Bioorganic & Medicinal Chemistry

Editorial board ()
Publication date: 15 July 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 14
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Graphical contents list ()
Publication date: 15 July 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 14
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Triglyceride-lowering agents ()
Publication date: 15 July 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 14 Author(s): Nariman F. Salakhutdinov , Sergey S. Laev This review is the first attempt at systematization of the literature data on the structures and activities of triglyceride-lowering agents which used in medical practice or are in development. The effects and mechanisms of action of statins, squalene synthase inhibitors, fibrates, PPARα and PPARα/γ agonists, nicotinic acid, omega-3 fatty acids and some other molecular targets were considered. Unfortunately, to date, harmless and effective triglyceride-lowering drug still does not exist and there is still need for development of better triglyceride-lowering agents. Graphical abstract image
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Synthesis of truncated analogues of preptin-(1–16), and investigation of their ability to stimulate osteoblast proliferation ()
Publication date: 15 July 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 14 Author(s): Renata Kowalczyk , Sung H. Yang , Margaret A. Brimble , Karen E. Callon , Maureen Watson , Young-Eun Park , Jillian Cornish Preptin, a 34-amino acid residue peptide hormone is co-secreted with insulin from the β-pancreatic cells and is active in fuel metabolism. We have previously established that a shorter fragment of preptin, namely preptin-(1–16), stimulates bone growth by proliferation and increasing the survival rate of osteoblasts. This was demonstrated in both in vitro and in vivo models. These findings suggest that preptin-(1–16) could play an important role in the anabolic therapy of osteoporosis. However, due to the large size of the peptide it is not an ideal therapeutic agent. The aim of this study was to identify the shortest preptin analogue that retains or even increases the bone anabolic activity as compared to the parent preptin-(1–16) peptide. Truncations were made in a methodical manner from both the N-terminus and the C-terminus of the peptide, and the effect of these deletions on the resulting biological activity was assessed. In order to improve the enzymatic stability of the shortest yet active analogue identified, ruthenium-catalysed ring closing metathesis was used to generate a macrocyclic peptide using allylglycine residues as handles for ring formation. We have successfully identified a short 8-amino acid preptin (1–8) fragment that retains an anabolic effect on the proliferation of primary rat osteoblasts and enhances bone nodule formation. Preptin (1–8) is a useful lead compound for the development of orally active therapeutics for the treatment of osteoporosis. Graphical abstract image
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Antiplasmodial activity of new 4-aminoquinoline derivatives against chloroquine resistant strain ()
Publication date: 15 July 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 14 Author(s): Manish Sinha , Vasanth R. Dola , Pooja Agarwal , Kumkum Srivastava , Wahajul Haq , Sunil K. Puri , Seturam B. Katti Emergence and spread of multidrug resistant strains of Plasmodium falciparum has severely limited the antimalarial chemotherapeutic options. In order to overcome the obstacle, a set of new side-chain modified 4-aminoquinolines were synthesized and screened against chloroquine-sensitive (3D7) and chloroquine-resistant (K1) strains of P. falciparum. The key feature of the designed molecules is the use of methylpiperazine linked α, β3- and γ-amino acids to generate novel side chain modified 4-aminoquinoline analogues. Among the evaluated compounds, 20c and 30 were found more potent than CQ against K1 and displayed a four-fold and a three-fold higher activity respectively, with a good selectivity index (SI=5846 and 11,350). All synthesized compounds had resistance index between 1.06 and >14.13 as against 47.2 for chloroquine. Biophysical studies suggested that this series of compounds act on heme polymerization target. Graphical abstract image
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Structure–activity relationship study of non-steroidal NPC1L1 ligands identified through cell-based assay using pharmacological chaperone effect as a readout ()
Publication date: 15 July 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 14 Author(s): Fumika Karaki , Kenji Ohgane , Hiromitsu Fukuda , Masahiko Nakamura , Kosuke Dodo , Yuichi Hashimoto Niemann-Pick type C1-like 1 (NPC1L1) is an intestinal cholesterol transporter that is known to be the target of the cholesterol absorption inhibitor ezetimibe. We previously discovered steroidal NPC1L1 ligands by using a novel cell-based assay that employs pharmacological chaperone effect as a readout. Those steroid derivatives bound to a site different from both the sterol-binding domain and the ezetimibe-binding site, implying that they may be a novel class of NPC1L1 inhibitors with a distinct mode of action. As an extension of that work, we aimed here to find non-steroidal NPC1L1 ligands, which may be better candidates for clinical application than steroidal ligands, by using the same assay to screen our focused library of ligands for liver X receptor (LXR), a nuclear receptor that recognizes oxysterols as endogenous ligands. Here we describe identification of a novel class of NPC1L1 ligands with a ring-fused quinolinone scaffold, and an analysis of the structure–activity relationships of their derivatives as NPC1L1 ligands. Graphical abstract image
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Sulfur, selenium and tellurium pseudopeptides: Synthesis and biological evaluation ()
Publication date: 15 July 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 14 Author(s): Saad Shaaban , Florenz Sasse , Torsten Burkholz , Claus Jacob A new series of sulfur, selenium and tellurium peptidomimetic compounds was prepared employing the Passerini and Ugi isocyanide based multicomponent reactions (IMCRs). These reactions were clearly superior to conventional methods traditionally used for organoselenium and organotellurium synthesis, such as classical nucleophilic substitution and coupling methods. From the biological point of view, these compounds are of considerable interest because of suspected anticancer and antimicrobial activities. While the sulfur and selenium containing compounds generally did not show either anticancer or antimicrobial activities, their tellurium based counterparts frequently exhibited antimicrobial activity and were also cytotoxic. Some of the compounds synthesized even showed selective activity against certain cancer cells in cell culture. These compounds induced a cell cycle delay in the G0/G1 phase. At closer inspection, the ER and the actin cytoskeleton appeared to be the primary cellular targets of these tellurium compounds, in line with some of our previous studies. As most of these peptidomimetic compounds also comply with Lipinski’s Rule of Five, they promise good bioavailability, which needs to be studied as part of future investigations. Graphical abstract image
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Novel 3-arylfuran-2(5H)-one-fluoroquinolone hybrid: Design, synthesis and evaluation as antibacterial agent ()
Publication date: 15 July 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 14 Author(s): Xu-Dong Wang , Wei Wei , Peng-Fei Wang , Yun-Tao Tang , Rui-Cheng Deng , Biao Li , Sha-Sha Zhou , Jing-Wen Zhang , Lei Zhang , Zhu-Ping Xiao , Hui Ouyang , Hai-Liang Zhu 3-Arylfuran-2(5H)-one, a novel antibacterial pharmacophore targeting tyrosyl-tRNA synthetase (TyrRS), was hybridized with the clinically used fluoroquinolones to give a series of novel multi-target antimicrobial agents. Thus, twenty seven 3-arylfuran-2(5H)-one-fluoroquinolone hybrids were synthesized and evaluated for their antimicrobial activities. Some of the hybrids exhibited merits from both parents, displaying a broad spectrum of activity against resistant strains including both Gram-negative and Gram-positive bacteria. The most potent compound (11) in antibacterial assay shows MIC50 of 0.11μg/mL against Multiple drug resistant Escherichia coli, being about 51-fold more potent than ciprofloxacin. The enzyme assays reveal that 11 is a potent multi-target inhibitor with IC50 of 1.15±0.07μM against DNA gyrase and 0.12±0.04μM against TyrRS, respectively. Its excellent inhibitory activities against isolated enzymes and intact cells strongly suggest that 11 deserves to further research as a novel antibiotic. Graphical abstract image
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Design, synthesis, antiviral and cytostatic activity of ω-(1H-1,2,3-triazol-1-yl)(polyhydroxy)alkylphosphonates as acyclic nucleotide analogues ()
Publication date: 15 July 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 14 Author(s): Iwona E. Głowacka , Jan Balzarini , Graciela Andrei , Robert Snoeck , Dominique Schols , Dorota G. Piotrowska The efficient synthesis of a new series of polyhydroxylated dibenzyl ω-(1H-1,2,3-triazol-1-yl)alkylphosphonates as acyclic nucleotide analogues is described starting from dibenzyl ω-azido(polyhydroxy)alkylphosphonates and selected alkynes under microwave irradiation. Selected O,O-dibenzylphosphonate acyclonucleotides were transformed into the respective phosphonic acids. All compounds were evaluated in vitro for activity against a broad variety of DNA and RNA viruses and for cytostatic activity against murine leukemia L1210, human T-lymphocyte CEM and human cervix carcinoma HeLa cells. Compound (1S,2S)-16b exhibited antiviral activity against Influenza A H3N2 subtype (EC50 =20μM—visual CPE score; EC50 =18μM—MTS method; MCC >100μM, CC50 >100μM) in Madin Darby canine kidney cell cultures (MDCK), and (1S,2S)-16k was active against vesicular stomatitis virus and respiratory syncytial virus in HeLa cells (EC50 =9 and 12μM, respectively). Moreover, compound (1R,2S)-16l showed activity against both herpes simplex viruses (HSV-1, HSV-2) in HEL cell cultures (EC50 =2.9 and 4μM, respectively) and feline herpes virus in CRFK cells (EC50 =4μM) but at the same time it exhibited cytotoxicity toward uninfected cell (MCC⩾4μM). Several other compounds have been found to inhibit proliferation of L1210, CEM as well as HeLa cells with IC50 in the 4–50μM range. Among them compounds (1S,2S)- and (1R,2S)-16l were the most active (IC50 in the 4–7μM range). Graphical abstract image Highlights Compound (1S,2S)-16b exhibited antiviral activity against Influenza A H3N2 subtype (EC50 =20μM—visual CPE score; EC50 =18μM—MTS method; MCC >100μM, CC50 >100μM) in Madin Darby canine kidney cell cultures (MDCK), and (1S,2S)-16k against vesicular stomatitis virus and respiratory syncytial virus in HeLa cells (EC50 =9 and 12μM, respectively). Moreover, (1R,2S)-16l showed activity against both herpes simplex viruses (HSV-1, HSV-2) in HEL cell cultures (EC50 =2.9 and 4μM, respectively) and feline herpes virus in CRFK cells (EC50 =4μM) but at the same time it exhibited cytotoxicity toward uninfected cell (MCC⩾4μM). Several compounds (1S,2S)-16i–l and (1R,2S)-16f–l inhibited proliferation of L1210, CEM as well as HeLa cells with IC50’s in the 4–50μM range.
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Design, synthesis and biological evaluation of novel 6,7-disubstituted-4-phenoxyquinoline derivatives bearing 4-oxo-3,4-dihydrophthalazine-1-carboxamide moieties as c-Met kinase inhibitors ()
Publication date: 15 July 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 14 Author(s): Zijian Liu , Rui Wang , Ruiming Guo , Jinxing Hu , Ruijuan Li , Yanfang Zhao , Ping Gong A series of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing 4-oxo-3,4-dihydrophthalazine-1-carboxamide moieties were designed, synthesized and evaluated for their c-Met kinase inhibition and cytotoxicity against H460, MKN-45, HT-29 and MDA-MB-231 cancer cell lines in vitro. Most compounds displayed good to excellent potency against four tested cancer cell lines as compared with foretinib. The SAR analyses indicated that compounds with halogen groups, especially fluoro groups at 4-position on the phenyl ring (moiety B) were more effective than those with nitro groups or methoxy groups. In this study, a promising compound 33 (c-Met IC50 =1.63nM) was identified, which showed the most potent antitumor activities with IC50 values of 0.055μM, 0.071μM, 0.13μM, and 0.43μM against H460, MKN-45, HT-29 and MDA-MB-231 cell lines, respectively. Graphical abstract image
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Synthesis and evaluation of (E)-2-(acrylamido)cyclohex-1-enecarboxylic acid derivatives as HCA1, HCA2, and HCA3 receptor agonists ()
Publication date: 15 July 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 14 Author(s): Olga Bobileva , Rasma Bokaldere , Vija Gailite , Ilze Kaula , Martins Ikaunieks , Gunars Duburs , Ramona Petrovska , Ilona Mandrika , Janis Klovins , Einars Loza 2-(3-(Naphthalen-2-yl)propanamido)cyclohex-1-enecarboxylic acid and its 6-hydroxynaphthalen-2-yl analogue are well-known hydroxyl-carboxylic acid (HCA) receptor HCA2 agonists. A series of novel aryl derivatives of 2-amidocyclohex-1-ene carboxylic acid that contained rigidity elements, such as an E-double bond, triple bond, and trans or cis-substituted cyclopropane rings, instead of the saturated ethane linker in the amide part of the molecules were designed and synthesized, and the derivatives’ potency for the activation of HCA1, HCA2, and HCA3 receptors by 3′–5′-cyclic adenosine monophosphate (cAMP) assay were evaluated. The SAR studies revealed that the rigidifying of appropriate molecules enabled modulation of the potency and selectivity of the HCA2 receptor activation. Graphical abstract image
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4-Quinolone-3-carboxylic acids as cell-permeable inhibitors of protein tyrosine phosphatase 1B ()
Publication date: 15 July 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 14 Author(s): Ying Zhi , Li-Xin Gao , Yi Jin , Chun-Lan Tang , Jing-Ya Li , Jia Li , Ya-Qiu Long Protein tyrosine phosphatase 1B is a negative regulator in the insulin and leptin signaling pathways, and has emerged as an attractive target for the treatment of type 2 diabetes and obesity. However, the essential pharmacophore of charged phosphotyrosine or its mimetic confer low selectivity and poor cell permeability. Starting from our previously reported aryl diketoacid-based PTP1B inhibitors, a drug-like scaffold of 4-quinolone-3-carboxylic acid was introduced for the first time as a novel surrogate of phosphotyrosine. An optimal combination of hydrophobic groups installed at C-6, N-1 and C-3 positions of the quinolone motif afforded potent PTP1B inhibitors with low micromolar IC50 values. These 4-quinolone-3-carboxylate based PTP1B inhibitors displayed a 2–10 fold selectivity over a panel of PTP’s. Furthermore, the bidentate inhibitors of 4-quinolone-3-carboxylic acids conjugated with aryl diketoacid or salicylic acid were cell permeable and enhanced insulin signaling in CHO/hIR cells. The kinetic studies and molecular modeling suggest that the 4-quinolone-3-carboxylates act as competitive inhibitors by binding to the PTP1B active site in the WPD loop closed conformation. Taken together, our study shows that the 4-quinolone-3-carboxylic acid derivatives exhibit improved pharmacological properties over previously described PTB1B inhibitors and warrant further preclinical studies. Graphical abstract image
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Carbonic anhydrase inhibitors: Synthesis, molecular docking, cytotoxic and inhibition of the human carbonic anhydrase isoforms I, II, IX, XII with novel benzenesulfonamides incorporating pyrrole, pyrrolopyrimidine and fused pyrrolopyrimidine moieties ()
Publication date: 15 July 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 14 Author(s): Mostafa M. Ghorab , Mansour S. Alsaid , Mariangela Ceruso , Yassin M. Nissan , Claudiu T. Supuran A series of novel pyrroles, pyrrolopyrimidines, pyrazolopyrrolopyrimidine, triazolopyrrolopyrimidines, tetrazolopyrrolopyrimidine, triazinopyrrolopyrimidines and pyrrolopyrimidotriazepines bearing the biologically active benzenesulfonamide moiety were synthesized by using pyrrole-o-amino-carbonitrile as key intermediate. All the synthesized compounds were evaluated for their in vitro carbonic anhydrase (CA, EC 4.2.1.1) inhibitory effects against the human (h) isoforms hCA I, II, IX and XII. Among the tested derivatives, compounds 16, 18 and 20–24 showed potent activity as inhibitors for the tumor associated transmembrane isoforms (hCA IX and XII) in the nanomolar and subnanomolar range, with high selectivity. All compounds underwent cytotoxic activity assays on human breast cancer cell line (MCF-7) showing effective activity, comparable to that of the clinically used drug doxorubicin. Graphical abstract image
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Macrocyclic diterpenes resensitizing multidrug resistant phenotypes ()
Publication date: 15 July 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 14 Author(s): Mariana A. Reis , Angela Paterna , Ricardo J. Ferreira , Hermann Lage , Maria-José U. Ferreira Herein, collateral sensitivity effect was exploited as a strategy to select effective compounds to overcome multidrug resistance in cancer. Thus, eleven macrocyclic diterpenes, namely jolkinol D (1), isolated from Euphorbia piscatoria, and its derivatives (2–11) were evaluated for their activity on three different Human cancer entities: gastric (EPG85-257), pancreatic (EPP85-181) and colon (HT-29) each with a variant selected for resistance to mitoxantrone (EPG85-257RN; EPP85-181RN; HT-29RN) and one to daunorubicin (EPG85-257RD; EPP85-181RD; HT-29RD). Jolkinol D (1) and most of its derivatives (2–11) exhibited significant collateral sensitivity effect towards the cell lines EPG85-257RN (associated with P-glycoprotein overexpression) and HT-29RD (altered topoisomerase II expression). The benzoyl derivative, jolkinoate L (8) demonstrated ability to target different cellular contexts with concomitant high antiproliferative activity. These compounds were previously assessed as P-glycoprotein modulators, at non-cytotoxic doses, on MDR1-mouse lymphoma cells. A regression analysis between the antiproliferative activity presented herein and the previously assessed P-glycoprotein modulatory effect showed a strong relation between the compounds that presented both high P-glycoprotein modulation and cytotoxicity. Graphical abstract image
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A novel and facile synthesis of tetra branched derivatives of nociceptin/orphanin FQ ()
Publication date: 15 July 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 14 Author(s): Remo Guerrini , Erika Marzola , Claudio Trapella , Michela Pela’ , Stefano Molinari , Maria Camilla Cerlesi , Davide Malfacini , Anna Rizzi , Severo Salvadori , Girolamo Calo’ Branched peptides have been found to be useful in several research fields however their synthesis and purification is complicated. Here we present a novel and facile synthesis of tetra branched derivatives of nociceptin/orphanin FQ (N/OFQ). Three N/OFQ tetra branched derivatives were prepared using novel cores (PWT1, PWT2 and PWT3) containing a maleimido moiety. [Cys18]N/OFQ-NH2 was linked to the cores via thiol-Michael reaction characterized by high yield and purity of the desired final product. In the electrically stimulated mouse vas deferens PWT-N/OFQ derivatives mimicked the inhibitory action of the natural sequence showing similar maximal effects and 3 fold higher potencies. The NOP selective antagonist SB-612111 antagonized the effects of N/OFQ and PWT derivatives with similar pK B values (8.02–8.48). In vivo after supraspinal administration PWT2-N/OFQ stimulated food intake in mice mimicking the action of N/OFQ. Compared to the natural peptide PWT2-N/OFQ was 40 fold more potent and elicited larger effects. These findings suggest that the PWT chemical strategy can be successfully applied to biologically active peptides to generate, with unprecedented high purity and yield, tetra branched derivatives displaying an in vitro pharmacological profile similar to that of the natural sequence associated, in vivo, to increased potency and effectiveness. Graphical abstract image
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Catechol–rhodanine derivatives: Specific and promiscuous inhibitors of Escherichia coli deoxyxylulose phosphate reductoisomerase (DXR) ()
Publication date: 15 July 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 14 Author(s): Catherine Zinglé , Denis Tritsch , Catherine Grosdemange-Billiard , Michel Rohmer To develop more effective inhibitors than fosmidomycin, a natural compound which inhibits the deoxyxylulose 5-phosphate reductoisomerase (DXR), the second enzyme of the MEP pathway, we designed molecules possessing on the one hand a catechol that is able to chelate the magnesium dication and on the other hand a group able to occupy the NADPH recognition site. Catechol–rhodanine derivatives (1–6) were synthesized and their potential inhibition was tested on the DXR of Escherichia coli. For the inhibitors 1 and 2, the presence of detergent in the enzymatic assays led to a dramatic decrease of the inhibition suggesting, that these compounds are rather promiscuous inhibitors. The compounds 4 and 5 kept their inhibition capacity in the presence of Triton X100 and could be considered as specific inhibitors of DXR. Compound 4 showed antimicrobial activity against Escherichia coli. The only partial protection of NADPH against the inhibition suggested that the catechol–rhodanine derivatives did not settle in the coenzyme binding site. This paper points out the necessity to include a detergent in the DXR enzymatic assays to avoid false positive when putative hydrophobic inhibitors are tested and especially when the IC50, are in the micromolar range. Graphical abstract image
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Design and synthesis of novel and highly-active pan-histone deacetylase (pan-HDAC) inhibitors ()
Publication date: 15 July 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 14 Author(s): Toshihiko Tashima , Hiroaki Murata , Hidehiko Kodama Histone deacetylase (HDAC) inhibitions are known to elicit anticancer effects. We designed and synthesized several HDAC inhibitors. Among these compounds, compound 40 exhibited a more than 10-fold stronger inhibitory activity compared with that of suberoylanilide hydroxamic acid (SAHA) against each human HDAC isozyme in vitro (IC50 values of 40: HDAC1, 0.0038μM; HDAC2, 0.0082μM; HDAC3, 0.015μM; HDAC8, 0.0060μM; HDAC4, 0.058μM; HDAC9, 0.0052μM; HDAC6, 0.058μM). The dose of the administered HDAC inhibitors that contain hydroxamic acid as the zinc-binding group may be reduced by 40. Because the carbostyril subunit is a time-tested structural component of drugs and biologically active compounds, 40 most likely exhibits good absorption, distribution, metabolism, excretion, and toxicity (ADMET). Thus, compound 40 is expected to be a promising therapeutic agent or chemical tool for the investigation of life process. Graphical abstract image
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New coumarin derivatives: Design, synthesis and use as inhibitors of hMAO ()
Publication date: 15 July 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 14 Author(s): Xu He , Yan-Yan Chen , Jing-Bo Shi , Wen-Jiang Tang , Zhi-Xiang Pan , Zhi-Qiang Dong , Bao-An Song , Jun Li , Xin-Hua Liu A series new 2H-chromene-3-carboxamides (4a–4i) and S-2H-chromene-3-carbothioates (5j–5t) were synthesized and evaluated as monoamine oxidase A and B inhibitors. Among them, compound 5k (IC50 =0.21μM, IC50 iproniazid =7.65μM) showed the most activity and higher MAO-B selectivity (189.2-fold vs 1-fold) with respect to the MAO-A isoform. The need to clarify at a 3D level some important molecular aspects of discussed SAR, we undertaked a number of docking simulations to better assess. The steric effect was analyzed interms of both posing and scoring by investigating the nature of the binding interactions. The docking results of active compound 5k with hMAO-B complex indicated that conserved residue ILE 199 was important for ligand binding via Sigma–Pi interaction. Graphical abstract image
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Combination of 2-methoxy-3-phenylsulfonylaminobenzamide and 2-aminobenzothiazole to discover novel anticancer agents ()
Publication date: 15 July 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 14 Author(s): Huan Li , Xiao-Meng Wang , Juan Wang , Teng Shao , Yi-Ping Li , Qi-Bing Mei , She-Min Lu , San-Qi Zhang The fragment of 2-substituted-3-sulfonylaminobenzamide has been proposed to replace the fragment of 2-substituted-3-sulfonylaminopyridine in PI3K and mTOR dual inhibitors to design novel anticancer agents based on bioisostere. The combination of the fragment of 2-substituted-3-sulfonylaminobenzamide with the fragment of 2-aminobenzothiazole or 2-aminothiazolo[5,4-b]pyridine, or 2-amino[1,2,4]triazolo[1,5-a]pyridine produced the novel structures of anticancer agents. As a result, nineteen target compounds were synthesized and characterized. Their antiproliferative activities in vitro were evaluated via MTT assay against four human cancer cell lines including HCT-116, A549, MCF-7 and U-87 MG. The SAR of target compounds was preliminarily discussed. Compound 1g with potent antiproliferative activity was examined for its effect on the AKT and p-AKT473. The anticancer effect of 1g was evaluated in established nude mice HCT-116 xenograft model. The results suggested that compound 1g can block PI3K/AKT/mTOR pathway and significantly inhibit tumor growth. These findings strongly support our assumption that the fragment of benzamide can replace the pyridine ring in some PI3K and mTOR dual inhibitor to design novel anticancer agents. Graphical abstract image
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Novel synthetic route for antimalarial benzo[a]phenoxazine derivative SSJ-183 and two active metabolites ()
Publication date: 15 July 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 14 Author(s): Yuki Mizukawa , Jian-Feng Ge , Abu Bakar Md , Isamu Itoh , Christian Scheurer , Sergio Wittlin , Reto Brun , Hiroyuki Matsuoka , Masataka Ihara A productive synthesis of benzo[a]phenoxazine derivative SSJ-183 (1), a promising lead for antimalarial agents, was developed using a one pot procedure. Furthermore, N-deethylated metabolite 3 and bis-N,N-deethylated metabolite 4 were synthesized by the application of the method. The metabolites 3 and 4 showed comparable and ∼2-fold increased activities against drug-sensitive and drug-resistant Plasmodium falciparum parasites. Graphical abstract image
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The design and discovery of water soluble 4-substituted-2,6-dimethylfuro[2,3-d]pyrimidines as multitargeted receptor tyrosine kinase inhibitors and microtubule targeting antitumor agents ()
Publication date: 15 July 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 14 Author(s): Xin Zhang , Sudhir Raghavan , Michael Ihnat , Jessica E. Thorpe , Bryan C. Disch , Anja Bastian , Lora C. Bailey-Downs , Nicholas F. Dybdal-Hargreaves , Cristina C. Rohena , Ernest Hamel , Susan L. Mooberry , Aleem Gangjee The design, synthesis and biological evaluations of fourteen 4-substituted 2,6-dimethylfuro[2,3-d]pyrimidines are reported. Four compounds (11–13, 15) inhibit vascular endothelial growth factor receptor-2 (VEGFR-2), platelet-derived growth factor receptor β (PDGFR-β), and target tubulin leading to cytotoxicity. Compound 11 has nanomolar potency, comparable to sunitinib and semaxinib, against tumor cell lines overexpressing VEGFR-2 and PDGFR-β. Further, 11 binds at the colchicine site on tubulin, depolymerizes cellular microtubules and inhibits purified tubulin assembly and overcomes both βIII-tubulin and P-glycoprotein-mediated drug resistance, and initiates mitotic arrest leading to apoptosis. In vivo, its HCl salt, 21, reduced tumor size and vascularity in xenograft and allograft murine models and was superior to docetaxel and sunitinib, without overt toxicity. Thus 21 affords potential combination chemotherapy in a single agent. Graphical abstract image
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Interaction analysis of a ladder-shaped polycyclic ether and model transmembrane peptides in lipid bilayers by using Förster resonance energy transfer and polarized attenuated total reflection infrared spectroscopy ()
Publication date: 15 July 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 14 Author(s): Kazuya Yamada , Haruki Kuriyama , Toshiaki Hara , Michio Murata , Raku Irie , Yanit Harntaweesup , Masayuki Satake , Seketsu Fukuzawa , Kazuo Tachibana Ladder-shaped polycyclic ethers (LSPs) are predicted to interact with membrane proteins; however, the underlying mechanism has not been satisfactorily elucidated. It has been hypothesized that LSPs possess non-specific affinity to α-helical segments of transmembrane proteins. To verify this hypothesis, we constructed a model LSP interaction system in a lipid bilayer. We prepared 5 types of α-helical peptides and reconstituted them in liposomes. The reconstitution and orientation of these peptides in the liposomes were examined using polarized attenuated total reflection infrared (ATR-IR) spectroscopy and gel filtration. The results revealed that 4 peptides were retained in liposomes, and 3 of them formed stable transmembrane structures. The interaction between the LSP and the peptides was investigated using Förster resonance energy transfer (FRET). In the lipid bilayer, the LSP strongly recognized the peptides that possessed aligned hydrogen donating groups with leucine caps. We propose that this leucine-capped 16-amino acid sequence is a potential LPS binding motif. Graphical abstract image Highlights
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Synthesis and biological evaluation of substituted 3-anilino-quinolin-2(1H)-ones as PDK1 inhibitors ()
Publication date: 15 July 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 14 Author(s): Nathan J. O’Brien , Martin Brzozowski , David J.D. Wilson , Leslie W. Deady , Belinda M. Abbott PDK1 is an important regulator of the PI3K/Akt pathway, which has been found frequently activated in a large number of human cancers. Herein we described the preparation of novel substituted 3-anilino-quinolin-2(1H)-ones as PDK1 inhibitors. The synthesis is based around a Buchwald–Hartwig cross-coupling of various 3-bromo-6-substituted-quinolin-2(1H)-ones with three different functionalised anilines. The modular nature of the designed synthesis allowed access to a series of novel inhibitors through derivatisation of a late-stage intermediate. All compounds were screened against isolated PDK1 enzyme, with modest inhibition observed. Graphical abstract image
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Design, Synthesis, and Biological Evaluation of Scaffold-Based Tripeptidomimetic Antagonists for CXC Chemokine Receptor 4 (CXCR4) ()
Publication date: Available online 14 July 2014 Source:Bioorganic & Medicinal Chemistry Author(s): Zack G. Zachariassen , Stefanie Thiele , Erik A. Berg , Pernille Rasmussen , Torgils Fossen , Mette M. Rosenkilde , Jon Våbenø , Bengt Erik Haug Structure-activity relationship studies of the cyclopentapeptide CXCR4 antagonists (cyclo(-L-/D-Arg1-Arg2-2-Nal3-Gly4-D-Tyr5-)) suggest that the L-/D-Arg1-Arg2-2-Nal3 tripeptide sequence contained within these cyclopentapeptides serves as a recognition motif for peptidic CXCR4 antagonists. Starting by dissecting the cyclopentapeptide structure and reintroducing cyclic constraints in a stepwise manner, we here report a novel class of scaffold-based tripeptidomimetic CXCR4 antagonists based on the D-Arg-Arg-2-Nal motif. Biological testing of the prototype compounds showed that they represent new peptidomimetic hits; importantly, the modular nature of the scaffold provides an interesting starting point for future ligand optimization. Graphical abstract image Highlights
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Design, Synthesis and Evaluation of Rivastigmine and Curcumin Hybirds as Site-activated Multitarget-directed Ligands for Alzheimer’s Disease Therapy ()
Publication date: Available online 11 July 2014 Source:Bioorganic & Medicinal Chemistry Author(s): Yujie Li , Peng Peng , Li Tang , Yunzhen Hu , Yongzhou Hu , Rong Sheng A series of novel 2-methoxy-phenyl dimethyl-carbamate derivatives were designed, synthesized and evaluated as site-activated MDTLs based on rivastigmine and curcumin. Most of them exhibited good to excellent AChE and BuChE inhibitory activities with sub-micromolar IC50 values. Among all the compounds, 6a demonstrated the most potent AChE inhibition with IC50 value of 0.097 μM, which is about 20-fold than that of rivastigmine. In addition, the three selected compounds 5a, 6a and 6e demonstrated inhibitory activity against Aβ self-aggregation similar to cucurmin in TEM assay, which is obviously different from the weak activity of rivastigmine. Moreover, the hydrolysate of 6a (compound 7) also showed potent ABTS•+ scavenging and moderate copper ion chelating activity in vitro. Graphical abstract image Highlights A series of novel 2-methoxy-phenyl dimethyl-carbamate derivatives were designed, synthesized and evaluated as site-activated MDTLs.
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Discovery of quinazolin-4-amines bearing benzimidazole fragments as dual inhibitors of c-Met and VEGFR-2 ()
Publication date: Available online 11 July 2014 Source:Bioorganic & Medicinal Chemistry Author(s): Lei Shi , Ting-Ting Wu , Zhi Wang , Jia-Yu Xue , Yun-Gen Xu Both c-Met and VEGFR-2 are important targets for the treatment of cancers. In this study, a series of N-(2-phenyl-1H-benzo[d]imidazol-5-yl)quinazolin-4-amine derivatives were designed and identified as dual c-Met and VEGFR-2 inhibitors. Among these compounds bearing quinazoline and benzimidazole fragments, compound 7j exhibited the most potent inhibitory activity against c-Met and VEGFR-2 with IC50 of 0.05μM and 0.02 μM, respectively. It also showed the highest anticancer activity against the tested cancer cell lines with IC50 of 1.5 μM against MCF-7 and 8.7 μM against Hep-G2. Docking simulation supported the initial pharmacophoric hypothesis and suggested a common mode of interaction at the ATP-binding site of c-Met and VEGFR-2, which demonstrates that compound 7j is a potential agent for cancer therapy deserving further researching. Graphical abstract image Highlights A series of quinazolin-4-amine derivatives containing benzimidazole moiety were discovered as potent dual inhibitors of c-Met and VEGFR-2. Compound 7j exhibited the most potent inhibitory activities with IC50 of 0.05 μM and 0.02 μM against c-Met and VEGFR-2, respectively.
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Structure-affinity relationships and pharmacological characterization of new alkyl-resorcinol cannabinoid receptor ligands: identification of a dual cannabinoid receptor/TRPA1 channel agonist ()
Publication date: Available online 11 July 2014 Source:Bioorganic & Medicinal Chemistry Author(s): Antonella Brizzi , Francesca Aiello , Pietro Marini , Maria Grazia Cascio , Federico Corelli , Luciano De Petrocellis , Alessia Ligresti , Livio Luongo , Stefania Lamponi , Sabatino Maione , Roger G. Pertwee , Vincenzo Di Marzo In our ongoing program aimed at deeply investigating the endocannabinoid system (ES), a set of new alkyl-resorcinol derivatives was prepared focusing on the nature and the importance of the carboxamide functionality. Binding studies on CB1 and CB2 receptors, monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH) showed that some of the newly developed compounds behaved as very potent cannabinoid receptor ligands (K i in the nanomolar range) while, however, none of them was able to inhibit MAGL and/or FAAH. Derivative 11 was a potent CB1 and CB2 ligand, with K i values similar to WIN 55,212, exhibiting a CB1 and CB2 agonist profile in vitro. In the formalin test of peripheral acute and inflammatory pain in mice, this compound showed a weak and delayed antinociceptive effect against the second phase of the nocifensive response, exhibiting, interestingly, a quite potent transient receptor potential ankyrin type-1 (TRPA1) channel agonist activity. Moreover, derivative 14, characterized by lower affinity but higher CB2 selectivity than 11, proved to behave as a weak CB2 competitive inverse agonist. Graphical abstract image Highlights
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A semi-synthetic derivative of artemisinin, artesunate inhibits prostaglandin E2 production in LPS/IFNγ-activated BV2 microglia ()
Publication date: Available online 11 July 2014 Source:Bioorganic & Medicinal Chemistry Author(s): Uchechukwu P Okorji , Olumayokun A Olajide Artesunate is a semi-synthetic derivative of artemisinin used to treat malaria, and has been shown to possess anti-inflammatory activity. In this study, we have investigated the effect of artesunate on PGE2 production/COX-2 protein expression in LPS + IFNγ -activated BV2 microglia. To further understand the mechanism of action of this compound, we investigated its interference with NF-κB and p38 MAPK signalling pathways. PGE2 production was determined using EIA, while protein expressions of inflammatory targets like COX-2, mPGES-1, IκB, p38 and MAPKAPK2 were evaluated using western blot. An NF-κB-bearing luciferase reporter gene assay was used to test the effect of artesunate on NF-κB-mediated pro-inflammatory gene expression in HEK293 cells stimulated with TNFα (1ng/ml). Artesunate (2 and 4μM), significantly (p<0.01) suppressed PGE2 production in LPS + IFNγ -activated BV2 microglia. This effect was found to be mediated via reduction in COX-2 and mPGES-1 proteins. Artesunate also produced significant inhibition of TNFα and IL-6 production in activated BV2 microglia. Further investigations showed that artesunate (0.5-4μM) significantly (p<0.001) reduced NF-κB-driven luciferase expression, and inhibited IκB phosphorylation and degradation, through inhibition of IKK. Artesunate inhibited phosphorylation of p38 MAPK and its substrate MAPKAPK2 following stimulation of microglia with LPS + IFNγ. Taken together, we have shown that artesunate prevents neuroinflammation in BV2 microglia by interfering with NF-κB and p38 MAPK signalling. Graphical abstract image Highlights
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Structural Optimization of a Retrograde Trafficking Inhibitor that Protects Cells from Infections by Human Polyoma- and Papillomaviruses ()
Publication date: Available online 10 July 2014 Source:Bioorganic & Medicinal Chemistry Author(s): Daniel W. Carney , Christian D.S. Nelson , Bennett D. Ferris , Julia P. Stevens , Alex Lipovsky , Temur Kazakov , Daniel C. DiMaio , Walter J. Atwood , Jason K. Sello Human polyoma- and papillomaviruses are non-enveloped DNA viruses that cause severe pathologies and mortalities. Under circumstances of immunosuppression, JC polyomavirus causes a fatal demyelinating disease called progressive multifocal leukoencephalopathy (PML) and the BK polyomavirus is the etiological agent of polyomavirus-induced nephropathy and hemorrhagic cystitis. Human papillomavirus type 16, another non-enveloped DNA virus, is associated with the development of cancers in tissues like the uterine cervix and oropharynx. Currently, there are no approved drugs or vaccines to treat or prevent polyomavirus infections. We recently discovered that the small molecule Retro-2cycl, an inhibitor of host retrograde trafficking, blocked infection by several human and monkey polyomaviruses. Here, we report diversity-oriented syntheses of Retro-2cycl and evaluation of the resulting analogs using an assay of human cell infections by JC polyomavirus. We defined structure-activity relationships and also discovered analogs with significantly improved potency as suppressors of human polyoma- and papillomavirus infection in vitro. Our findings represent an advance in the development of drug candidates that can broadly protect humans from non-enveloped DNA viruses and toxins that exploit retrograde trafficking as a means for cell entry. Graphical abstract image Highlights
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Mono- and Di-Halogenated Histamine, Histidine and Carnosine Derivatives are Potent Carbonic Anhydrase I, II, VII, XII and XIV Activators ()
Publication date: Available online 10 July 2014 Source:Bioorganic & Medicinal Chemistry Author(s): Mohamed-Chiheb Saada , Daniela Vullo , Jean-Louis Montero , Andrea Scozzafava , Claudiu T. Supuran , Jean-Yves. Winum Mono- and di- halogenated histamines, L-histidine methyl ester derivatives and carnosine derivatives incorporating chlorine, bromine and iodine were prepared and investigated as activators of five carbonic anhydrase (CA, EC 4.2.1.1) isoforms, the cytosolic hCA I, II and VII, and the transmembrane hCA XII and XIV. All of them were activated in a diverse manner by the investigated compounds, with a distinct activation profile. Graphical abstract image Highlights
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Synthesis of Protoporphyrin-Lipids and Biological Evaluation of Micelles and Liposomes ()
Publication date: Available online 8 July 2014 Source:Bioorganic & Medicinal Chemistry Author(s): Shoji Tachikawa , Mohamed E. El-Zaria , Ryu Inomata , Shinichi Sato , Hiroyuki Nakamura Protoporphyrin IX (PPIX) lipids were synthesized by introducing a long alkyl chain, such as C13, C15, and C17, at each vinyl group on PPIX via hydrobromination. The PPIX lipids exhibited a water-soluble property by forming their micelles in water and the PPIX-lipid micelles showed relatively low cytotoxicity toward HeLa cells (IC50 = 151.7–379.9 μM) without light irradiation. PL-C17 liposomes (post-inserted liposomes) were readily prepared by adding PL-C17 micelle solution to the liposome solution. The IC50 values of PPIX, PL-C17 micelles, and PL-C17 liposomes toward HeLa cells were 0.53, 5.65, and 12.9 μM, respectively, after irradiation with a xenon lamp in the 400 to 800 nm range for 2 min. PL-C17 liposomes were selectively accumulated in the Golgi apparatus in cells. Graphical abstract image Highlights
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Antinociceptive and antidepressant-like action of endomorphin-2 analogs with proline surrogates in position 2 ()
Publication date: Available online 8 July 2014 Source:Bioorganic & Medicinal Chemistry Author(s): Renata Perlikowska , Justyna Piekielna , Marzena Mazur , Robert Koralewski , Jacek Olczak , Jean-Claude do Rego , Jakub Fichna , Jakub Modranka , Tomasz Janecki , Anna Janecka In our efforts to develop new candidate drugs with antinociceptive and/or antidepressant-like activity, two novel endomorphin-2 (EM-2, Tyr-Pro-Phe-Phe-NH2) analogs, containing proline surrogates in position 2 were synthesized using commercially available racemic trans-4-phenylpyrrolidine-3-carboxylic acid (4-Ph-β-Pro). The obtained mixture of two diastereoisomeric peptides (2a and 2b) was separated by HPLC and both enantiopure analogs were used in the in vitro and in vivo studies. To assign the absolute configuration to the 4-Ph-β-Pro residues in both peptides, the stereoselective synthesis of (3R,4S)-4-phenylpyrrolidine-3-carboxylic acid was performed and this enantiomer was introduced into position 2 of EM-2 sequence. Based on the HPLC retention times we were able to assign the absolute configuration of 4-Ph-β-Pro residues in both peptide analogs. Analog 2a incorporating (3R,4S)-4-Ph-β-Pro residue produced strong analgesia in mice after intracerebroventricular (icv) administration which was antagonized by the μ-opioid receptor (MOR) antagonist, β-funaltrexamine (β-FNA). This analog also influenced an emotion-related behavior of mice, decreasing immobility time in the forced swimming and tail susspension tests, without affecting locomotor activity. The antidepressant-like effect was reversed by the δ-selective antagonist, naltrindole (NLT) and κ-selective nor-binaltorphimine (nor-BNI). Thus, the experiments with selective opioid receptor antagonists revealed that analgesic action of analog 2a was mediated through the MOR, while the δ- and κ- receptors (DOR and KOR, respectively) were engaged in the antidepressant-like activity. Analog 2b with (3S,4R)-4-Ph-β-Pro in position 2 showed no antinociceptive or antidepressant-like activity in animal studies. Graphical abstract image Highlights Novel endomorphin-2 analogs modified by introduction of β-Pro with a phenyl substituent in position 4 were synthesized. Tyr-(3R,4S)-4-Ph-β-Pro-Phe-Phe-NH2 produced antinociceptive and antidepressant-like effect, while the second analog containing (3S,4R)-4-Ph-β-Pro was inactive.
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Syntheses of Coumarin–Tacrine Hybrids as Dual-site Acetylcholinesterase Inhibitors and Their activity against Butylcholinesterase, Aβ aggregation, and β-secretase ()
Publication date: Available online 8 July 2014 Source:Bioorganic & Medicinal Chemistry Author(s): Qi Sun , Peng Da-Yong , Yang Sheng-Gang , Zhu Xiao-Lei , Yang Wen-Chao , Yang Guang-Fu Exploring small-molecule acetylcholinesterase (AChE) inhibitors to slow the breakdown of acetylcholine (Ach) represents the mainstream direction for Alzheimer’s disease (AD) therapy. As the first acetylcholinesterase inhibitor approved for the clinical treatment of AD, tacrine has been widely used as a pharmacophore to design hybrid compounds in order to combine its potent AChE inhibition with other multi-target profiles. In present study, a series of novel tacrine-coumarin hybrids were designed, synthesized and evaluated as potent dual-site AChE inhibitors. Moreover, compound 1g was identified as the most potent candidate with about 2-fold higher potency (K i = 16.7 nM) against human AChE and about 2-fold lower potency (K i = 16.1 nM) against BChE than tacrine (K i = 35.7 nM for AChE, K i = 8.7 nM for BChE), respectively. In addition, some of the tacrine-coumarin hybrids showed simultaneous inhibitory effects against both Aβ aggregation and β-secretase. We therefore conclude that tacrine-coumarin hybrid is an interesting multifunctional lead for the AD drug discovery. Graphical abstract image Highlights
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Development of Potent Antagonists for Formyl Peptide Receptor 1 Based on Boc-Phe-D-Leu-Phe-D-Leu-Phe-OH ()
Publication date: Available online 8 July 2014 Source:Bioorganic & Medicinal Chemistry Author(s): Ryo Hayashi , Toshiki Kitajima , Hikaru Mizuguchi , Miki Fujimoto , Aya Yamaguchi , Shuichiro Koga , Yuya Koga , Satoshi Osada , Hiroaki Kodama While stimulation of formyl peptide receptors (FPR) on the surface of human neutrophils induces several immune responses, under conditions of continuous activation of the receptor by agonists such as formyl-Met-Leu-Phe-OH (fMLP), neutrophil-dependent tissue damage ensues. Thus, FPR antagonists could be anticipated as drugs for FPR-related disease. In this study, Boc-Phe-D-Leu-Phe-D-Leu-Phe-OH (Boc-FlFlF), one of several FPR subtype selective antagonists, was chosen and the positions at the Phe residues were optimized. We found that substitution with unnatural amino acids resulted in an improvement of two orders of magnitude. The most potent antagonist indicated FPR subtype selectivity at 1 μM. In addition to finding a potent antagonist, the structure–activity trends observed in this study should be valuable in designing a new type of FPR subtype selective antagonist. Graphical abstract image Highlights
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A new rhodamine B-based “on-off” chemical sensor with high selectivity and sensitivity toward Fe3+ and its imaging in living cells ()
Publication date: Available online 8 July 2014 Source:Bioorganic & Medicinal Chemistry Author(s): Xiaofeng Bao , Jiaxin Shi , Xuemei Nie , Baojing Zhou , Xinlong Wang , Luyong Zhang , Hong Liao , Tao Pang A new fluorescent chemosensor based on a Rhodamine B and pyrrole conjugate (RBPY) has been designed and synthesized. UV-Vis absorption and fluorescence spectroscopic studies show that RBPY exhibits a high selectivity and sensitivity toward Fe3+ among many other metal cations in a MeOH/H2O solution (3:2, v/v, pH 7.10, HEPES buffer, 0.1 mM) by forming a 1:1 complex with Fe3+. Furthermore, results reveal that the formation of the RBPY-Fe3+ complex is fully reversible in the presence of sulfide anions and could also be used as an efficient sensor for S2-. Importantly, fluorescence microscopy experiments further demonstrated that RBPY can be utilized as a fluorescent probe for the detection of Fe3+ in human liver (L-02) cells. Graphical abstract image Highlights A new fluorescent chemosensor, RBPY, was synthesized. Studies show that RBPY exhibits a high selectivity and sensitivity toward Fe3+ in a MeOH/H2O (3:2, v: v, pH 7.10, HEPES buffer, 0.1 mM) solution. Fluorescence microscopy experiments demonstrated that RBPY can be used as a fluorescent probe for the detection of Fe3+ in living cells.
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Synthesis and biological evaluation of new simple indolic non peptidic HIV Protease inhibitors: the effect of different substitution patterns ()
Publication date: Available online 4 July 2014 Source:Bioorganic & Medicinal Chemistry Author(s): C. Bonini , L. Chiummiento , N. Di Blasio , M. Funicello , P. Lupattelli , F. Tramutola , F. Berti , A. Ostric , S. Miertus , V. Frecer , D.-X. Kong New structurally simple indolic non peptidic HIV Protease inhibitors were synthesized from (S)-glycidol by regioselective methods. Following the concept of targeting the protein backbone, different substitution patterns were introduced onto the common stereodefined isopropanolamine core modifying the type of functional group on the indole, the position of the functional group on the indole and the type of the nitrogen containing group (sulfonamides or perhydroisoquinoline), alternatively. The systematic study on in vitro inhibition activity of such compounds confirmed the general beneficial effect of the 5-indolyl substituents in presence of arylsulfonamide moieties, which furnished activities in the micromolar range. Preliminary docking analysis allowed to identify several key features of the binding mode of such compounds to the protease. Graphical abstract image Highlights
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Enzymatic Resolution of Racemates with a “Remote” Stereogenic Center as an Efficient Tool in Drug, Flavor and Vitamin Synthesis ()
Publication date: Available online 3 July 2014 Source:Bioorganic & Medicinal Chemistry Author(s): Maria Alfaro Blasco , Harald Gröger The enantioselective recognition of “remote” stereogenic centers represents a scientific task in organic chemistry being also of current interest in the pharmaceutical industry. This is due to a range of pharmaceutically relevant molecules or intermediates thereof bearing a stereo-genic center, which is separated from the functional group by a larger non-chiral moiety such as, e.g., a longer sequence of bonds of at least three carbon or hetero-atoms or by a planar aromatic moiety. Notably, biocatalysis turned out to provide an excellent solution for a range of challenging syntheses in this field. For example, efficient enzymatic resolution processes of racemates with such a “remote” stereogenic center were developed for the synthesis of pelitrexol, lasofoxifene and (S)-monastrol. In general, good yields accompanied by high enantioselectivities were obtained, thus underlining the tremendous potential of enzymes to recognize and enantioselectively transform enantiomers of racemates with “remote” stereogenic centers. Such or similar types of stereoselective recognitions of “remote” stereogenic centers by means of enzymes have been also reported in the field of flavor and vitamin synthesis. Thus, biocatalysis represents a promising solution for the efficient approach to enantiomerically pure complex chiral molecules with stereogenic centers being located apart from the functional group, and it can be expected that enzymatic resolution will be increasingly applied when searching for an efficient and also technically feasible process for also novel complex chiral molecules bearing a “remote” stereogenic center. Graphical abstract image Highlights
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Cytotoxicity of synthesized 1,4-naphthoquinone analogues on selected human cancer cell lines ()
Publication date: Available online 3 July 2014 Source:Bioorganic & Medicinal Chemistry Author(s): Navneet Kishore , Brigitte Binneman , Anita Mahapatra , Maryna van de Venter , Debbie du Plessis-Stoman , Gerhardt Boukes , Peter Houghton , J.J. Marion Meyer , Namrita Lall In an effort to establish new candidates with enhanced anticancer activity of 5-hydroxy-7-methyl-1,4-naphthoquinone scaffold (7-methyljuglone) previously isolated from the root extract of Euclea natalensis, a series of 7-methyljuglone derivatives have been synthesized and assessed for cytotoxicity on selected human cancer lines. These compounds were screened in vitro for anticancer activity on MCF-7, HeLa, SNO and DU145 human cancer cell lines by MTT assay. Most of them exhibited significant toxicity on cancer cell lines with lower IC50 values. The most potent derivative (19) exhibited the toxicity on HeLa and DU145 cell lines with IC50 value of 5.3 and 6.8 μM followed by compound (5) with IC50 value of 10.1 and 9.3 μM, respectively. Structure-activity relationship reveals that the fluoro substituents at position C-8 while hydroxyl substituents at C-2 and C-5 positions played an important role in toxicity. Graphical abstract image Highlights
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Editorial board ()
Publication date: 1 July 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 13
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Graphical contents list ()
Publication date: 1 July 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 13
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Synthesis and antimalarial activity of metal complexes of cross-bridged tetraazamacrocyclic ligands ()
Publication date: 1 July 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 13 Author(s): Timothy J. Hubin , Prince N.-A. Amoyaw , Kimberly D. Roewe , Natalie C. Simpson , Randall D. Maples , TaRynn N. Carder Freeman , Amy N. Cain , Justin G. Le , Stephen J. Archibald , Shabana I. Khan , Babu L. Tekwani , M.O. Faruk Khan Using transition metals such as manganese(II), iron(II), cobalt(II), nickel(II), copper(II), and zinc(II), several new metal complexes of cross-bridged tetraazamacrocyclic chelators namely, cyclen- and cyclam-analogs with benzyl groups, were synthesized and screened for in vitro antimalarial activity against chloroquine-resistant (W2) and chloroquine-sensitive (D6) strains of Plasmodium falciparum. The metal-free chelators tested showed little or no antimalarial activity. All the metal complexes of the dibenzyl cross-bridged cyclam ligand exhibited potent antimalarial activity. The Mn2+ complex of this ligand was the most potent with IC50s of 0.127 and 0.157μM against the chloroquine-sensitive (D6) and chloroquine-resistant (W2) P. falciparum strains, respectively. In general, the dibenzyl hydrophobic ligands showed better anti-malarial activity compared to the activity of monobenzyl ligands, potentially because of their higher lipophilicity and thus better cell penetration ability. The higher antimalarial activity displayed by the manganese complex for the cyclam ligand in comparison to that of the cyclen, correlates with the larger pocket of cyclam compared to that of cyclen which produces a more stable complex with the Mn2+. Few of the Cu2+ and Fe2+ complexes also showed improvement in activity but Ni2+, Co2+ and Zn2+ complexes did not show any improvement in activity upon the metal-free ligands for anti-malarial development. Graphical abstract image
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Ultrapure ajulemic acid has improved CB2 selectivity with reduced CB1 activity ()
Publication date: 1 July 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 13 Author(s): Mark A. Tepper , Robert B. Zurier , Sumner H. Burstein Ajulemic acid, a side-chain analog of Δ8-THC-11-oic acid, was designed as a potent therapeutic agent free of the psychotropic adverse effects typical of most cannabinoids. Subsequent studies of ajulemic acid have yielded widely divergent findings on the occurrence of these adverse effects. To help resolve these discrepancies, we have prepared highly purified ajulemic acid using a different synthetic method than previously reported in the literature and compared its cannabinoid receptor binding constants with those obtained using several other preparations from different sources. Whereas CB2 binding did not vary greatly among all of the samples, the CB1 binding showed a wide range of affinities. The highly purified product (JBT-101) reported here had the weakest affinity for CB1 while the original preparation (HU-239) showed the strongest affinity for CB1. The CB1/CB2 ratio of affinities was 12.3 for JBT-101 whereas that for HU-239 was 0.19, a 65-fold difference. Functional responses such as catalepsy and hypothermia using JBT-101 versus HU-239 displayed reduced CB1 activity in keeping with the receptor binding data. Thus, earlier conclusions on the limited therapeutic index for ajulemic acid need to be reconsidered in the light of the data now obtained using JBT-101. Graphical abstract image
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SAR studies on hydropentalene derivatives—Important core units of biologically active tetramic acid macrolactams and ptychanolides ()
Publication date: 1 July 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 13 Author(s): Vanessa Lutz , Fabian Mannchen , Michael Krebs , Natja Park , Claudia Krüger , Aruna Raja , Florenz Sasse , Angelika Baro , Sabine Laschat Structurally diverse bicyclo[3.3.0]octanes were prepared and tested for their biological activity. Both the antiproliferative activity and the results of phenotypic characterization varied with the substitution patterns. Two derivatives displayed high inhibitory (IC50 ⩽3μM) activity against the L-929 cell line, but differed in their mode of action. A cluster analysis with impedance profiling data showed the two compounds in relationship to microtubule interfering compounds. In PtK2 cells treated with both derivatives a perturbing effect on the microtubular network was observed, whereas the actin cytoskeleton in incubated PtK2 cells was disturbed only by one compound. The effects on tubulin and actin polymerization could be confirmed by in vitro polymerization experiments. Graphical abstract image
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New rhenium complexes with ciprofloxacin as useful models for understanding the properties of [99mTc]-ciprofloxacin radiopharmaceutical ()
Publication date: 1 July 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 13 Author(s): Joan Lecina , Pilar Cortés , Montserrat Llagostera , Carlos Piera , Joan Suades Rhenium complexes with the antibiotic ciprofloxacin have been prepared to be studied as models of technetium radiopharmaceuticals. With this aim, the new rhenium complexes 1 {[ReO(Cpf)2]Cl}, 2 {[ReO(CpfH)2]Cl3} and 3 {fac-[Re(CO)3(H2O)(Cpf)]} with ciprofloxacin (CpfH=ciprofloxacin; Cpf=conjugated base of ciprofloxacin) have been synthesised and characterised by elemental analyses, IR, NMR (1H, 19F and 13C CP-MAS) spectroscopy, as well as MS measurements. All spectroscopic data are consistent with the coordination of ciprofloxacin in all these complexes through the carbonyl and the carboxylate oxygen atoms with the formation of a six member chelate ring. The study of a Tc-ciprofloxacin solution by ESI–MS reveals the presence of [TcO(Cpf)2]+ cations, which agrees with the hypothesis that complexes 1 and 2 can be seen as model rhenium complexes of this radiopharmaceutical. Antimicrobial and DNA gyrase inhibition studies performed with complexes 2 and 3 have shown a very similar behaviour between complex 2 and the free antibiotic, whereas complex 3 exhibit a lower antimicrobial activity. Based on a joint analysis of the data reported in the literature and the chemical and biological results obtained in this study, a tentative proposal to explain some aspects of the behaviour of Tc-ciprofloxacin radiopharmaceutical has been made. Graphical abstract image Highlights
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Synthesis and evaluation of 18F-labeled mitiglinide derivatives as positron emission tomography tracers for β-cell imaging ()
Publication date: 1 July 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 13 Author(s): Hiroyuki Kimura , Hirokazu Matsuda , Hiroyuki Fujimoto , Kenji Arimitsu , Kentaro Toyoda , Eri Mukai , Hiroshi Nakamura , Yu Ogawa , Mikako Takagi , Masahiro Ono , Nobuya Inagaki , Hideo Saji Measuring changes in β-cell mass in vivo during progression of diabetes mellitus is important for understanding the pathogenesis, facilitating early diagnosis, and developing novel therapeutics for this disease. However, a non-invasive method has not been developed. A novel series of mitiglinide derivatives (o-FMIT, m-FMIT and p-FMIT; FMITs) were synthesized and their binding affinity for the sulfonylurea receptor 1 (SUR1) of pancreatic islets were evaluated by inhibition studies. (+)-(S)-o-FMIT had the highest affinity of our synthesized FMITs (IC50 =1.8μM). (+)-(S)-o-[18F]FMIT was obtained with radiochemical yield of 18% by radiofluorination of racemic precursor 7, hydrolysis, and optical resolution with chiral HPLC; its radiochemical purity was >99%. In biodistribution experiments using normal mice, (+)-(S)-o-[18F]FMIT showed 1.94±0.42% ID/g of pancreatic uptake at 5min p.i., and decreases in radioactivity in the liver (located close to the pancreas) was relatively rapid. Ex vivo autoradiography experiments using pancreatic sections confirmed accumulation of (+)-(S)-o-[18F]FMIT in pancreatic β-cells. These results suggest that (+)-(S)-o-[18F]FMIT meets the basic requirements for an radiotracer, and could be a candidate positron emission tomography tracer for in vivo imaging of pancreatic β-cells. Graphical abstract image
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Design, synthesis and biological evaluation of hydroxy- or methoxy-substituted 5-benzylidene(thio) barbiturates as novel tyrosinase inhibitors ()
Publication date: 1 July 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 13 Author(s): Zhiyong Chen , Dachuan Cai , Dehai Mou , Qin Yan , Yifeng Sun , Wenlong Pan , Yiqian Wan , Huacan Song , Wei Yi Here a new class of hydroxy- or methoxy-substituted 5-benzylidene(thio)barbiturates were designed, synthesized and their inhibitory effects on the diphenolase activity of mushroom tyrosinase were evaluated. The results showed that several compounds had more potent tyrosinase inhibitory activities than the widely used tyrosinase inhibitor kojic acid (IC50 =18.25μM). In particular, 3′,4′-dihydroxylated 1e was found to be the most potent inhibitor with IC50 value of 1.52μM. The inhibition mechanism analysis revealed that the potential compounds 1e and 2e exhibited such inhibitory effects on tyrosinase by acting as the irreversible inhibitors. Structure–activity relationships’ (SARs) analysis also suggested that further development of such compounds might be of interest. Graphical abstract image
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Identification and characterization of a new reversible MAGL inhibitor ()
Publication date: 1 July 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 13 Author(s): Tiziano Tuccinardi , Carlotta Granchi , Flavio Rizzolio , Isabella Caligiuri , Vittoria Battistello , Giuseppe Toffoli , Filippo Minutolo , Marco Macchia , Adriano Martinelli Monoacylglycerol lipase is a serine hydrolase that play a major role in the degradation of 2-arachidonoylglycerol, an endocannabinoid neurotransmitter implicated in several physiological processes. Recent studies have shown the possible role of MAGL inhibitors as anti-inflammatory, anti-nociceptive and anti-cancer agents. The use of irreversible MAGL inhibitors determined an unwanted chronic MAGL inactivation, which acquires a functional antagonism function of the endocannabinoid system. However, the application of reversible MAGL inhibitors has not yet been explored, mainly due to the scarcity of known compounds possessing efficient reversible inhibitory activities. In this study we reported the first virtual screening analysis for the identification of reversible MAGL inhibitors. Among the screened compounds, the (4-(4-chlorobenzoyl)piperidin-1-yl)(4-methoxyphenyl)methanone (CL6a) is a promising reversible MAGL inhibitor lead (K i =8.6μM), which may be used for the future development of a new class of MAGL inhibitors. Furthermore, the results demonstrate the validity of the methodologies that we followed, encouraging additional screenings of other commercial databases. Graphical abstract image
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Synthesis of triterpenoid triazine derivatives from allobetulone and betulonic acid with biological activities ()
Publication date: 1 July 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 13 Author(s): Thuc Dinh Ngoc , Nico Moons , Youngju Kim , Wim De Borggraeve , Anastassiya Mashentseva , Graciela Andrei , Robert Snoeck , Jan Balzarini , Wim Dehaen The synthetic transformation and modification of natural products with the aim to improve the biological properties is an area of current interest. The triterpenoids betulin and betulinic acid are very abundant in nature and now are commercially available. In our study, starting from betulin and betulinic acid, we obtained allobetulone and betulonic acid in a few synthetic steps. The ketone function at the A-ring was used as the starting point for the synthesis of a series of 1,2,4-triazine-fused triterpenoids. The alkylation and Liebeskind–Srogl coupling were used for further substitution of 1,2,4-triazines, and the intramolecular hetero Diels–Alder reaction leads to interesting fused thienopyridine derivatives. All new compounds were tested for their cytostatic activities against murine leukemia L1210, human cervix carcinoma HeLa and human lymphoblast CEM tumor cells. The results show that some triterpenoid triazine betulonic acid derivatives have a promising cytostatic activity in vitro and could be used as potential leads for the development of new type of anti-cancer agents. Several compounds were also endowed with anti-HCMV activity in the low micromolar range. Graphical abstract image
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Inhibition by active site directed covalent modification of human glyoxalase I ()
Publication date: 1 July 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 13 Author(s): Ronald J. Holewinski , Donald J. Creighton The glyoxalase pathway is responsible for conversion of cytotoxic methylglyoxal (MG) to d-lactate. MG toxicity arises from its ability to form advanced glycation end products (AGEs) on proteins, lipids and DNA. Studies have shown that inhibitors of glyoxalase I (GLO1), the first enzyme of this pathway, have chemotherapeutic effects both in vitro and in vivo, presumably by increasing intracellular MG concentrations leading to apoptosis and cell death. Here, we present the first molecular inhibitor, 4-bromoacetoxy-1-(S-glutathionyl)-acetoxy butane (4BAB), able to covalently bind to the free sulfhydryl group of Cys60 in the hydrophobic binding pocket adjacent to the enzyme active site and partially inactivate the enzyme. Our data suggests that partial inactivation of homodimeric GLO1 is due to the modification at only one of the enzymatic active sites. Although this molecule may have limited use pharmacologically, it may serve as an important template for the development of new GLO1 inhibitors that may combine this strategy with ones already reported for high affinity GLO1 inhibitors, potentially improving potency and specificity. Graphical abstract image
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Synthesis of a novel legumain-cleavable colchicine prodrug with cell-specific toxicity ()
Publication date: 1 July 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 13 Author(s): Robert Løvsletten Smith , Ove Alexander Høgmoen Åstrand , Luan Minh Nguyen , Tina Elvestrand , Gunnar Hagelin , Rigmor Solberg , Harald Thidemann Johansen , Pål Rongved Conventional chemotherapy has undesirable toxic side-effects to healthy tissues due to low cell selectivity of cytotoxic drugs. One approach to increase the specificity of a cytotoxic drug is to make a less toxic prodrug which becomes activated at the tumour site. The cysteine protease legumain have remarkable restricted substrate specificity and is the only known mammalian asparaginyl (Asn) endopeptidase. Over-expression of legumain is reported in cancers and unstable atherosclerotic plaques, and utilizing legumain is a promising approach to activate prodrugs. In this study we have synthesized the legumain-cleavable peptide sequence N-Boc-Ala-Ala-Asn-Val-OH. The peptide was subsequently conjugated to deacetyl colchicine during three steps to produce Suc-Ala-Ala-Asn-Val-colchicine (prodrug) with >90% chemical purity. Several cell lines with different expressions and activities of legumain were used to evaluate the general toxicity, specificity and efficacy of the microtubule inhibitor colchicine, valyl colchicine and the legumain-cleavable colchicine prodrug. The prodrug was more toxic to the colorectal cancer HCT116 cells (expressing both the 36kDa active and 56kDa proform of legumain) than SW620 cells (only expressing the 56kDa prolegumain) indicating a relationship between toxicity of the prodrug and activity of legumain in the cells. Also, in monoclonal legumain over-expressing HEK293 cells the prodrug toxicity was higher compared to native HEK293 cells. Furthermore, co-administration of the prodrug either with the potent legumain inhibitor cystatin E/M or the endocytosis inhibitor Dyngo-4a inhibited cell death, indicating that the prodrug toxicity was dependent on both asparaginyl endopeptidase activity and endocytosis. This colchicine prodrug adds to a legumain-activated prodrug strategy approach and could possibly be of use both in targeted anticancer and anti-inflammatory therapy. Graphical abstract image
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