Bioorganic & Medicinal Chemistry

Tubulin-binding dibenz[c,e]oxepines: Part 2.1 Structural variation and biological evaluation as tumour vasculature disrupting agents ()
Publication date: Available online 19 January 2017 Source:Bioorganic & Medicinal Chemistry Author(s): Steven B. Rossington, John A. Hadfield, Steven D. Shnyder, Timothy W. Wallace, Kaye J. Williams 5,7-Dihydro-3,9,10,11-tetramethoxybenz[c,e]oxepin-4-ol 1, prepared from a dibenzyl ether precursor via Pd-catalysed intramolecular direct arylation, possesses broad-spectrum in vitro cytotoxicity towards various tumour cell lines, and induces vascular shutdown, necrosis and growth delay in tumour xenografts in mice at sub-toxic doses. The biological properties of 1 and related compounds can be attributed to their ability to inhibit microtubule assembly at the micromolar level, by binding reversibly to the same site of the tubulin αβ-heterodimer as colchicine 2 and the allocolchinol, N-acetylcolchinol 4. Graphical abstract image
>> read more

A Strategy for Dual Inhibition of the Proteasome and Fatty Acid Synthase with Belactosin C-Orlistat Hybrids ()
Publication date: Available online 19 January 2017 Source:Bioorganic & Medicinal Chemistry Author(s): Mingzhao Zhu, Wayne D. Harshbarger, Omar Robles, Joanna Krysiak, Kenneth G. Hull, Sung Wook Cho, Robyn D. Richardson, Yanyan Yang, Andres Garcia, Lindsey Spiegelman, Bianca Ramirez, Christopher T. Wilson, Ju Anne Yau, James T. Moore, Caitlen B. Walker, James C. Sacchettini, Wenshe Liu, Stephan A. Sieber, Jeffrey W. Smith, Daniel Romo The proteasome, a validated cellular target for cancer, is central for maintaining cellular homeostasis, while fatty acid synthase (FAS), a novel target for numerous cancers, is responsible for palmitic acid biosynthesis. Perturbation of either enzymatic machine results in decreased proliferation and ultimately cellular apoptosis. Based on structural similarities, we hypothesized that hybrid molecules of belactosin C, a known proteasome inhibitor, and orlistat, a known inhibitor of the thioesterase domain of FAS, could inhibit both enzymes. Herein, we describe proof-of-principle studies leading to the design, synthesis and enzymatic activity of several novel, β-lactone-based, dual inhibitors of these two enzymes. Validation of dual enzyme targeting through activity-based proteome profiling with an alkyne probe modeled after the most potent inhibitor, and preliminary serum stability studies of selected derivatives are also described. These results provide proof of concept for dual targeting of the proteasome and FAS-TE enabling a new approach for the development of drug-candidates with potential to overcome resistance. Graphical abstract image
>> read more

Lynamicin D an Antimicrobial Natural Product Affects Splicing by Inducing the Expression of SR Protein Kinase 1 ()
Publication date: Available online 19 January 2017 Source:Bioorganic & Medicinal Chemistry Author(s): Ioanna Sigala, George Ganidis, Savvas Thysiadis, Alexandros L. Zografos, Thomas Giannakouros, Vasiliki Sarli, Eleni Nikolakaki The first total synthesis of the antimicrobial natural product lynamicin D has been developed using a Suzuki coupling to construct the bisindole pyrrole skeleton. An evaluation of the biological activity of lynamicin D reveals that it has a minor effect on cell viability but it can modulate splicing of pre-mRNAs. We provide evidence that this effect is mainly due to the ability of lynamicin D to alter the levels of SRPK1, the key kinase involved in both constitutive and alternative splicing. Graphical abstract image
>> read more

Design, synthesis, molecular modeling and anti-hyperglycemic evaluation of novel quinoxaline derivatives as potential PPARγ and SURs agonists ()
Publication date: Available online 16 January 2017 Source:Bioorganic & Medicinal Chemistry Author(s): Mohamed.K. Ibrahim, Ibrahim H. Eissa, AbdallahE. Abdallah, Ahmed M. Metwaly, M.M. and M.A. Radwan ElSohly In our effort to develop potent anti-hyperglycemic agents with potential agonistic activities toward PPARγ and SURs, three novel series of quinoxaline derivatives bearing sulfonylurea or sulfonylthiourea moieties with different linkers were designed and synthesized. Some of the newly synthesized compounds were evaluated in vivo for their anti-hyperglycemic activities in STZ-induced hyperglycemic rats. Compounds 15a , 15e, 19b and 24a exhibited the highest anti-hyperglycemic activities with% reduction in blood glucose level of (50.58, 43.84, 45.10 and 49.62, respectively). Additionally, eight compounds revealed potent anti-hyperglycemic activities were further evaluated in vitro for their PPARγ binding affinity and insulin-secreting ability as potential mechanisms for anti-hyperglycemic activity. Four compounds (15a , 15b , 15d and 15e ) significantly bound to PPARγ with IC50 values of 0.482, 0.491, 0.350 and 0.369 μM, respectively. Moreover, Compounds 15a and 15b have demonstrated induction of insulin-secretion with EC50 values of 0.92 and 0.98 μM, respectively. Furthermore, molecular docking and pharmacophore generation techniques were carried out to investigate binding patterns and fit values of the designed compounds with PPARγ and SUR, respectively. Graphical abstract image
>> read more

Identification of allosteric binding sites for PI3Kα oncogenic mutant specific inhibitor design ()
Publication date: Available online 16 January 2017 Source:Bioorganic & Medicinal Chemistry Author(s): Michelle S. Miller, Sweta Maheshwari, Fiona M. McRobb, Kenneth W. Kinzler, L. Mario Amzel, Bert Vogelstein, Sandra B. Gabelli PIK3CA, the gene that encodes the catalytic subunit of phosphatidylinositol 3-kinase α (PI3Kα), is frequently mutated in breast and other types of cancer. A specific inhibitor that targets the mutant forms of PI3Kα could maximize treatment efficiency while minimizing side-effects. Herein we describe the identification of novel binding pockets that may provide an opportunity for the design of mutant selective inhibitors. Using a fragment-based approach, we screened a library of 352 fragments (MW <300 Da) for binding to PI3Kα by X-ray crystallography. Five novel binding pockets were identified, each providing potential opportunities for inhibitor design. Of particular interest was a binding pocket near Glu542, which is located in one of the two most frequently mutated domains. Graphical abstract image
>> read more

Identification of Novel Inverse Agonists of Estrogen-Related Receptors ERRγ and ERRβ ()
Publication date: Available online 16 January 2017 Source:Bioorganic & Medicinal Chemistry Author(s): Donna D. Yu, Janice M. Huss, Hongzhi Li, Barry M. Forman Estrogen-related receptors (ERRs, α, β, and γ) are orphan nuclear receptors most closely related in sequence to estrogen receptors (ERα and ERβ). Much attention has been paid recently to the functions of ERRs for their potential roles as new therapeutic targets implicated in the etiology of metabolic disorders. While no endogenous ligand has been identified for any of the ERR isoforms to date, the potential for using synthetic small molecules to modulate their activity has been demonstrated. In the present study, a series of novel inverse agonists of ERRγ and ERRβ were synthesized using regio- and stereo-specific direct substitution of triarylethylenes. These compounds were evaluated for their ability to modulate the activities of ERRs. The rational directed substitution approach and extensive SAR studies resulted in the discovery of compound 4a (DY40) as the most potent ERRγ inverse agonist described to date with mixed ERRγ/ERRβ functional activities, which potently suppressed the transcriptional functions of ERRγ with IC50 = 0.01 μM in a cell-based reporter gene assay and antagonized ERRγ with a potency approximately 60 times greater than its analog Z-4-OHT (Z-4-hydroxytamoxifen). In addition, compound 3h (DY181) was identified as the most potent synthetic inverse agonist for the ERRβ that exhibited excellent selectivity over ERRα/γ in functional assays. This selectivity was also supported by computational docking models that suggest DY181 forms more extensive hydrogen bound network with ERRβ which should result in higher binding affinity on ERRβ over ERRγ. Graphical abstract image
>> read more

Synthesis of new spirooxindole-pyrrolothiazoles derivatives: Anti-cancer activity and molecular docking ()
Publication date: Available online 16 January 2017 Source:Bioorganic & Medicinal Chemistry Author(s): Gehad Lotfy, Mohamed M. Said, El Sayed H. El Ashry, El Sayed H. El Tamany, Abdullah Al-Dhfyan, Yasmine M. Abdel Aziz, Assem Barakat The 1,3-dipolar cycloadditions of an azomethine ylide generated from isatin and thiazolidinecarboxylic acid to a series of 2,6-bis[(E)-arylmethylidene]cyclohexanones afforded new di-spiro heterocycles incorporating pyrrolidine and oxindole rings in quantitative yields and chemo-, regio-, and stereoselectively. The newly synthesized compounds were characterized using spectroscopic techniques. Furthermore, the molecular structures of 4a, 4e, and 4n were confirmed by X-ray crystallography. These newly synthesized compounds were screened for their in vitro activity against breast cancer cell line MCF-7 and K562-leukemia. 4k was found to be the most potent compound of this series in targeting MCF-7 breast cancer cells and K562-leukemia, with IC50 values of 15.32 ± 0.02 and 14.74 ± 0.7 μM, respectively. The molecular studies of the synthesized compounds were investigated. Graphical abstract image
>> read more

Chiral resolution of serial potent and selective σ1 ligands and biological evaluation of (-)-[18F]TZ3108 in rodent and the nonhuman primate brain ()
Publication date: Available online 16 January 2017 Source:Bioorganic & Medicinal Chemistry Author(s): Xuyi Yue, Hongjun Jin, Zonghua Luo, Hui Liu, Xiang Zhang, Ethan D. McSpadden, Linlin Tian, Hubert P. Flores, Joel S. Perlmutter, Stanley M. Parsons, Zhude Tu Twelve optically pure enantiomers were obtained using either crystallization or chiral high performance liquid chromatography (HPLC) separation methodologies to resolve six racemic sigma-1 (σ 1) receptor ligands. The in vitro binding affinities of each enantiomer for σ 1, σ 2 receptors and vesicular acetylcholine transporter (VAChT) were determined. Out of the 12 optically pure enantiomers, five displayed very high affinities for σ 1 (K i < 2 nM) and high selectivity for σ 1 versus σ 2 and VAChT (>100-fold). The minus enantiomer, (-)-14a ((-)-TZ3108)) (Ki- σ 1 = 1.8 ± 0.4 nM, Ki- σ 2 = 6960 ± 810 nM, Ki-VAChT = 980 ± 87 nM), was chosen for radiolabeling and further in vivo evaluation in rodents and nonhuman primates (NHPs). A biodistribution study in Sprague Dawley rats showed brain uptake (%ID/gram) of (-)-[18F]TZ3108 reached 1.285 ± 0.062 at 5 min and 0.802 ± 0.129 at 120 min. NHP microPET imaging studies revealed higher brain uptake of (-)-[18F]TZ3108 and more favorable pharmacokinetics compared to its racemic counterpart. Pretreatment of the animal using two structurally different σ 1 ligands significantly decreased accumulation of (-)-[18F]TZ3108 in the brain. Together, our in vivo evaluation results suggest that (-)-[18F]TZ3108 is a promising positron emission tomography (PET) tracer for quantifying σ 1 receptor in the brain. Graphical abstract image
>> read more

Editorial board ()
Publication date: 15 January 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2
>> read more

Design, synthesis and biological evaluation of alkylamino biphenylamides as Hsp90 C-terminal inhibitors ()
Publication date: 15 January 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2 Author(s): Gaurav Garg, Huiping Zhao, Brian S.J. Blagg Hsp90 is a promising therapeutic target for the development of anti-cancer agents due to its integral role in the stability and function of proteins associated with all ten hallmarks of cancer. Novobiocin, a coumarin antibiotic, was the first natural product identified that targeted the Hsp90 C-terminal domain and manifested anti-proliferative activity (SKBr3 IC50 ∼700μM). Subsequent structural investigations on novobiocin led to analogues with significantly improved anti-proliferative activity against multiple cancer cell lines. In an effort to develop more efficacious and diverse analogues, it was recently found that the coumarin ring of novobiocin could be replaced with the biphenyl core without compromising activity. Based on these prior studies, a series of alkylamino biphenylamides was designed, synthesized and evaluated for anti-proliferative activity against two breast cancer cell lines. SAR studies demonstrated that the incorporation of an alkylamino side chain onto the biphenyl core improved anti-proliferative activity and resulted in compounds that exhibit sub-micromolar to mid-nanomolar activity through Hsp90 inhibition. Importantly, these studies indicate the presence of a hydrophilic region about the central core that can be exploited for the design of new inhibitors. Graphical abstract image
>> read more

Design, synthesis and antithrombotic evaluation of novel non-peptide thrombin inhibitors ()
Publication date: 15 January 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2 Author(s): Dongxing Chen, Jinyu Shi, Jing Liu, Xueying Zhang, Xiaoying Deng, Yanyan Yang, Shuang Cui, Qihua Zhu, Guoqing Gong, Yungen Xu Ten derivatives of 4-((1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazin-1-yl)methyl)benzimida-mide (I-1∼I-2, II-1∼II-8) were designed, synthesized and evaluated for their inhibitory effect on human thrombin. Compound II-7 (IC50 =82.8nM), which showed the strongest thrombin inhibitory activity among the tested compounds, was chosen as the lead compound, and ten carbamate derivatives (II-9a∼II-13a, II-9b∼II-12b, II-14) were prepared and evaluated for their anticoagulant activity. The results indicate that most of the tested compounds exhibit a certain degree of inhibitory effect on thrombin-induced platelet aggregation, among which compounds II-11a (IC50 =8.16μM) and II-14 (IC50 =1.95μM) show better anti-platelet aggregation activity than the others. The in vivo experimental results in rat venous thrombosis model also demonstrate compounds II-11a and II-14 can significantly reduce thrombosis in a dose-response manner. It is worth pointing out that the enhanced potency of compound II-14 may be the synergetic effect of 2-hydroxymethyl-3,5,6-trimethylpyrazine (HTMP) and II-7 which are generated by hydrolysis in vivo. Graphical abstract image
>> read more

Structure-anticonvulsant activity studies in the group of (E)-N-cinnamoyl aminoalkanols derivatives monosubstituted in phenyl ring with 4-Cl, 4-CH3 or 2-CH3 ()
Publication date: 15 January 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2 Author(s): Agnieszka Gunia-Krzyżak, Dorota Żelaszczyk, Anna Rapacz, Ewa Żesławska, Anna M. Waszkielewicz, Katarzyna Pańczyk, Karolina Słoczyńska, Elżbieta Pękala, Wojciech Nitek, Barbara Filipek, Henryk Marona A series of twenty two (E)-N-cinnamoyl aminoalkanols derivatives monosubstituted in phenyl ring with 4-Cl, 4-CH3 or 2-CH3 was designed, synthesized and evaluated for anticonvulsant activity in rodent models of seizures: maximal electroshock (MES) test, subcutaneous pentylenetetrazole (scPTZ) test, and 6-Hz test. There were identified three most active compounds: S-(2E)-N-(1-hydroxypropan-2-yl)-3-(2-methylphenyl)prop-2-enamide (5) (ED50 MES=42.56, ED50 scPTZ=58.38, ED50 6-Hz 44mA=42.27mg/kg tested in mice after intraperitoneal (i.p.) administration); R,S-(2E)-3-(4-chlorophenyl)-N-(1-hydroxybutan-2-yl)prop-2-enamide (6) (ED50 MES=53.76, ED50 scPTZ=90.31, ED50 6-Hz 44mA=92.86mg/kg mice, i.p.); and R,S-(2E)-3-(4-chlorophenyl)-N-(2-hydroxypropyl)prop-2-enamide (11) (ED50 MES=55.58, ED50 scPTZ=102.15, ED50 6-Hz 44mA=51.27mg/kg mice, i.p.). Their structures and configurations were confirmed by crystal X-ray diffraction method. The structure-activity studies among the tested series showed that chlorine atom in position para or methyl group in position ortho of phenyl ring were beneficial for anticonvulsant activity. Methyl group in position para of phenyl ring decreased anticonvulsant activity in reported series of cinnamamide derivatives. Graphical abstract image
>> read more

Computer design, synthesis, and bioactivity analyses of drugs like fingolimod used in the treatment of multiple sclerosis ()
Publication date: 15 January 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2 Author(s): Gurbet Çelik Turgut, Doğukan Doyduk, Yılmaz Yıldırır, Serkan Yavuz, Atilla Akdemir, Ali Dişli, Alaattin Şen Multiple sclerosis (MS) is a very common disease of vital importance. In the MS treatment, some drugs such as fingolimod which help to protect nerves from damage are used. The main goal of the drug therapy in MS is to take control of the inflammation which leads to the destruction of myelin and axons in nerve cell and thus prevent and stop the progression of the disease. Fingolimod (FTY720) is an orally active immunomodulatory drug that has been used for the treatment of relapsing-remitting multiple sclerosis. It is a sphingosine-1-phosphate receptor modulator which prevents lymphocytes from contributing to an autoimmune reaction by inhibiting egress of lymphocytes them from lymph nodes. In this study, we have computer designed, synthesized and characterized two novel derivatives of FTY720, F1-12h and F2-9, and have determined their underlying mechanism of their beneficial effect in SH-SY5Y, SK-N-SH, and U-118 MG cell lines. For this purpose, we first determined the regulation of the cAMP response element (CRE) activity and cAMP concentration by F1-12h and F2-9 together with FTY720 using pGL4.29 luciferase reporter assay and cAMP immunoassay, respectively. Then, we have determined their effect on MS- and GPCR-related gene expression profiles using custom arrays along with FTY720 treatment at non-toxic doses (EC10). It was found that both derivatives significantly activate CRE and increase cAMP concentration in all three cell lines, indicating that they activate cAMP pathway through cell surface receptors as FTY720 does. Furthermore, F1-12h and F2-9 modulate the expression of the pathway related genes that are important in inflammatory signaling, cAMP signaling pathway, cell migration as well as diverse receptor and transcription factors. Expression of the genes involved in myelination was also increased by the treatment with F1-12h and F2-9. In summary, our data demonstrate that the two novel FTY720 derivatives act as anti-inflammatory ultimately by influencing the gene expression via the cAMP and downstream transcription factor CRE pathway. In conclusion, F1-12h and F2-9 might contribute future therapies for autoimmune diseases such as multiple sclerosis. Graphical abstract image
>> read more

Triazolopyridine ethers as potent, orally active mGlu2 positive allosteric modulators for treating schizophrenia ()
Publication date: 15 January 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2 Author(s): Mendi A. Higgins, Lawrence R. Marcin, F. Christopher Zusi, Robert Gentles, Min Ding, Bradley C. Pearce, Amy Easton, Walter A. Kostich, Matthew A. Seager, Clotilde Bourin, Linda J. Bristow, Kim A. Johnson, Regina Miller, John Hogan, Valerie Whiterock, Michael Gulianello, Meredith Ferrante, Yanling Huang, Adam Hendricson, Andrew Alt, John E. Macor, Joanne J. Bronson Triazolopyridine ethers with mGlu2 positive allosteric modulator (PAM) activity are disclosed. The synthesis, in vitro activity, and metabolic stability data for a series of analogs is provided. The effort resulted in the discovery of a potent, selective, and brain penetrant lead molecule BMT-133218 ((+)-7m). After oral administration at 10mg/kg, BMT-133218 demonstrated full reversal of PCP-stimulated locomotor activity and prevented MK-801-induced working memory deficits in separate mouse models. Also, reversal of impairments in executive function were observed in rat set-shifting studies at 3 and 10mg/kg (p.o.). Extensive plasma protein binding as the result of high lipophilicity likely limited activity at lower doses. Optimized triazolopyridine ethers offer utility as mGlu2 PAMs for the treatment of schizophrenia and merit further preclinical investigation. Graphical abstract image
>> read more

Anti-inflammatory tetraquinane diterpenoids from a Crinipellis species ()
Publication date: 15 January 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2 Author(s): Markus Rohr, Katharina Oleinikov, Mathias Jung, Louis P. Sandjo, Till Opatz, Gerhard Erkel The small pro-inflammatory 10kDa chemokine CXCL10 (Interferon-inducible protein 10, IP-10) plays an important role in mediating immune responses through the activation and recruitment of leukocytes such as T cells, eosinophils, monocytes and NK cells to the sites of inflammation. Elevated levels of CXCL10 have been associated with chronic inflammatory and infectious diseases and therefore CXCL10 represents an attractive target for the development of new anti-inflammatory drugs. In a search for anti-inflammatory compounds from fungi inhibiting the inducible CXCL10 promoter activity, four new tetraquinane diterpenoids, crinipellin E (1), crinipellin F (2), crinipellin G (3) and crinipellin H (4) were isolated from fermentations of a Crinipellis species. The structures of the compounds were elucidated by a combination of one- and two-dimensional NMR spectroscopy and mass spectrometry. Compounds 1, 2, and 3 inhibited the LPS/IFN-γ induced CXCL10 promoter activity in transiently transfected human MonoMac6 cells in a dose-dependent manner with IC50 values of 15μM, 1.5μM, and 3.15μM respectively, whereas compound 4 was devoid of any biological activity. Moreover, compounds 1, 2 and 3 reduced mRNA levels and synthesis of pro-inflammatory mediators such as cytokines and chemokines in LPS/IFN-γ stimulated MonoMac6 cells. Graphical abstract image
>> read more

Synthesis and binding monitoring of a new nanomolar PAMAM-based matrix metalloproteinases inhibitor (MMPIs) ()
Publication date: 15 January 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2 Author(s): Linda Cerofolini, Veronica Baldoneschi, Elisa Dragoni, Andrea Storai, Marianna Mamusa, Debora Berti, Marco Fragai, Barbara Richichi, Cristina Nativi Dendrimers are efficient drug delivery systems particularly useful in ocular diseases. In particular, low generation PAMAM dendrimers are non-toxic and non-immunogenic and they provide an enhancement of the residence time of drugs in the eyes. In this context, the synthesis of the PAMAM-based matrix metalloproteinases inhibitor 5, is reported. In particular, we demonstrated that 5 strongly binds (18.0nM±2.5nM) MMP-9, the most relevant MMP responsible of ocular surface damages in induced dry eyes syndrome (DES). Graphical abstract image
>> read more

Cyclic citrullinated MBP87–99 peptide stimulates T cell responses: Implications in triggering disease ()
Publication date: 15 January 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2 Author(s): Vasso Apostolopoulos, George Deraos, Minos-Timotheos Matsoukas, Stephanie Day, Lily Stojanovska, Theodore Tselios, Maria-Eleni Androutsou, John Matsoukas Amino acid mutations to agonist peptide epitopes of myelin proteins have been used to modulate immune responses and experimental autoimmune encephalomyelitis (EAE, animal model of multiple sclerosis). Such amino acid alteration are termed, altered peptide ligands (APL). We have shown that the agonist myelin basic protein (MBP) 87–99 epitope (MBP87–99) with crucial T cell receptor (TCR) substitutions at positions 91 and 96 (K91,P96 (TCR contact residues) to R91,A96; [R91,A96]MBP87–99) results in altered T cell responses and inhibits EAE symptoms. In this study, the role of citrullination of arginines in [R91,A96]MBP87–99 peptide analog was determined using in vivo experiments in combination with computational studies. The immunogenicity of linear [Cit91,A96,Cit97]MBP87–99 and its cyclic analog – cyclo(87–99)[Cit91,A96,Cit97]MBP87–99 when conjugated to the carrier mannan (polysaccharide) were studied in SJL/J mice. It was found that mannosylated cyclo(87–99)[Cit91,A96,Cit97]MBP87–99 peptide induced strong T cell proliferative responses and IFN-gamma cytokine secretion compared with the linear one. Moreover, the interaction of linear and cyclic peptide analogs with the major histocompatibility complex (MHC II, H2-IAs) and TCR was analyzed using molecular dynamics simulations at the receptor level, in order to gain a better understanding of the molecular recognition mechanisms that underly the different immunological profiles of citrullinated peptides compared to its agonist native counterpart MBP87–99 epitope. The results demonstrate that the citrullination of arginine in combination with the backbone conformation of mutated linear and cyclic analogs are significant elements for the immune response triggering the induction of pro-inflammatory cytokines. Graphical abstract image
>> read more

Discovery of 4-sulfamoyl-phenyl-β-lactams as a new class of potent carbonic anhydrase isoforms I, II, IV and VII inhibitors: The first example of subnanomolar CA IV inhibitors ()
Publication date: 15 January 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2 Author(s): Srinivas Angapelly, P.V. Sri Ramya, Andrea Angeli, Simona Maria Monti, Martina Buonanno, Mallika Alvala, Cladiu T. Supuran, Mohammed Arifuddin A series of benzenesulfonamides incorporating 1,3,4-trisubstituted-β-lactam moieties was prepared from sulfanilamide Schiff bases and in situ obtained ketenes, by using the Staudinger cycloaddition reaction. The new compounds were assayed as inhibitors of four human isoforms of the metalloenzyme carbonic anhydrase (hCA, EC 4.2.1.1) involved in various physiological/pathological conditions, hCA I, II, IV and VII. Excellent inhibitory activity was observed against all these isoforms, as follows: hCA I, involved in some eye diseases was inhibited with KIs in the range of 7.3–917nM; hCA II, an antiglaucoma drug target, with KIs in the range of 0.76–163nM. hCA IV, an isoform involved in several pathological conditions such as glaucoma, retinitis pigmentosa and edema was potently inhibited by the lactam-sulfonamides, with KIs in the range of 0.53–51.0nM, whereas hCA VII, a recently validated anti-neuropathic pain target was the most inhibited isoform by these derivatives, with KIs in the range of 0.68–9.1nM. The structure-activity relationship for inhibiting these CAs with the new lactam-sulfonamides is discussed in detail. Graphical abstract image
>> read more

Discovery and preclinical evaluation of 7-benzyl-N-(substituted)-pyrrolo[3,2-d]pyrimidin-4-amines as single agents with microtubule targeting effects along with triple-acting angiokinase inhibition as antitumor agents ()
Publication date: 15 January 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2 Author(s): Roheeth Kumar Pavana, Shruti Choudhary, Anja Bastian, Michael A. Ihnat, Ruoli Bai, Ernest Hamel, Aleem Gangjee The utility of cytostatic antiangiogenic agents (AA) in cancer chemotherapy lies in their combination with cytotoxic chemotherapeutic agents. Clinical combinations of AA with microtubule targeting agents (MTAs) have been particularly successful. The discovery, synthesis and biological evaluations of a series of 7-benzyl-N-substituted-pyrrolo[3,2-d]pyrimidin-4-amines are reported. Novel compounds which inhibit proangiogenic receptor tyrosine kinases (RTKs) including vascular endothelial growth factor receptor-2 (VEGFR-2), platelet-derived growth factor receptor-β (PDGFR-β) and epidermal growth factor receptor (EGFR), along with microtubule targeting in single molecules are described. These compounds also inhibited blood vessel formation in the chicken chorioallantoic membrane (CAM) assay, and some potently inhibited tubulin assembly (with activity comparable to that of combretastatin A-4 (CA)). In addition, some of the analogs circumvent the most clinically relevant tumor resistance mechanisms (P-glycoprotein and β-III tubulin expression) to microtubule targeting agents (MTA). These MTAs bind at the colchicine site on tubulin. Two analogs displayed two to three digit nanomolar GI50 values across the entire NCI 60 tumor cell panel and one of these, compound 7, freely water soluble as its HCl salt, afforded excellent in vivo antitumor activity against an orthotopic triple negative 4T1 breast cancer model and was superior to doxorubicin. Graphical abstract image
>> read more

Biotransformation of rutabaga phytoalexins by the fungus Alternaria brassicicola: Unveiling the first hybrid metabolite derived from a phytoalexin and a fungal polyketide ()
Publication date: 15 January 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2 Author(s): M. Soledade C. Pedras, Abbas Abdoli The biotransformations of the rutabaga phytoalexins rutalexin, brassicanate A, isalexin and rapalexin A by the plant pathogenic fungus Alternaria brassicicola are reported. While the biotransformations of rutalexin, brassicanate A, and isalexin are fast, rapalexin A is resistant to fungal transformation. Unexpectedly, biotransformation of rutalexin yields a hybrid metabolite named rutapyrone, derived from rutalexin metabolism and phomapyrone G, a fungal metabolite produced by A. brassicicola. These fungal transformations are detoxification reactions likely carried out by different enzymes. The discovery of rapalexin A resistance to detoxification suggests that this phytoalexin in combination with additional phytoalexins could protect crucifers against this pathogen. Phytoalexins resistant to degradation by A. brassicicola are expected to provide the producing plants with higher disease resistance levels. Graphical abstract image
>> read more

SRC2-3 binds to vitamin D receptor with high sensitivity and strong affinity ()
Publication date: 15 January 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2 Author(s): Daichi Egawa, Toshimasa Itoh, Akira Kato, Saori Kataoka, Yasuaki Anami, Keiko Yamamoto Vitamin D receptor (VDR) is a member of the nuclear receptor superfamily and regulates the expression of target genes through ligand binding. To express the target gene, coactivator binding to the VDR/ligand complex is essential. Although there are many coactivators in living cells, precise interactions between coactivators and VDR have not been clarified. Here, we synthesized two coactivator peptides, DRIP205-2 and SRC2-3, evaluated their affinity for the ligand-binding domain (LBD) of VDR using 1α,25-dihydroxyvitamin D3, partial agonist 1, and antagonist 2 by surface plasmon resonance (SPR), and assessed their interaction modes with VDR-LBD using X-ray crystallographic analysis. This study showed that the SRC2-3 peptide is more sensitive to the ligands (agonist, partial agonist, and antagonist) and shows more intimate interactions with VDR-LBD than DRIP205-2 peptide. Graphical abstract image
>> read more

Anion inhibition profiles of the γ-carbonic anhydrase from the pathogenic bacterium Burkholderia pseudomallei responsible of melioidosis and highly drug resistant to common antibiotics ()
Publication date: 15 January 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2 Author(s): Sonia Del Prete, Daniela Vullo, Pietro Di Fonzo, Sameh M. Osman, Zeid AlOthman, Claudiu T. Supuran, Clemente Capasso Burkholderia pseudomallei is a Gram-negative saprophytic bacterium responsible of melioidosis, an endemic disease of tropical and sub-tropical regions of the world. A recombinant γ-CA (BpsγCA) identified in the genome of this bacterium was cloned and purified. Its catalytic activity and anion inhibition profiles were investigated. The enzyme was an efficient catalyst for the CO2 hydration showing a kcat of 5.3×105 s−1 and kcat/Km of 2.5×107 M−1 ×s−1. The best BpsγCA inhibitors were sulfamide, sulfamic acid, phenylboronic acid and phenylarsonic acid, which showed KI in the range of 49–83μM (these inhibitors showed millimolar inhibition constant against hCA II), followed by diethyldithiocarbamate, selenate, tellurate, perrhenate, selenocyanate, trithiocarbonate, tetraborato, pyrophosphate, stannate, carbonate, bicarbonate, azide, cyanide, thiocyanate and cyanate with KIs in the range of 0.55–9.1mM. In our laboratories, work is in progress to resolve the X-ray crystal structures of BpsγCA, which may allow the development of small molecule inhibitors with desired properties for targeting and inhibiting specifically the bacterial over the human CAs, considering the fact that B. pseudomallei is involved in a serious bacterial disease. Graphical abstract image
>> read more

A novel curcumin derivative which inhibits P-glycoprotein, arrests cell cycle and induces apoptosis in multidrug resistance cells ()
Publication date: 15 January 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2 Author(s): Vanessa Lopes-Rodrigues, Ana Oliveira, Marta Correia-da-Silva, Madalena Pinto, Raquel T. Lima, Emília Sousa, M. Helena Vasconcelos Cancer multidrug resistance (MDR) is a major limitation to the success of cancer treatment and is highly associated with the overexpression of drug efflux pumps such as P-glycoprotein (P-gp). In order to achieve more effective chemotherapeutic treatments, it is important to develop P-gp inhibitors to block/decrease its activity. Curcumin (1) is a secondary metabolite isolated from the turmeric of Curcuma longa L.. Diverse biological activities have been identified for this compound, particularly, MDR modulation in various cancer cell models. However, curcumin (1) has low chemical stability, which severely limits its application. In order to improve stability and P-gp inhibitory effect, two potential more stable curcumin derivatives were synthesized as building blocks, followed by several curcumin derivatives. These compounds were then analyzed in terms of antitumor and anti-P-gp activity, in two MDR and sensitive tumor lines (from chronic myeloid leukemia and non-small cell lung cancer). We identified from a series of curcumin derivatives a novel curcumin derivative (1,7-bis(3-methoxy-4-(prop-2-yn-1-yloxy)phenyl)hepta-1,6-diene-3,5-dione, 10) with more potent antitumor and anti-P-gp activity than curcumin (1). This compound (10) was shown to promote cell cycle arrest (at the G2/M phase) and induce apoptosis in the MDR chronic myeloid leukemia cell line. Therefore it is a really interesting P-gp inhibitor due to its ability to inhibit both P-gp function and expression. Graphical abstract image
>> read more

Structure-activity relationship study of a small cyclic peptide H-c[Lys-Pro-Glu]-Arg-OH: a potent inhibitor of Vascular Endothelial Growth Factor interaction with Neuropilin-1 ()
Publication date: 15 January 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2 Author(s): Karolina Grabowska, Anna K. Puszko, Piotr F.J. Lipiński, Anna K. Laskowska, Beata Wileńska, Ewa Witkowska, Gerard Y. Perret, Aleksandra Misicka Inhibition of angiogenesis is one of the most promising approaches in anticancer therapy. It was recently suggested that Neuropilin-1 (NRP-1) in tumour cells may serve as a separate receptor for Vascular Endothelial Growth Factor-165 (VEGF165) which is one of the main pro-angiogenic agents in the organism. Therefore molecules inhibiting VEGF165 binding to NRP-1 could be potential candidates for new antiangiogenic and anticancer drugs. Here we present a structure-activity relationship study of the peptide H-c[Lys-Pro-Glu]-Arg-OH which showed high inhibitory effect on VEGF165/NRP-1 binding (IC50 =0.18μM) in our previous study. We report the design, synthesis, in vitro assays and docking analysis of four small cyclic peptides (14-,15-membered ring) and one bigger cyclic compound (30-membered ring). Our study shows that both the ring size and configuration of amino acid residues present in the structure are crucial for high inhibitory effect. Graphical abstract image
>> read more

Synthesis of a biological active β-hairpin peptide by addition of two structural motifs ()
Publication date: 15 January 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2 Author(s): Sabrina Fischer, Matthias Lamping, Maike Gold, Yvonne Röttger, Dörte Brödje, Richard Dodel, Renate Frantz, Mobarak Abu Mraheil, Trinad Chakraborty, Armin Geyer The idea of privileged scaffolds – that there seem to be more bioactive compounds found around some structures than others – is well established for small drug molecules, but has little significance for standalone peptide secondary structures whose adaptable shapes escape the definition of a 3D motif in the absence of a protein scaffold. Here, we joined two independent biological functions in a single highly restricted peptide to support the hypothesis that the β-hairpin shape is the common basis of two otherwise unrelated biological recognition processes. To achieve this, the hydrophobic cluster HWX4LV from the decapeptide cyclic hairpin model peptide C1-C10 cyclo-CHWEGNKLVC was included in the bicyclic peptide 2. The designed β-hairpin peptide C4-C17, C8-C13 bicyclo-KHQCHWECTZGRCRLVCGRSGS (2, Z=citrulline), serves, on the one hand, as a specific epitope for rheumatoid autoantibodies and, on the other hand, shows a not negligible antibiotic effect against the bacterial strain E. coli AS19. Graphical abstract image
>> read more

Synthesis, evaluation and molecular modelling studies of 2-(carbazol-3-yl)-2-oxoacetamide analogues as a new class of potential pancreatic lipase inhibitors ()
Publication date: 15 January 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2 Author(s): S.N.C. Sridhar, George Ginson, P.O. Venkataramana Reddy, Mukund P. Tantak, Dalip Kumar, Atish T. Paul A series of twenty four 2-(carbazol-3-yl)-2-oxoacetamide analogues were synthesized, characterized and evaluated for their pancreatic lipase (PL) inhibitory activity. Porcine PL was used against 4-nitrophenyl butyrate (method A) and tributyrin (methods B and C) as substrates during the PL inhibition assay. Compounds 7e, 7f and 7p exhibited potential PL inhibitory activity (IC50 values of 6.31, 8.72 and 9.58μM, respectively in method A; and Xi50 of 21.85, 21.94 and 26.2, respectively in method B). Further, inhibition kinetics of 7e, 7f and 7p against PL, using method A, revealed their competitive nature of inhibition. A comparison of the inhibition profiles of the top three compounds in methods B and C, provided a preliminary idea of covalent bonding of the compounds with Ser 152 of PL. Molecular docking studies of the compounds 7a–x into the active site of human PL (PDB ID: 1LPB) was in agreement with the in vitro results, and highlighted probable covalent bond formation with Ser 152 apart from hydrophobic interactions with the lid domain. Molecular dynamics simulation of 7e complexed with PL, further confirmed the role of aromatic groups in stabilising the ligand (RMSD ⩽4Å). The present study led to the identification of 2-(carbazol-3-yl)-2-oxoacetamide analogues 7a–x as a new class of potential PL inhibitors. Graphical abstract image
>> read more

Synthesis, antioxidant and antichagasic properties of a selected series of hydroxy-3-arylcoumarins ()
Publication date: 15 January 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2 Author(s): Natalia Robledo-O’Ryan, Maria João Matos, Saleta Vazquez-Rodriguez, Lourdes Santana, Eugenio Uriarte, Mauricio Moncada-Basualto, Francisco Mura, Michel Lapier, Juan Diego Maya, Claudio Olea-Azar Oxidative stress is involved in several parasitic diseases such as Chagas. Agents able to selectively modulate biochemical processes involved in the disease represent promising multifunctional agents for the delay or abolishment of the progression of this pathology. In the current work, differently substituted hydroxy-3-arylcoumarins are described, exerting both antioxidant and trypanocidal activity. Among the compounds synthesized, compound 8 showed the most interesting profile, presenting a moderate scavenging ability for peroxyl radicals (ORAC-FL=2.23) and a high degree of selectivity towards epimastigotes stage of the parasite T. cruzi (IC50 =1.31μM), higher than Nifurtimox (drug currently used for treatment of Chagas disease). Interestingly, the current study revealed that small structural changes in the hydroxy-3-arylcoumarin core allow modulating both activities, suggesting that this scaffold has desirable properties for the development of promising classes of antichagasic compounds. Graphical abstract image
>> read more

N-Propargylpiperidines with naphthalene-2-carboxamide or naphthalene-2-sulfonamide moieties: Potential multifunctional anti-Alzheimer’s agents ()
Publication date: 15 January 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2 Author(s): Urban Košak, Damijan Knez, Nicolas Coquelle, Boris Brus, Anja Pišlar, Florian Nachon, Xavier Brazzolotto, Janko Kos, Jacques-Philippe Colletier, Stanislav Gobec In the brains of patients with Alzheimer’s disease, the enzymatic activities of butyrylcholinesterase (BChE) and monoamine oxidase B (MAO-B) are increased. While BChE is a viable therapeutic target for alleviation of symptoms caused by cholinergic hypofunction, MAO-B is a potential therapeutic target for prevention of neurodegeneration in Alzheimer’s disease. Starting with piperidine-based selective human (h)BChE inhibitors and propargylamine-based MAO inhibitors, we have designed, synthesized and biochemically evaluated a series of N-propargylpiperidines. All of these compounds inhibited hBChE with good selectivity over the related enzyme, acetylcholinesterase, and crossed the blood-brain barrier in a parallel artificial membrane permeation assay. The crystal structure of one of the inhibitors (compound 3) in complex with hBChE revealed its binding mode. Three compounds (4, 5, 6) showed concomitant inhibition of MAO-B. Additionally, the most potent hBChE inhibitor 7 and dual BChE and MAO-B inhibitor 6 were non-cytotoxic and protected neuronal SH-SY5Y cells from toxic amyloid β-peptide species. Graphical abstract image
>> read more

Influence of chain length on the activity of tripeptidomimetic antagonists for CXC chemokine receptor 4 (CXCR4) ()
Publication date: 15 January 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2 Author(s): Markus Baumann, Mohammad Musarraf Hussain, Nina Henne, Daniel Moya Garrote, Stefanie Karlshøj, Torgils Fossen, Mette M. Rosenkilde, Jon Våbenø, Bengt Erik Haug Here we report a series of close analogues of our recently published scaffold-based tripeptidomimetic CXCR4 antagonists, containing positively charged guanidino groups in R1 and R2, and an aromatic group in R3. While contraction/elongation of the guanidine carrying side chains (R1 and R2) resulted in loss of activity, introduction of bromine in position 1 on the naphth-2-ylmethyl moiety (R3) resulted in an EC50 of 61μM (mixture of diastereoisomers) against wild-type CXCR4; thus, the antagonistic activity of these tripeptidomimetics seems to be amenable to optimization of the aromatic moiety. Moreover, for analogues carrying a naphth-2-ylmethyl substituent, we observed that a Pictet-Spengler like cyclization side reaction depended on the nature of the R1 substituent. Graphical abstract image
>> read more

3-Amino-thieno[2,3-b]pyridines as microtubule-destabilising agents: Molecular modelling and biological evaluation in the sea urchin embryo and human cancer cells ()
Publication date: 15 January 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2 Author(s): Chatchakorn Eurtivong, Victor Semenov, Marina Semenova, Leonid Konyushkin, Olga Atamanenko, Jóhannes Reynisson, Alex Kiselyov A series of 3-amino-thieno[2,3-b]pyridines was prepared and tested in a phenotypic sea urchin embryo assay to identify potent and specific molecules that affect tubulin dynamics. The most active compounds featured a tricyclic core ring system with a fused cycloheptyl or cyclohexyl substituent and unsubstituted or alkyl-substituted phenyl moiety tethered via a carboxamide. Low nano-molar potency was observed in the sea urchin embryos for the most active compounds (1–5) suggestive of a microtubule-destabilising effect. The molecular modelling studies indicated that the tubulin colchicine site is inhibited, which often leads to microtubule-destabilisation in line with the sea urchin embryo results. Finally, the identified hits displayed a robust growth inhibition (GI50 of 50–250nM) of multidrug-resistant melanoma MDA-MB-435 and breast MDA-MB-468 human cancer cell lines. This work demonstrates that for the thieno[2,3-b]pyridines the most effective mechanism of action is microtubule-destabilisation initiated by binding to the colchicine pocket. Graphical abstract image
>> read more

Design, synthesis and analgesic/anti-inflammatory evaluation of novel diarylthiazole and diarylimidazole derivatives towards selective COX-1 inhibitors with better gastric profile ()
Publication date: 15 January 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2 Author(s): Ahmed H. Abdelazeem, Mohammed T. El-Saadi, Asmaa G. Safi El-Din, Hany A. Omar, Samir M. El-Moghazy The inhibition of gastric cyclooxygenase 1 (COX-1) enzyme was believed to be the major cause of non-steroidal anti-inflammatory drugs (NSAIDs)-induced gastric ulcer. Recent studies disproved this belief and showed that the gastric tissues vulnerability is not solely connected to COX-1 inhibition. This work aimed at exploring and rationalizing the differential analgesic and anti-inflammatory activities of novel selective COX-1 inhibitors with improved gastric profile. Two novel series of 4,5-diarylthiazole and diarylimidazole were designed, synthesized in analogy to selective COX-1 inhibitors (mofezolac and FR122047) which lack gastric damaging effects. The new compounds were evaluated in vitro for their COXs inhibitory activity and in vivo for their anti-inflammatory and analgesic potentials. Four compounds; diphenylthiazole glycine derivatives (15a, 15b) and diphenylimidazolo acetic acid derivatives (19a, 19b), which possess carboxylic acid group exhibited significant activity and selectivity against COX-1 over COX-2. Of these compounds, (4,5-bis(4-methoxyphenyl)thiazol-2-yl)glycine 15b was the most potent compound against COX-1 with an inhibitory half maximal concentration (IC50) of 0.32μM and a selectivity index (COX-2 IC50/COX-1 IC50) of 28.84. Furthermore, an ulcerogenicity study was performed where the tested compounds demonstrated a significant gastric tolerance. Interestingly, the most selective COX-1 inhibitor showed higher analgesic activity in vivo as expected compared to their moderate anti-inflammatory activity. This study underscores the need for further design and development of novel analgesic agents with low tendency to cause gastric damage based on improving their COX-1 affinity and selectivity profile. Graphical abstract image
>> read more

Coumarins and other fused bicyclic heterocycles with selective tumor-associated carbonic anhydrase isoforms inhibitory activity ()
Publication date: 15 January 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2 Author(s): Murat Bozdag, Ahmed Mahmoud Alafeefy, Abdul Malik Altamimi, Daniela Vullo, Fabrizio Carta, Claudiu T. Supuran Herein we report for the first time a series of 2-benzamido-N-(2-oxo-4-(methyl/trifluoromethyl)-2H-chromen-7-yl) benzamide 3a–f and substituted quinazolin-4(3H)-ones and 2H-benzo[e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxides (5, 6, 8 and 10a–c) as selective inhibitors of the tumor associated hCA IX and XII isoforms. Among the compounds reported the trifluoromethyl derivative 3d resulted the most potent against these CA isoforms with KIs of 10.9 and 6.7nM. Graphical abstract image
>> read more

Synthesis and biological evaluation of phosphate isosters of fosmidomycin and analogs as inhibitors of Escherichia coli and Mycobacterium smegmatis 1-deoxyxylulose 5-phosphate reductoisomerases ()
Publication date: 15 January 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2 Author(s): Mathilde Munier, Denis Tritsch, Fanny Krebs, Jérémy Esque, Andréa Hemmerlin, Michel Rohmer, Roland H. Stote, Catherine Grosdemange-Billiard Hydroxamate analogs of fosfoxacin, the phosphate homolog of fosmidomycin, have been synthesized and their activity tested on Escherichia coli and Mycobacterium smegmatis DXRs. Except for compound 4b, the IC50 values of phosphate derivatives are approximately 10-fold higher than those of the corresponding phosphonates. Although their inhibitory activity on Escherichia coli DXR is less efficient than their phosphonate analogs, we report the ability of phosphate compounds to inhibit the growth of Escherichia coli. This work points out that the uptake of fosfoxacin and its analogs is taking place via the GlpT and UhpT transporters. As expected, these compounds are inefficient to inhibit the growth of M. smegmatis growth inhibition probably due to a lack of uptake. Graphical abstract image
>> read more

Synthesis and evaluation of a 68Ga-labeled bradykinin B1 receptor agonist for imaging with positron emission tomography ()
Publication date: 15 January 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2 Author(s): Guillaume Amouroux, Zhengxing Zhang, Jinhe Pan, Silvia Jenni, Chengcheng Zhang, Navjit Hundal-Jabal, Nadine Colpo, Jutta Zeisler, Kuo-Shyan Lin, François Bénard A novel 68Ga-labeled bradykinin B1 receptor (B1R) agonist, 68Ga-Z01115, was synthesized and evaluated for imaging with positron emission tomography (PET). Z01115 exhibited good binding affinity (Ki =25.4±5.1nM) to hB1R. 68Ga-Z01115 was prepared in 74±5 decay-corrected radiochemical yield with >99% radiochemical purity and 155±89GBq/µmol (4.2±2.4Ci/μmol) specific activity. 68Ga-Z01115 was stable in vitro in mouse plasma (93% remaining intact after 60min incubation), and relatively stable in vivo (51±5% remaining intact at 5min post-injection). PET imaging and biodistribution studies in mice showed that 68Ga-Z01115 cleared rapidly from nontarget tissues/organs, and generated high target-to-nontarget contrast images. The uptake of 68Ga-Z01115 in B1R-positive (B1R+) tumor was 5.65±0.59%ID/g at 1h post-injection. Average contrast ratios of B1R+ tumor-to-B1R− tumor, -to-blood and -to-muscle were 24.3, 24.4 and 82.9, respectively. Uptake of 68Ga-Z01115 in B1R+ tumors was reduced by ∼90% with co-injection of cold standard, confirming it was mediated by B1R. Our data suggest that 68Ga-Z01115 is a promising tracer for imaging the expression of B1R that is overexpressed in a variety of cancers. Graphical abstract image
>> read more

Synthesis and immunological evaluation of a low molecular weight saccharide with TLR-4 agonist activity ()
Publication date: 15 January 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2 Author(s): Vikram Basava, Heather Romlein, Constantine Bitsaktsis, Cecilia H. Marzabadi The paucity of FDA approved adjuvants renders the synthesis, characterization, and use of new compounds as vaccine adjuvants, a necessity. For this purpose, a novel saccharide analog has been synthesized from glucosamine, pyruvylated galactose and 1,4-cyclohexanediol and its biological efficacy was determined in innate immune cells. More specifically, we assessed the production of pro-inflammatory cytokines from the murine monocyte cell line, Raw 264.7 and from C57 BL/6 mouse peritoneal macrophages following exposure to the saccharide analog. Our data conclude that the novel saccharide has immunostimulatory activity on mouse macrophages as indicated by the elevated levels of IL-6 and TNF-α in culture supernatants. This effect was TLR-4-dependent but TLR-2-independent. Our data, suggest TLR-4 agonism; a key feature of vaccine adjuvants. Graphical abstract image
>> read more

Cellular uptake of glucoheptoamidated poly(amidoamine) PAMAM G3 dendrimer with amide-conjugated biotin, a potential carrier of anticancer drugs ()
Publication date: 15 January 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2 Author(s): Łukasz Uram, Magdalena Szuster, Aleksandra Filipowicz, Magdalena Zaręba, Elżbieta Wałajtys-Rode, Stanisław Wołowiec In search for soluble derivatives of PAMAM dendrimers as potential carriers for hydrophobic drugs, the conjugates of PAMAM G3 with biotin, further converted into glycodendrimer with d-glucoheptono-1,4-lactone, were prepared. Polyamidoamine dendrimer (PAMAM) of third generation, G3 was functionalized with four biotin equivalents covalently attached to terminal amine nitrogens via amide bond G34B. The remaining 28 amine groups were blocked by glucoheptoamide substituents (gh) to give G34B28gh or with one fluorescein equivalent (attached by reaction of G34B with fluorescein isothiocyanate, FITC) via thiourea bond as FITC followed by exhaustive glucoheptoamidation to get G34B27gh1F. As a control the G3 substituted totally with 32 glucoheptoamide residues, G3gh and its fluorescein labeled analogue G331gh1F were synthesized. The glucoheptoamidation of PAMAM G0 dendrimer with glucoheptono-1,4-lactone was performed in order to fully characterize the 1H NMR spectra of glucoheptoamidated PAMAM dendrimers and to control the derivatization of G3 with glucoheptono-1,4-lactone. Another two derivatives of G3, namely G34B28gh1F′ and G332ghF′, with ester bonded fluorescein were also obtained. Biological properties of obtained dendrimer conjugates were estimated in vitro with human cell lines: normal fibroblast (BJ) and two cancer glioblastoma (U-118 MG) and squamous carcinoma (SCC-15), including cytotoxicity by reduction of XTT and neutral red (NR) assays. Cellular uptake of dendrimer conjugates was evaluated with confocal microscopy. Obtained results confirmed, that biotinylated bioconjugates have always lower cytotoxicity and 3–4 times higher cellular uptake than non-biotinylated dendrimer conjugates in all cell lines. Comparison of various cell lines revealed different dose-dependent cell responses and the lower cytotoxicity of examined dendrimer conjugates for normal fibroblasts and squamous carcinoma, as compared with much higher cytotoxic effects seen in glioblastoma cell line. Synthetized multi-functional conjugate (G34B27gh1F) is a promising candidate as biocompatible vehicle for hydrophobic molecules used in anticancer therapy. Graphical abstract image
>> read more

Multitarget drug design strategy against Alzheimer’s disease: Homoisoflavonoid Mannich base derivatives serve as acetylcholinesterase and monoamine oxidase B dual inhibitors with multifunctional properties ()
Publication date: 15 January 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2 Author(s): Yan Li, Xiaoming Qiang, Li Luo, Xia Yang, Ganyuan Xiao, Yunxiaozhu Zheng, Zhongcheng Cao, Zhipei Sang, Fu Su, Yong Deng A series of homoisoflavonoid Mannich base derivatives were designed, synthesized and evaluated as multifunctional agents against Alzheimer’s disease. It demonstrated that most of the derivatives were selective AChE and MAO-B dual inhibitors with good multifunctional properties. Among them, compound 10d displayed the comprehensive advantages, with excellent AChE and MAO-B inhibitory activities (IC50 =2.49±0.08nM and 1.74±0.0581μM, respectively), good self- and Cu2+-induced Aβ 1-42 aggregation inhibitory potency, antioxidant activity, biometal chelating ability and high BBB permeability. These multifunctional properties make 10d as an excellent candidate for the development of efficient drugs against AD. Graphical abstract image
>> read more

Synthesis and optimization of novel α-phenylglycinamides as selective TRPM8 antagonists ()
Publication date: 15 January 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2 Author(s): Jun-ichi Kobayashi, Hideaki Hirasawa, Tetsuji Ozawa, Tomonaga Ozawa, Hiroo Takeda, Yoshikazu Fujimori, Osamu Nakanishi, Noboru Kamada, Tetsuya Ikeda Transient receptor potential melastatin 8 (TRPM8) is activated by innocuous cold and chemical substances, and antagonists of this channel have been considered to be effective for pain and urinary diseases. N-(3-aminopropyl)-2-{[(3-methylphenyl)methyl]oxy}-N-(2-thienylmethyl)benzamide hydrochloride (AMTB), a TRPM8 antagonist, was proposed to be effective for overactive bladder and painful bladder syndrome; however, there is a potential risk of low blood pressure. We report herein the synthesis and structure–activity relationships of novel phenylglycine derivatives that led to the identification of KPR-2579 (20l), a TRPM8 selective antagonist. KPR-2579 reduced the number of icilin-induced wet-dog shakes and rhythmic bladder contraction in rats, with no negative cardiovascular effects at the effective dose. Graphical abstract image
>> read more

Coating lanthanide nanoparticles with carbohydrate ligands elicits affinity for HeLa and RAW264.7 cells, enhancing their photodamaging effect ()
Publication date: 15 January 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2 Author(s): Takashi Kanamori, Takashi Sawamura, Tatsumi Tanaka, Izumi Sotokawa, Ryota Mori, Kotaro Inada, Akihiro Ohkubo, Shun-Ichiro Ogura, Yasutoshi Murayama, Eigo Otsuji, Hideya Yuasa Lanthanide nanoparticles (LNPs) conjugated with monosaccharides were synthesized as a photon energy-upconverting nanodevice with affinity to cancer cells. The conjugates were designed to selectively damage the cancer cells containing protoporphyrin IX, a photosensitizer endogenously synthesized from priorly administrated 5-aminolevlunic acid (ALA), by a highly tissue-penetrative near-infrared (NIR) irradiation. First of all, the affinities of monosaccharides toward cells (HeLa, RAW264.7, and MKN45) were assessed by a novel cell aggregation assay with trivalent monosaccharide-citric acid conjugates. As a result, HeLa exhibited high affinity for glucose, while RAW264.7 for glucose, galactose, mannose, and fucose. A similar cell-monosaccharide affinity was microscopically observed when the cells were mixed with monosaccharide-LNP conjugates and rinsed, in which the high affinity LNP probes luminesced on the cells. The high affinity monosaccharide-LNPs showed greater photodamaging effects than the unmodified LNP toward the corresponding cells, when the cells were pretreated with ALA and irradiated by NIR. This study demonstrates that carbohydrates can be used as selective ligands for cancer cells in a photodynamic therapy with LNP. Graphical abstract image
>> read more

Discovery of biphenyl imidazole derivatives as potent antifungal agents: Design, synthesis, and structure-activity relationship studies ()
Publication date: 15 January 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2 Author(s): Dongmei Zhao, Shizhen Zhao, Liyu Zhao, Xiangqian Zhang, Peng Wei, Chunchi Liu, Chenzhou Hao, Bin Sun, Xin Su, Maosheng Cheng Fungal infections have became a serious medical problem due to their high incidence and mortality. We describe the discovery and structure-activity relationships studies (SARs) of a series of novel biphenyl imidazole derivatives with excellent antifungal activities against Candida albicans and Cryptococcus neoformans. The most promising compounds 12f–g and 19a–b exhibited excellent activity with minimum inhibitory concentration (MIC) values in the range of 0.03125–2μg/mL. Preliminary mechanism studies showed that the potent antifungal activity of compound 12g stemed from inhibition of CYP51 in Candida albicans. Furthermore, compounds 12g and 19b exhibited low inhibition profiles for various human cytochrome P450 isoforms. The SARs and binding mode established in this study will be useful for further lead optimization. Graphical abstract image
>> read more

Effects of new fluorinated analogues of GABA, pregabalin bioisosters, on the ambient level and exocytotic release of [3H]GABA from rat brain nerve terminals ()
Publication date: 15 January 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2 Author(s): T. Borisova, N. Pozdnyakova, E. Shaitanova, I. Gerus, M. Dudarenko, G. Haufe, V. Kukhar Recently, we have shown that new fluorinated analogues of γ-aminobutyric acid (GABA), bioisosters of pregabalin (β-i-Bu-GABA), i.e. β-polyfluoroalkyl-GABAs (FGABAs), with substituents: β-CF3-β-OH (1), β-CF3 (2); β-CF2CF2H (3), are able to increase the initial rate of [3H]GABA uptake by isolated rat brain nerve terminals (synaptosomes), and this effect is higher than that of pregabalin. So, synthesized FGABAs are structural but not functional analogues of GABA. Herein, we assessed the effects of synthesized FGABAs (100μM) on the ambient level and exocytotic release of [3H]GABA in nerve terminals and compared with those of pregabalin (100μM). It was shown that FGABAs 1–3 did not influence the ambient level of [3H]GABA in the synaptosomal preparations, and this parameter was also not altered by pregabalin. During blockage of GABA transporters GAT1 by specific inhibitor NO-711, FGABAs and pregabalin also did not change ambient [3H]GABA in synaptosomal preparations. Exocytotic release of [3H]GABA from synaptosomes decreased in the presence of FGABAs 1–3 and pregabalin, and the effects of FGABAs 1 & 3 were more significant than those of FGABAs 2 and pregabalin. FGABAs 1–3/pregabalin-induced decrease in exocytotic release of [3H]GABA from synaptosomes was not a result of changes in the potential of the plasma membrane. Therefore, new synthesized FGABAs 1 & 3 were able to decrease exocytotic release of [3H]GABA from nerve terminals more effectively in comparison to pregabalin. Absence of unspecific side effects of FGABAs 1 & 3 on the membrane potential makes these compounds perspective for medical application. Graphical abstract image
>> read more

Design and synthesis of phosphoryl-substituted diphenylpyrimidines (Pho-DPPYs) as potent Bruton’s tyrosine kinase (BTK) inhibitors: Targeted treatment of B lymphoblastic leukemia cell lines ()
Publication date: 15 January 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2 Author(s): Yang Ge, Haijun Yang, Changyuan Wang, Qiang Meng, Lei Li, Huijun Sun, Yuhong Zhen, Kexin Liu, Yanxia Li, Xiaodong Ma A family of phosphoryl-substituted diphenylpyrimidine derivatives (Pho-DPPYs) were synthesized and biologically evaluated as potent BTK inhibitors in this study. Compound 7b was found to markedly inhibit BTK activity at concentrations of 0.82nmol/L, as well as to suppress the proliferations of B-cell leukemia cell lines (Ramos and Raji) expressing high levels of BTK at concentrations of 3.17μM and 6.69μM. Moreover, flow cytometry analysis results further indicated that 7b promoted cell apoptosis to a substantial degree. In a word, compound 7b is a promising BTK inhibitor for the treatment of B-cell lymphoblastic leukemia. Graphical abstract image
>> read more

Synthesis and characterization of novel, conjugated, fluorescent DNJ derivatives for α-glucosidase recognition ()
Publication date: 15 January 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2 Author(s): Akihiko Hatano, Yuichi Kanno, Yuya Kondo, Yuta Sunaga, Hatsumi Umezawa, Munehiro Okada, Hideshi Yamada, Ren Iwaki, Atsushi Kato, Koji Fukui A series of five new fluorescent deoxynojirimycin (DNJ) conjugates were synthesized and evaluated for their inhibitory effect (IC50) on several α- and β-glucosidases. Three of the conjugates showed enhanced activity. The two synthetic conjugates, DNJ-CF3 1 and DNJ-Me 2, exhibited improved α-glucosidase inhibitory effects compared to DNJ and miglitol. Interestingly, conjugates 1 and 2 showed strong inhibition of almond-derived β-glucosidase, in contrast to the inhibition tendencies of other inhibitors. Conjugate 5 strongly inhibited rat intestinal maltase, even at 0.10μM. A docking study indicated that all five conjugates bind to the active site of α-glucosidase (PDB: 3L4V, derived from Homo sapiens). The DNJ portion of the conjugate fits into the cavity of the enzyme, and the fluorescent part locates randomly on the outside surface. Thus, it is likely that these conjugates can specifically recognize intestinal cells, specifically the α-glucosidase on cell membranes. Graphical abstract image
>> read more

Structure-activity relationship of the inhibitory effects of flavonoids on nitric oxide production in RAW264.7 cells ()
Publication date: 15 January 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2 Author(s): Wen-Jun Jiang, Akihiro Daikonya, Mitsuyoshi Ohkawara, Takashi Nemoto, Ryusuke Noritake, Tomoko Takamiya, Susumu Kitanaka, Hiroshi Iijima We isolated flavonoids from herbal specimens from the Tibetan region (Sophora yunnanensis and Rhodiola sacra) that suppress nitric oxide (NO) production in macrophages stimulated by lipopolysaccharide and interferon-γ. The isolated flavonoids carry symmetric substitutions in the B ring (R3′ =R5′). We analyzed the quantitative structure-activity relationship of the inhibitory activity by comparative molecular field analysis (CoMFA) using this series of flavonoids. Use of flavonoids with symmetrical substitutions in the B ring made it simpler to align molecules because it was not necessary to consider a huge number of combinations due to the B-ring conformation. The CoMFA model, whose cross-validated q 2 value was 0.705, suggested the existence of a hydroxy group at the 5-position, the choice of the A/C-ring scaffold (chromane or chromene) and electrostatic field around the B ring are important for NO inhibitory activity. Flavonoids synthesized based on the CoMFA model exhibited significant inhibitory potential against NO production, validating the predictive capability of the CoMFA model. Graphical abstract image
>> read more

Synthesis of novel C4-benzazole naphthalimide derivatives with potent anti-tumor properties against murine melanoma ()
Publication date: 15 January 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2 Author(s): Yen-Ta Lu, Tien-Ling Chen, Kuo-Song Chang, Chia-Ming Chang, Tsai-Yin Wei, Jen-Wei Liu, Chih-Ang Hsiao, Tzenge-Lien Shih Novel C4-benzazole naphthalimide derivatives were synthesized and tested in vitro and in vivo as anti-cancer drugs. Among these synthetic molecules, compounds 9 and 10 exhibited cytotoxicity against murine B16F10 melanoma cells. In addition, the above-mentioned compounds significantly suppressed lung tumor metastasis with no visible sign of toxicity. Graphical abstract image
>> read more

α-Pyrone derivatives, tetra/hexahydroxanthones, and cyclodepsipeptides from two freshwater fungi ()
Publication date: 15 January 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2 Author(s): Tamam El-Elimat, Huzefa A. Raja, Cynthia S. Day, Hana McFeeters, Robert L. McFeeters, Nicholas H. Oberlies Eighteen (1–18) and seven (1, 4, 6–8, 17 and 18) compounds were isolated from organic extracts of axenic cultures of two freshwater fungi Clohesyomyces sp. and Clohesyomyces aquaticus (Dothideomycetes, Ascomycota), respectively. Compounds 1–12 belong to the α-pyrone class of natural products, compounds 13 and 14 were tetrahydroxanthones, compounds 15 and 16 were hexahydroxanthones, while compounds 17 and 18 were cyclodepsipeptides. The structures were elucidated using a set of spectroscopic and spectrometric techniques. The absolute configurations of compounds 2, 3, 6, and 7 were assigned via a modified Mosher’s ester method using 1H NMR data. The relative configurations of compounds 14–16 were determined through NOE data. Compounds 1, 2, 6, 8, 13, 14, and 15 were found to inhibit the essential enzyme bacterial peptidyl-tRNA hydrolase (Pth1), with (13; secalonic acid A) being the most potent. Compounds 1 and 4–18 were also evaluated for antimicrobial activity against an array of bacteria and fungi but were found to be inactive. Graphical abstract image
>> read more

Design, synthesis and pharmacological evaluation of 4-hydroxyphenylglycine and 4-hydroxyphenylglycinol derivatives as GPR88 agonists ()
Publication date: 15 January 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 2 Author(s): Chunyang Jin, Ann M. Decker, Tiffany L. Langston The orphan receptor GPR88 is an attractive therapeutic target because of its implications in a number of basal ganglia-associated disorders. To date, pharmacological characterization of GPR88 has been limited due to the lack of potent and selective agonists and antagonists appropriate for CNS investigations. We have previously reported that GPR88 couples to Gαi proteins and modulates cAMP levels upon treatment with a small molecule agonist 2-PCCA. Recently, another chemotype of GPR88 agonist, represented by 2-AMPP [(2S)-N-((1R)-2-amino-1-(4-(2-methylpentyloxy)-phenyl)ethyl)-2-phenylpropanamide], has also been discovered. In this report, a new series of 2-AMPP structurally related 4-hydroxyphenylglycine and 4-hydroxyphenylglycinol derivatives have been designed and evaluated for agonist activity at GPR88. The structure-activity relationship (SAR) studies suggest that the amine group in 2-AMPP can be replaced by hydroxyl, ester and amide groups, resulting in analogues with good to moderate potency, whereas the phenyl group on the amide cap is essential for activity and has limited size, shape and electronic tolerance. Graphical abstract image
>> read more

Novel salicylanilides from 4,5-dihalogenated salicylic acids: Synthesis, antimicrobial activity and cytotoxicity ()
Publication date: Available online 14 January 2017 Source:Bioorganic & Medicinal Chemistry Author(s): Georgios Paraskevopoulos, Sara Monteiro, Rudolf Vosátka, Martin Krátký, Lucie Navrátilová, František Trejtnar, Jiřina Stolaříková, Jarmila Vinšová Salicylanilides have proved their activity against tuberculosis (TB). One weak electron-withdrawing substituent is favored at the salicylic part, specially Cl or Br atoms at positions 4 or 5. On the other hand, the antimycobacterial activity of salicylanilides is negatively affected when a strong electron-withdrawing substituent (-NO2) is present at the same positions. Herein we describe the synthesis and characterization of novel salicylanilides possessing two weak electron-withdrawing groups (halogen atoms) at their salicylic part and compare their antitubercular activity with their monohalogenated analogues. All dihalogenated derivatives proved to possess antitubercular activity at a very narrow micromolar range (MIC= 1-4 μM), similar with their most active monohalogenated analogues. More importantly, the most active final molecules were further screened against multidrug resistant strains and found to inhibit their growth at the range of 0.5-4 μM. Graphical abstract image
>> read more

Optical probes and Sensors as peRSpective tools In epigenetics ()
Publication date: Available online 13 January 2017 Source:Bioorganic & Medicinal Chemistry Author(s): Zdeněk Kejík, Robert Kaplánek, Martin Havlík, Tomáš Bříza, Milan Jakubek, Jarmila Králová, Ivan Mikula, Pavel Martásek, Vladimír Král Modifications of DNA cytosine bases and histone posttranslational modifications play key roles in the control of gene expression and specification of cell states. Such modifications affect many important biological processes and changes to these important regulation mechanisms can initiate or significantly contribute to the development of many serious pathological states. Therefore, recognition and determination of chromatin modifications is an important goal in basic and clinical research. Two of the most promising tools for this purpose are optical probes and sensors, especially colourimetric and fluorescence devices. The use of optical probes and sensors is simple, without highly expensive instrumentation, and with excellent sensitivity and specificity for target structural motifs. Accordingly, the application of various probes and sensors in the recognition and determination of cytosine modifications and structure of histones and histone posttranslational modifications, are discussed in detail in this review. Graphical abstract image
>> read more

Synthesis of α,β-unsaturated aldehydes as potential substrates for bacterial luciferases ()
Publication date: Available online 13 January 2017 Source:Bioorganic & Medicinal Chemistry Author(s): Eveline Brodl, Jakov Ivkovic, Chaitanya R. Tabib, Rolf Breinbauer, Peter Macheroux Bacterial luciferase catalyzes the monooxygenation of long-chain aldehydes such as tetradecanal to the corresponding acid accompanied by light emission with a maximum at 490nm. In this study even numbered aldehydes with eight, ten, twelve and fourteen carbon atoms were compared with analogs having a double bond at the α,β-position. These α,β-unsaturated aldehydes were synthesized in three steps and were examined as potential substrates in vitro. The luciferase of Photobacterium leiognathi was found to convert these analogs and showed a reduced but significant bioluminescence activity compared to tetradecanal. This study showed the trend that aldehydes, both saturated and unsaturated, with longer chain lengths had higher activity in terms of bioluminescence than shorter chain lengths. The maximal light intensity of (E)-tetradec-2-enal was approximately half with luciferase of P. leiognathi, compared to tetradecanal. Luciferases of Vibrio harveyi and Aliivibrio fisheri accepted these newly synthesized substrates but light emission dropped drastically compared to saturated aldehydes. The onset and the decay rate of bioluminescence were much slower, when using unsaturated substrates, indicating a kinetic effect. As a result the duration of the light emission is doubled. These results suggest that the substrate scope of bacterial luciferases is broader than previously reported. Graphical abstract image
>> read more

Site Search