blockade, and phospholipidosis. Nonetheless, a systematic characterization of the acid/base profile of epigenomic databases has not been reported. The present study describes an analysis of the acidic ionization constants distribution of a library of 7820 compounds with reported activity against epigenetic targets. Furthermore, the epigenomics databa...
Source: ChemMedChem - February 16, 2021 Category: Chemistry Authors: Santibáñez-Morán MG, Medina-Franco JL Tags: ChemMedChem Source Type: research

Into the Fray! A Beginner's Guide to Medicinal Chemistry.
Abstract Modern medicinal chemistry is a complex, multidimensional discipline that operates at the interface of the chemical and biological sciences. The medicinal chemistry contribution to drug discovery is typically described in the context of the well-recited linear progression of the drug discovery pipeline. However, compound optimization is idiosyncratic to each project, and clear definitions of hit and lead molecules and the subsequent progress along the pipeline becomes easily blurred. In addition, this description lacks insight into the entangled relationship between chemical and pharmacological properties...
Source: ChemMedChem - February 16, 2021 Category: Chemistry Authors: Veale CGL Tags: ChemMedChem Source Type: research

Design, Synthesis, and Biological Evaluation of Orally Bioavailable CHK1 Inhibitors Active against Acute Myeloid Leukemia.
Abstract Checkpoint kinase 1 (CHK1) is a central component in DNA damage response and has emerged as a target for antitumor therapeutics. Herein, we describe the design, synthesis, and biological evaluation of a novel series of potent diaminopyrimidine CHK1 inhibitors. The compounds exhibited moderate to potent CHK1 inhibition and could suppress the proliferation of malignant hematological cell lines. The optimized compound 13 had a CHK1 IC50 value of 7.73±0.74 nM, and MV-4-11 cells were sensitive to it (IC50 =0.035±0.007 μM). Furthermore, compound 13 was metabolically stable in mouse liver mi...
Source: ChemMedChem - February 16, 2021 Category: Chemistry Authors: Jin T, Wang P, Long X, Jiang K, Song P, Wu W, Xu G, Zhou Y, Li J, Liu T Tags: ChemMedChem Source Type: research

One-Pot Synthesis of Coumarin-Indomethacin Hybrids as COX-2 Targeting Probes for Cancer Imaging.
Abstract Facile synthesis of 6-or 7-substituted coumarin-indomathacin hybrids (Coum-IDM) has been developed for specific cyclooxygenase-2 (COX-2) binding along with their intrinsic fluorescent properties.  A mild and rapid condensation/dehydrative cyclization of 2-hydroxy benzaldehyde with activated indomethacin was carried out in one step under ultrasound irradiation.  Coum-IDM4 was found to be the best of this series as it presented significant binding to COX-2 and exhibited higher fluorescent intensity in cancer cell compared to that in the normal cells.  Therefore, in the light of drug developme...
Source: ChemMedChem - February 14, 2021 Category: Chemistry Authors: Kamkaew A, Wet-Osot S, Pewklang T, Chansaenpak K, Chudapongse N, Lai RY Tags: ChemMedChem Source Type: research

Helical Antimicrobial Peptide Foldamers Containing Non-proteinogenic Amino Acids.
Abstract Antimicrobial peptides (AMPs) are potential novel therapeutic drugs against microbial infections. Most AMPs function by disrupting microbial membranes because of their amphipathic properties and ordered secondary structures. In this minireview, we describe recent efforts to develop helical AMP foldamers containing non-proteinogenic amino acids, such as α,α-disubstituted α-amino acids, β-amino acids, γ-amino acids, side-chain stapling and N-alkyl glycines. PMID: 33565721 [PubMed - as supplied by publisher] (Source: ChemMedChem)
Source: ChemMedChem - February 10, 2021 Category: Chemistry Authors: Yokoo H, Hirano M, Misawa T, Demizu Y Tags: ChemMedChem Source Type: research

Newer Non-ionic A2B2 Type Enzyme Responsive Amphiphiles for Drug Delivery Applications.
SK Abstract A newer series of non-ionic Gemini amphiphiles have been synthesized using a novel A 2 B 2 type central core constituted by conjugating glycerol and propargyl bromide on 5-hydroxy isophthalic acid via multi-step chemo-enzymatic approach. A pair of hydrophilic monomethoxy polyethylene glycol (mPEG) and hydrophobic linear alkyl chains (C 12 /C 15 ) were then incorporated on the core to obtain amphiphilic architectures. The aggregation tendency in aqueous medium was studied by dynamic light scattering, fluorescence spectroscopy and cryogenic transmission electron microscopy. The nano-transport potential ...
Source: ChemMedChem - February 8, 2021 Category: Chemistry Authors: Krishna K, Parshad B, Achazi K, Böttcher C, Haag R, Sharma SK Tags: ChemMedChem Source Type: research

Pyrazoloadenine Inhibitors of the RET Lung Cancer Oncoprotein Discovered via a Fragment Optimization Approach.
Abstract A fragment-based drug discovery approach using a pyrazoloadenine fragment library was utilized to uncover new molecules that target the RET (REarranged during Transfection) oncoprotein, which is a driver oncoprotein in ~2% of non-small cell lung cancer. The fragment library was screened against the RET kinase and LC-2/ad (RET-driven), KM-12 (TRKA driven- matched control) and A549 (cytotoxic control) cells to identify selective scaffolds that could inhibit RET-driven growth. An unsubstituted pyrazoloadenine fragment was found active on RET in a biochemical assay but reduced cell viability in non-RET driven...
Source: ChemMedChem - February 8, 2021 Category: Chemistry Authors: Frett B, Saha D, Ryan KR, Lakkaniga NR, Smith EL Tags: ChemMedChem Source Type: research

Improving strategies in the development of protein-downregulation based antiandrogens.
Abstract AR plays a crucial role in the occurrence and development of prostate cancer (PCa) and its signaling pathway remains active in castration-resistant prostate cancer (CRPC) patients. The drug resistance of current clinical used antiandrogens is a major challenge for the treatment of PCa, thus the development of new generations of antiandrogens is highly demanded. Recently, strategies of the downregulation of AR protein have been attracted the huge attention due to its potential in the discovery and development of new antiandrogens, including the stabilizers of G-Quadruplex, inhibitors of ROR-γ, AR tar...
Source: ChemMedChem - February 7, 2021 Category: Chemistry Authors: Zhou J, Zhang R, Huang C, Xiao X Tags: ChemMedChem Source Type: research

Design, Synthesis and Biological Activity of New Amides Derived From 3-Benzhydryl and 3-Sec-butyl-2,5-dioxo-pyrrolidin-1-yl-acetic Acid.
ski K Abstract The aim of studies was to design and synthesize two new series of pyrrolidine-2,5-dione-acetamides with benzhydryl or sec-butyl group at position-3 as potential anticonvulsants. Their anticonvulsant activity was evaluated in standard animal models of epilepsy: the maximal electroshock (MES), the 6 Hz, and the subcutaneous pentylenetetrazole (scPTZ) tests. The in vivo studies revealed the most potent anticonvulsant activity for 15 (3-(sec-butyl)-1-(2-(4-(3-trifluoromethylphenyl)piperazin-1-yl)-2-oxoethyl)pyrrolidine-2,5-dione), with ED50 values of 80.38 mg/kg (MES) and 108.80 mg/kg (6 Hz). The plausi...
Source: ChemMedChem - February 4, 2021 Category: Chemistry Authors: Góra M, Czopek A, Rapacz A, Giza A, Koczurkiewicz-Adamczyk P, Pękala E, Obniska J, Kamiński K Tags: ChemMedChem Source Type: research

Phenotypic discovery of SB1501, an anti-obesity agent via modulating mitochondrial activities.
Abstract Obesity has become a pandemic that threatens the quality of life and discovering novel therapeutic agents that can reverse obesity and obesity-related metabolic disorders are necessary. Here, we aimed to identify new anti-obesity agents using a phenotype-based approach. We performed image-based high-content screening with a fluorogenic bioprobe (SF44), which visualizes cellular lipid droplets (LDs), to identify initial hit compounds. A structure-activity relationship study led us to yield a bioactive compound SB1501, which reduces cellular LDs in 3T3-L1 adipocytes without cytotoxicity. SB1501 induced the ...
Source: ChemMedChem - February 3, 2021 Category: Chemistry Authors: Jo A, Kim M, Kim JI, Ha J, Hwang YS, Nam H, Hwang I, Kim JB, Park SB Tags: ChemMedChem Source Type: research

Synthesis of Carboxamide-Containing Tranylcypromine Analogues as LSD1 (KDM1A) Inhibitors Targeting Acute Myeloid Leukemia.
We report a novel series of tranylcypromine analogues with a carboxamide at the 4-position of the aryl ring. These compounds, such as 5 a and 5 b with benzyl and phenethylamide substituents, respectively, had potent sub-micromolar IC50 values for the inhibition of LSD1 as well as cell proliferation in a panel of AML cell lines. The dose-dependent increase in cellular expression levels of H3K4me2, CD86, CD11b and CD14 supported a mechanism involving LSD1 inhibition. The tert-butyl and ethyl carbamate derivatives of these tranylcypromines, although inactive in LSD1 inhibition, were of similar potency in cell-ba...
Source: ChemMedChem - February 3, 2021 Category: Chemistry Authors: Teresa Borrello M, Benelkebir H, Lee A, Hin Tam C, Shafat M, Rushworth SA, Bowles KM, Douglas L, Duriez PJ, Bailey S, Crabb SJ, Packham G, Ganesan A Tags: ChemMedChem Source Type: research

A Box of Chemistry to Inhibit the  MEN1 Tumor Suppressor Gene Promoting Leukemia.
A Box of Chemistry to Inhibit the MEN1 Tumor Suppressor Gene Promoting Leukemia. ChemMedChem. 2021 Feb 03;: Authors: Timmers HTM, Özyerli Göknar E, Nizamuddin S Abstract Targeting protein-protein interactions (PPIs) by small-molecule inhibitors has become the hotbed for modern drug development. In this review we describe a new class of PPI inhibitors, which block menin from binding to MLL proteins. Menin is encoded by the  MEN1  tumor suppressor, but it acts as an essential cofactor for  MLL/KMT2A  rearranged leukemias. The most promising menin-MLL inhibitors be...
Source: ChemMedChem - February 3, 2021 Category: Chemistry Authors: Timmers HTM, Özyerli Göknar E, Nizamuddin S Tags: ChemMedChem Source Type: research

Mechanistic investigations of metallo- β-lactamase inhibitors: Strong zinc binding is not required for potent enzyme inhibition.
Mechanistic investigations of metallo-β-lactamase inhibitors: Strong zinc binding is not required for potent enzyme inhibition. ChemMedChem. 2021 Feb 03;: Authors: Wade N, Tehrani K, Brüchle N, van Haren M, Mashayekhi V, Martin NI Abstract Metallo-β-lactamases (MBLs) are zinc-dependent bacterial enzymes that inactivate essentially all classes of β-lactam antibiotics, including last resort carbapenems. At present there are no clinically approved MBL inhibitors and in order to develop such agents it is essential to understand their inhibitory mechanisms. We here describe a comprehens...
Source: ChemMedChem - February 3, 2021 Category: Chemistry Authors: Wade N, Tehrani K, Brüchle N, van Haren M, Mashayekhi V, Martin NI Tags: ChemMedChem Source Type: research

Design, Synthesis, and Structure-Activity Relationship Study of Pyrazolones as Potent Inhibitors against Pancreatic Lipase.
In this study, a series of pyrazolones were synthesized and their inhibitory effects against PL were assayed using 4-methylumbelliferyl oleate (4-MUO) as optical substrate for PL. Comprehensive structure-activity relationship analysis of these pyrazolones brought us to design and synthesize a novel compound P32 (5-(naphthalen-2-yl)-2-phenyl-4-(thiophen-2-ylmethyl)-2,4-dihydro-3H-pyrazol-3-one) as a potent mixed-competitive inhibitor against PL (IC50 0.30 µM). In addition, P32 displayed some selectivity over other known serine hydrolase. Molecular docking study for P32 demonstrated that the inhibitory activity of P32 ...
Source: ChemMedChem - February 2, 2021 Category: Chemistry Authors: Bao X, Zhang J, Yang Y, Qian XK, Song PF, Zhao YS, Guan XQ, Zou LW, Wang H Tags: ChemMedChem Source Type: research

The Role of Chronic Inflammation in Various Diseases and Anti-inflammatory Therapies Containing Natural Products.
Abstract Chronic inflammation represents a long-term reaction of body's immune system to noxious stimuli. Such a sustained inflammatory response sometimes results in lasting damage to healthy tissues and organs. In fact, chronic inflammation is implicated in the development and progression of various diseases, including cardiovascular diseases, respiratory diseases, metabolic diseases, neurodegenerative diseases, and even cancers. Targeting non-resolving inflammation thus provides new opportunities for treating relevant diseases. In this review article, we will go over several chronic inflammation-associated disea...
Source: ChemMedChem - February 2, 2021 Category: Chemistry Authors: Wang R, Zhou M, Ma HL, Li QS Tags: ChemMedChem Source Type: research

Ligand sensitised LaF3:Eu3+ and SrF2:Eu3+ nanocrystals and their in vitro haemocompatiblity studies.
Lis S Abstract Luminescent Ln 3+ -doped nanoparticles (NCs) functionalised with the desired organic ligand molecules for haemocompatibility studies were obtained by a one-pot synthesis method. The ability to chelate various aromatic organic ligands such as: Isophthalic acid (IA) /Terephthalic acid (TA)/ Ibuprofen / Aspirin / 1, 2, 4, 5-Benzenetetracarboxylic acid (1, 2, 4, 5-BTCA) / 2,6-Pyridine dicarboxylic acid (2,6-PDA) and Adenosine were applied for surface functionalisation. The modification of the nanoparticles is based on the donor-acceptor character of the ligand-nanoparticle system, which is an alternativ...
Source: ChemMedChem - February 1, 2021 Category: Chemistry Authors: Adusumalli VNKB, Mrówczyńska L, Kwiatek D, Piosik Ł, Lesicki A, Lis S Tags: ChemMedChem Source Type: research

Malaria Pigment Crystals, the Achilles Heel of the Malaria Parasite.
We present observation of quantities of hemozoin found in the digestive vacuole and our model whereby heme liberation from hemoglobin and hemozoin formation is an assembly-line process. The crystallization is preceded by reaction between heme monomers yielding hematin dimers, which constitute hemozoin. Biogenic hemozoin embodies fewer types of dimeric hematin isomers than synthetic hemozoin, indicative of protein-activated heme dimerization. This assembly-line process has implications on the drug types, which inhibit hemozoin formation. We review antimalarial drugs and models of their adsorption onto hemozoin surfaces. Fin...
Source: ChemMedChem - February 1, 2021 Category: Chemistry Authors: Kapishnikov S, Hempelmann E, Elbaum M, Als-Nielsen J, Leiserowitz L Tags: ChemMedChem Source Type: research

E7766, a Macrocycle-Bridged Stimulator of Interferon Genes (STING) Agonist with Potent Pan-Genotypic Activity.
Abstract A strategy for creating potent and pan-genotypic stimulator of interferon genes (STING) agonists is described. Locking a bioactive U-shaped conformation of cyclic dinucleotides by introducing a transannular macrocyclic bridge between the nucleic acid bases leads to a topologically novel macrocycle-bridged STING agonist (MBSA). In addition to substantially enhanced potency, the newly designed MBSAs, exemplified by clinical candidate E7766, exhibit broad pan-genotypic activity in all major human STING variants. E7766 is shown to have potent anti-tumor activity with long lasting immune memory response in a m...
Source: ChemMedChem - January 31, 2021 Category: Chemistry Authors: Kim DS, Endo A, Fang FG, Huang KC, Bao X, Choi HW, Majumder U, Shen YY, Mathieu S, Zhu X, Sanders K, Noland T, Hao MH, Chen Y, Wang JY, Yasui S, TenDyke K, Wu J, Ingersoll C, Loiacono KA, Hutz JE, Sarwar N Tags: ChemMedChem Source Type: research

Rational Design and Synthesis of Selective PRMT4 Inhibitors: a New Chemotype for Development of Cancer Therapeutics.
ton R Abstract Protein arginine N-methyl transferase 4 (PRMT4) asymmetrically dimethylates arginine residues of histone H3 and non-histone proteins. The overexpression of PRMT4 in several cancers has stimulated interest in the discovery of inhibitors as biological tools and potentially therapeutics. While several PRMT4 inhibitors have been reported, most display poor selectivity against other members of the PRMT family of methyl transferases. Here, we report the structure-based design of a new class of alanine containing 3-arylindoles as potent and selective PRMT4 inhibitors and describe key structure activity rel...
Source: ChemMedChem - January 29, 2021 Category: Chemistry Authors: Santhakumar V, Sutherland M, Li A, Kaghad A, Panagopoulos D, Li F, Szewczyk M, Smil D, Scholten C, Bouché L, Stellfeld T, Arrowsmith CH, Barsyte D, Vedadi M, Hartung IV, Steuber H, Britton R Tags: ChemMedChem Source Type: research

Preparing (Metalla)carboranes for Nanomedicine.
Abstract "There's plenty of room at the bottom" (Richard Feynman, 1959): an invitation for (metalla)carboranes to enter the (new) field of nanomedicine. Since two decades, the number of publications on boron cluster compounds designed for potential applications in medicine is constantly increasing. Hundreds of compounds have been screened in vitro or in vivo for a variety of biological activities (chemotherapeutics, radiotherapeutics, antiviral, etc.), and some have shown rather promising potential for further development. However, until today, no boron cluster compounds have made it to the clinics, and ...
Source: ChemMedChem - January 28, 2021 Category: Chemistry Authors: Gozzi M, Schwarze B, Hey-Hawkins E Tags: ChemMedChem Source Type: research

Synthesis and In vitro Evaluation of novel 5-nitroIndole Derivatives as c-Myc G-Quadruplex Binders with Anticancer Activities.
e H Abstract Lead optimization strategies for compounds targeting c-Myc G quadruplex (G4) DNA are actively pursued to develop anticancer drugs. Here, we investigate the structure-activity-relationship (SAR) of a newly synthesized series of molecules based on the pyrrolidine-substituted 5-nitro indole scaffold to target G4 DNA. Our synthesized series allows modulation of flexible elements with a structurally preserved scaffold. Biological and biophysical analyses illustrate that substituted 5-nitroindole scaffolds bind to the c-Myc promoter G-quadruplex. These compounds downregulate c-Myc expression and induce cell...
Source: ChemMedChem - January 28, 2021 Category: Chemistry Authors: Nimbarte VD, Wirmer-Bartoschek J, Gande SL, Alshamleh I, Seibert M, Nasiri HR, Schnütgen F, Serve H, Schwalbe H Tags: ChemMedChem Source Type: research

Phosphonate as Stable Zinc-binding Group for Inhibitors of Clostridial Collagenase H (ColH) as Pathoblocker Agents.
Ducho C Abstract Microbial infections are a significant threat to public health and resistances are on the rise, so new antibiotics with novel modes of action are urgently needed. The extracellular zinc metalloprotease collagenase H (ColH) from Clostridium histolyticum is a virulence factor that catalyzes tissue damage, leading to improved host invasion and colonisation. Besides the major role of ColH in pathogenicity, its extracellular localisation makes it a highly attractive target for the development of new antivirulence agents. Previously, we had found that a highly selective and potent thiol prodrug (with a ...
Source: ChemMedChem - January 27, 2021 Category: Chemistry Authors: Voos K, Schönauer E, Alhayek A, Haupenthal J, Andreas A, Müller R, Hartmann RW, Brandstetter H, Hirsch AKH, Ducho C Tags: ChemMedChem Source Type: research

Construction and Biological Evaluation of Small Libraries Based of the Intermediates within the Total Synthesis of Uvaretin.
Abstract The synthesis of new small chemical screening libraries (CSL) constructed from the intermediates of our total synthesis route of the uvaretin class of natural products is demonstrated herein. Numerous chalcone based CSLs were assembled, with varying substitution upon the phenolic groups within the chalcone core. Through cytotoxicity investigations it was found that the level of hydrophobicity of the phenolic core of the chalcones gives biases; less cytotoxicity with more hydrophobic cores. In addition to this, it was observed that potentiation property, evaluated with 6-thiopurine in the pancreatic cancer...
Source: ChemMedChem - January 25, 2021 Category: Chemistry Authors: Perera S, Fernando A, Dallman J, Weeramange C, Lansakara A, Nguyen T, Rafferty RJ Tags: ChemMedChem Source Type: research

Design, synthesis and biological evaluation of steroidal glycoconjugates as potential antiproliferative agents.
Abstract To systematically evaluate the impact of neoglycosylation upon the anticancer activities and selectivity of the steroids, four series of neoglycosides of diosgenin, pregnenolone, dehydroepiandrosterone and estrone were designed and synthesized via the neoglycosylation approach. All the structures of the products were elucidated through NMR analysis and the stereochemistry of C20-MeON-pregnenolone (compound 8/9 ) were confirmed by crystal X-ray diffraction experiment. Their cytotoxicity on five human cancer cell lines was evaluated by the Cell Counting Kit-8 assay and structure-activity relationships (SAR)...
Source: ChemMedChem - January 21, 2021 Category: Chemistry Authors: Du Z, Li G, Ge H, Zhou X, Zhang J Tags: ChemMedChem Source Type: research

Design, Synthesis, and Biological Evaluation of Lysine Demethylase 5C Degraders.
Abstract Lysine demethylase 5C (KDM5C) controls epigenetic gene expression and is attracting great interest in the field of chemical epigenetics. KDM5C has emerged as a therapeutic target for anti-prostate cancer agents, and recently we identified compound 1 as an inhibitor of KDM5C. Compound 1 exhibited highly potent KDM5C-inhibitory activity in in vitro enzyme assays but did not show strong anticancer effects. Therefore, a different approach is needed for the development of anticancer agents targeting KDM5C. Here, we attempted to identify KDM5C degraders by focusing on a protein knockdown strategy. Compound 3b ,...
Source: ChemMedChem - January 20, 2021 Category: Chemistry Authors: Iida T, Itoh Y, Takahashi Y, Yamashita Y, Kurohara T, Miyake Y, Oba M, Suzuki T Tags: ChemMedChem Source Type: research

Do Drug-likeness Rules Apply for Oral Prodrugs?
lo VG Abstract This paper describes a comparative analysis of the physicochemical and structural properties between prodrugs and their corresponding drugs regarding drug-likeness rules. The dataset used in this work was obtained from the DrugBank. Sixty-five pairs of prodrugs/drugs were retrieved and divided into the following categories: carrier-linked to increase hydrophilic character, carrier-linked to increase absorption, and bioprecursors. We compared physicochemical properties related to drug-likeness between prodrugs and drugs. Our results show that prodrugs do not always follow Lipinski's Rule of 5, especi...
Source: ChemMedChem - January 20, 2021 Category: Chemistry Authors: Protti ÍF, Rodrigues DR, Fonseca SK, Alves RJ, de Oliveira RB, Maltarollo VG Tags: ChemMedChem Source Type: research

Exploiting the folding and degradation machineries to target undruggable proteins: What can the computational approach tell us?
Abstract Advances in genomics and proteomics have unveiled an ever-growing number of key proteins and provided mechanistic insights into the genesis of pathologies. This wealth of data showed that changes in expression levels of specific proteins, mutations, and post-translational modifications can result in (often subtle) perturbations of functional protein-protein interaction networks, which ultimately determine disease phenotypes. Although many such validated pathogenic proteins have emerged as ideal drug targets, there are also several that escape traditional pharmacological regulation; these proteins have thu...
Source: ChemMedChem - January 14, 2021 Category: Chemistry Authors: Serapian SA, Castelli M, Marchetti F, Triveri A, Colombo G Tags: ChemMedChem Source Type: research

Synthesis and cell growth inhibitory activity of six non-glycosaminoglycan-type heparin-analogue trisaccharides.
te;s A, Herczeg M Abstract The design and synthesis of heparin mimetics with high anticancer activity but no anticoagulant activity is an important task in medicinal chemistry. Here, we present the efficient synthesis of five Glc-GlcA-Glc sequenced and one Glc-IdoA-Glc sequenced non-glycosaminoglycan, heparin-related trisaccharides with various sulfation/sulfonylation and methylation patterns. The cell growth inhibitory effects of the compounds were tested against four cancerous human cell lines and two non-cancerous cell lines. Two D-glucuronate-containing tetra- O -sulfated, partially methylated trisaccharides d...
Source: ChemMedChem - January 12, 2021 Category: Chemistry Authors: Lisztes E, Mező E, Demeter F, Horváth L, Bősze S, Tóth BI, Borbás A, Herczeg M Tags: ChemMedChem Source Type: research

Advances in Nucleoside and Nucleotide Analogues in Tackling Human Immunodeficiency Virus and Hepatitis Virus Infections.
Abstract Nucleoside and nucleotide analogues are structurally similar antimetabolites and are promising small-molecule chemotherapeutic agents against various infectious DNA and RNA viruses. To date, an in-depth review for these analogues as anti-human immunodeficiency virus (HIV) and anti-hepatitis virus agents, which are at various stages of testing ranging from pre-clinical, to those withdrawn from trials, or those that are approved as drugs have not been documented. Hence, in this review, the importance of these analogues in tackling the HIV and hepatitis virus infections are discussed with a focus towards the...
Source: ChemMedChem - January 11, 2021 Category: Chemistry Authors: Ramesh D, Vijayakumar BG, Kannan T Tags: ChemMedChem Source Type: research

Strategies to Design Selective Histone Deacetylase Inhibitors.
Robaa D Abstract This review classifies drug design strategies successfully implemented in the development of histone deacetylase (HDAC) inhibitors, which have many applications including cancer treatment. Our focus is on especially demanded selective HDAC inhibitors and their structure-activity relationships in relation to corresponding protein structures. The main part of the paper is divided into six subsections narrating how optimization of the six corresponding structural features can influence inhibitor selectivity. It starts with the impact of the zinc binding group on selectivity, continues with the optimi...
Source: ChemMedChem - January 11, 2021 Category: Chemistry Authors: Sippl W, Melesina J, Simoben CV, Bülbül EF, Praetorius L, Robaa D Tags: ChemMedChem Source Type: research

HIV-1 Envelope Spike MPER: From a Vaccine Target to a New Druggable Pocket for Novel and Effective Fusion Inhibitors.
Abstract Here we highlight a sound and unique work reported by Chen and co-workers entitled "HIV-1 fusion inhibitors targeting the membrane-proximal external region of Env spikes" (Xiao et al., Nat. Chem. Biol. 2020, 16, 529). In this article, the authors identify, by means of a clever antibody-guided strategy, several small molecules as fusion inhibitors of HIV-1 replication acting at the membrane proximal external region (MPER) of the HIV-1 envelope (Env) spike. MPER, which was previously recognized as a vaccine target, emerges as a novel druggable target for the discovery of HIV-1 fusion inhibitors....
Source: ChemMedChem - January 8, 2021 Category: Chemistry Authors: Luque FJ, Camarasa MJ Tags: ChemMedChem Source Type: research

The Triazole Ring as a Privileged Scaffold for Putative Antifungals: Synthesis and Evaluation of a Series of New Analogues.
Abstract The significant antifungal activity of a series of novel 1,2,4-triazole derivatives against different strains of Candida albicans, Candida krusei and Aspergillus fumigatus, compared to the commercial fungicides ketoconazole and itraconazole, is reported. Systemic mycosis and invasive fungal infections, whether from immunodeficiency or hospital-acquired infection, have been on an upward trend for several years. The 1,2,4-triazole ring substituted with other aromatic and heteroaromatic systems plays an important role in the field of antifungal drug discovery and development. Thus, an extensive series of 29...
Source: ChemMedChem - January 8, 2021 Category: Chemistry Authors: Zoidis G, Kritsi E, Lecinska P, Ivanov M, Zoumpoulakis P, Sokovic M, Catto M Tags: ChemMedChem Source Type: research

Fabulous at Fifteen!
Abstract Pop the Champagne! ChemMedChem turns fifteen in 2021! Editor David Peralta reflects on the journal's transformation in the past fifteen years, looks back at 2020, and presents some exciting changes within the journal and Chemistry Europe. PMID: 33421339 [PubMed - as supplied by publisher] (Source: ChemMedChem)
Source: ChemMedChem - January 8, 2021 Category: Chemistry Authors: Peralta D Tags: ChemMedChem Source Type: research

Design of Trehalose-based Amide/Sulfonamide C-type Lectin Receptor Ligands.
Abstract Mincle agonists have been shown to induce inflammatory cytokine production, such as tumor necrosis factor-alpha the (TNF) and promote the development of a Th1/Th17 immune response that may be crucial to development of effective vaccination against pathogens such as Mycobacterium tuberculosis. As an expansion of our previous work, a library of 6,6΄-amide and sulfonamide α,α-D-trehalose compounds with various substituents on the aromatic ring were synthesized efficiently in good to excellent yields. These compounds were evaluated for their ability to activate the human C-Type Lectin Receptor Mi...
Source: ChemMedChem - January 7, 2021 Category: Chemistry Authors: Ryter KT, Rasheed OK, Buhl C, Evans JT Tags: ChemMedChem Source Type: research

Discovery of a novel inhibitor of human purine nucleoside phosphorylase by a simple hydrophilic interaction liquid chromatography (HILIC-UV) enzymatic assay.
This study provides both new tools and a new lead for developing novel Hs PNP inhibitors. PMID: 33405358 [PubMed - as supplied by publisher] (Source: ChemMedChem)
Source: ChemMedChem - January 6, 2021 Category: Chemistry Authors: Rabuffetti M, Rinaldi F, Lo Bianco A, Speranza G, Ubiali D, de Moraes MC, Claudio Rodrigues Pereira da Silva L, Massolini G, Calleri E, Lavecchia A Tags: ChemMedChem Source Type: research

Discovery of Benzofuroxan Derivatives as Potent Agents Active Against Multidrug-Resistant Mycobacterium tuberculosis.
Abstract Tuberculosis (TB) is currently the leading cause of deaths related to infectious diseases worldwide, as reported by the World Health Organization. Moreover, the increasing number of MultiDrug-Resistant Tuberculosis (MDR-TB) cases has alarmed the health agencies, warranting extensive efforts to discover novel drugs that are effective and also safe. In the present study, 23 novel compounds were synthesized and evaluated in vitro against the drug-resistant strains of M. tuberculosis. The compound 6-((3-fluoro-4-thiomorpholinophenyl)carbamoyl)benzo [c] [1,2,5]oxadiazole 1-N-oxide (5b) was particular...
Source: ChemMedChem - January 6, 2021 Category: Chemistry Authors: Fernandes GFDS, Campos DL, Cristiane da Silva I, Bruno Prates JL, Pavan AR, Pavan FR, Dos Santos JL Tags: ChemMedChem Source Type: research

Improving Antibody-Tubulysin Conjugates Through Linker Chemistry and Site-Specific Conjugation.
Abstract Tubulysins have emerged in recent years as a compelling drug class for delivery to tumor cells via antibodies. The ability of this drug class to exert bystander activity while retaining potency against multi-drug resistant cell lines differentiate them from other microtubule disrupting agents. Tubulysin M, a synthetic analogue, has proven to be active and well-tolerated as an antibody-drug conjugate (ADC) payload, but has the liability of being susceptible to acetate hydrolysis at the C11 position, leading to attenuated potency. In this work, we examine the ability of the drug-linker and conjugation site ...
Source: ChemMedChem - December 24, 2020 Category: Chemistry Authors: Hamilton JZ, Pires TA, Mitchell JA, Cochran JH, Emmerton KK, Zaval M, Stone IJ, Anderson ME, Jin S, Waight AB, Lyon RP, Senter PD, Jeffrey SC, Burke PJ Tags: ChemMedChem Source Type: research

2020 Italian Special Anniversary Collection: Celebrating NMMC 2019  and 40 Years of the DCF-SCI.
2020 Italian Special Anniversary Collection: Celebrating NMMC 2019 and 40 Years of the DCF-SCI. ChemMedChem. 2020 Dec 23;: Authors: Carini M, De Amici M Abstract Marina Carini and Marco De Amici, Guest Editors of this Special Collection dedicated to NMMC 2019 and the 40th Anniversary of the DCF-SCI, look back at key events in the Italian medicinal chemistry community within the past year and introduce the collection. PMID: 33354905 [PubMed - as supplied by publisher] (Source: ChemMedChem)
Source: ChemMedChem - December 23, 2020 Category: Chemistry Authors: Carini M, De Amici M Tags: ChemMedChem Source Type: research

Heteroaromatic Inhibitors of the Astacin Proteinases Meprin α, Meprin β and Ovastacin Discovered by a Scaffold-Hopping Approach.
Heteroaromatic Inhibitors of the Astacin Proteinases Meprin α, Meprin β and Ovastacin Discovered by a Scaffold-Hopping Approach. ChemMedChem. 2020 Dec 23;: Authors: Tan K, Jäger C, Körschgen H, Geissler S, Schlenzig D, Buchholz M, Stöcker W, Ramsbeck D Abstract Astacin metalloproteinases, in particular meprins α and β, as well as ovastacin, are emerging drug targets. Drug-discovery efforts have led to the development of the first potent and selective inhibitors in the last few years. However, the most recent compounds are based on a highly flexible tertiary amine s...
Source: ChemMedChem - December 23, 2020 Category: Chemistry Authors: Tan K, Jäger C, Körschgen H, Geissler S, Schlenzig D, Buchholz M, Stöcker W, Ramsbeck D Tags: ChemMedChem Source Type: research

Coumarin-Thiourea Hybrids Show Potent Carbonic Anhydrase IX and XIII Inhibitory Action.
Abstract A series of coumarin-thiourea hybrids (4a-o) was synthesized and the synthesized compounds were subjected for evaluation against the tumor-associated transmembrane isoform, hCA IX and the comparatively lesser-explored cytosolic isoform, hCA XIII. All the compounds exhibited potent inhibition of both the isoforms. Except compounds 4d and 4e, all the compounds inhibited hCA IX with a KI value of
Source: ChemMedChem - December 21, 2020 Category: Chemistry Authors: Arifuddin M, Thacker PS, Danaboina Srikanth DS, Angeli A, Singh P, Chinchilli KK, Supuran CT Tags: ChemMedChem Source Type: research

Action of dipeptidyl peptidase-4 inhibitors on SARS-CoV-2 main protease.
Abstract In a recent publication in this journal Eleftheriou et al. proposed inhibitors of dipeptidyl peptidase-4 (DPP-4) to be functional inhibitors of the main protease (M pro ) of SARS-CoV-2. Their predictions prompted the authors to suggest linagliptin, a DPP-4 inhibitor and approved anti-diabetes drug, as a repurposed drug candidate against the ongoing COVID-19 pandemic. We used an enzymatic assay measuring inhibition of M pro catalytic activity in the presence of four different commercially available gliptins (linagliptin, sitagliptin, alogliptin and saxagliptin) and several structural analogues of linaglipt...
Source: ChemMedChem - December 21, 2020 Category: Chemistry Authors: Klein T, Nar H, Schnapp G, Hucke O, Hardman TC Tags: ChemMedChem Source Type: research

Stimuli-Responsive Nanomaterials for Smart Tumor-Specific Phototherapeutics.
Abstract Phototherapy, a type of photoresponsive regulation of biological activities, together with additional stimuli-responsive features, offers significant potential for enhancing the precision and efficacy of cancer treatments. To achieve tumor-specific therapeutics, numerous studies have focused on the development of smart phototherapeutic nanomaterials (PNMs) that can respond to endogenous pathological characteristics ( e.g. , mild acidity, the overproduction of glutathione, the overproduction of hydrogen peroxide, the overexpression of specific surface receptors, etc .) present in the tumor and/or exogenous...
Source: ChemMedChem - December 20, 2020 Category: Chemistry Authors: Zhou B, Guo Z, Lin Z, Jiang BP, Shen XC Tags: ChemMedChem Source Type: research

Pentafluoro-3-hydroxy-pent-2-en-1-ones potently inhibit FNT-type lactate transporters from all five human-pathogenic  Plasmodium species.
Pentafluoro-3-hydroxy-pent-2-en-1-ones potently inhibit FNT-type lactate transporters from all five human-pathogenic Plasmodium species. ChemMedChem. 2020 Dec 18;: Authors: Walloch P, Hansen C, Priegann T, Schade D, Beitz E Abstract The protozoan parasite Plasmodium falciparum causes the most severe and prevailing form of malaria in sub-Saharan Africa. Previously, we identified the plasmodial lactate transporter, PfFNT, a member of the microbial formate-nitrite transporter family, as a novel antimalarial drug target. With the pentafluoro-3-hydroxy-pent-2-en-1-ones, we discovered PfFNT inhibi...
Source: ChemMedChem - December 18, 2020 Category: Chemistry Authors: Walloch P, Hansen C, Priegann T, Schade D, Beitz E Tags: ChemMedChem Source Type: research

Synthesis of σ receptor ligands with a spirocyclic system connected with a tetrahydroisoquinoline moiety via different linkers.
Synthesis of σ receptor ligands with a spirocyclic system connected with a tetrahydroisoquinoline moiety via different linkers. ChemMedChem. 2020 Dec 17;: Authors: Wünsch B, Bergkemper M, Schepmann D Abstract With the aim to develop new σ 2 receptor ligands, spirocyclic piperidines or cyclohexanamines with 2-benzopyran and 2-benzofuran scaffold were connected with the 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline moiety by variable linkers. In addition to flexible alkyl chains, linkers containing an amide as functional group were synthesized. The 2-benzopyran and 2-benzofuran scaffold ...
Source: ChemMedChem - December 17, 2020 Category: Chemistry Authors: Wünsch B, Bergkemper M, Schepmann D Tags: ChemMedChem Source Type: research