Design, synthesis, and biological characterization of novel PEG-linked dimeric modulators for CXCR4.


:CXCR4 dimerization has been widely demonstrated both biologically and structurally. This paper mainly focused on the development of structure-based dimeric ligands that target CXCL12-CXCR4 interaction and signaling. This study presents the design and synthesis of a series of [PEG]n linked dimeric ligands of CXCR4 based on the knowledge of the homodimeric crystal structure of CXCR4 and our well established platform of chemistry and bioassays for CXCR4. These new ligands include [PEG]n linked homodimeric or heterodimeric peptides consisting of either two DV3-derived moieties (where DV3 is an all-d-amino acid analog of N-terminal modules of 1-10 (V3) residues of vMIP-II) or hybrids of DV3 moieties and CXCL121-8. Among a total of 24 peptide ligands, four antagonists and three agonists showed good CXCR4 binding affinity, with IC50 values of <50nM and <800nM, respectively. Chemotaxis and calcium mobilization assays with SUP-T1 cells further identified two promising lead modulators of CXCR4: ligand 4, a [PEG3]2 linked homodimeric DV3, was an effective CXCR4 antagonist (IC50=22nM); and ligand 21, a [PEG3]2 linked heterodimeric DV3-CXCL121-8, was an effective CXCR4 agonist (IC50=407nM). These dimeric CXCR4 modulators represent new molecular probes and therapeutics that effectively modulate CXCL12-CXCR4 interaction and function.


Bioorg Med Chem


Yang Y,Gao M,Zhang Q,Zhang C,Yang X,Huang Z,An J




Has Abstract


2016-11-01 00:00:00














  • Chemoenzymatic synthesis and biological evaluation of 2- and 3-hydroxypyridine derivatives against Leishmania mexicana.

    abstract::A series of hydroxyalkyl and acyloxyalkyl derivatives of 2- and 3-hydroxypyridine was synthesized and their biological activity was evaluated as growth inhibitors of protozoan Leishmania mexicana. Thirty novel compounds were obtained through a chemoenzymatic methodology in two reaction steps. The influence of various ...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: García Liñares G,Parraud G,Labriola C,Baldessari A

    更新日期:2012-08-01 00:00:00

  • The novel GABA adamantane derivative (AdGABA): design, synthesis, and activity relationship with gabapentin.

    abstract::A facile preparation of 2-aminomethyl-2-tricyclo[,7)]decaneacetic acid hydrochloride 5 (AdGABA) is described. The synthesis of AdGABA involves the hydrogenation of 2-cyano-2-tricyclo[,7)]decaneacetic acid 11, which was synthesized by two different synthetic routes. AdGABA was found to antagonize the ...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Zoidis G,Papanastasiou I,Dotsikas I,Sandoval A,Dos Santos RG,Papadopoulou-Daifoti Z,Vamvakides A,Kolocouris N,Felix R

    更新日期:2005-04-15 00:00:00

  • Stereoselective preparation of pyridoxal 1,2,3,4-tetrahydro-β-carboline derivatives and the influence of their absolute and relative configuration on the proliferation of the malaria parasite Plasmodium falciparum.

    abstract::We have selectively synthesized by Pictet-Spengler condensation of tryptophan and pyridoxal the four stereoisomers of a pyridoxal β-carboline derivative that was designed to inhibit the proliferation of Plasmodium falciparum. Biological investigation of the four compounds revealed that they all inhibit the growth of P...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Brokamp R,Bergmann B,Müller IB,Bienz S

    更新日期:2014-03-15 00:00:00

  • Synthesis and evaluation of antitumoral activity of ester and amide derivatives of 2-arylamino-6-trifluoromethyl-3-pyridinecarboxylic acids.

    abstract::The synthesis and antitumoral activity of ester and amide derivatives of 2-arylamino-6-trifluoromethyl-3-pyridinecarboxylic acids 8-58 is described. Trifluoromethylpyridine derivatives 8-58 were evaluated for their anticancer activity toward human tumoral cell lines by the National Cancer Institute (NCI). Most of them...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Onnis V,Cocco MT,Lilliu V,Congiu C

    更新日期:2008-03-01 00:00:00

  • Catechol derivatives of aminopyrazine and cell protection against UVB-induced mortality.

    abstract::A series of 5-aryl- and 3,5-bis-aryl-2-amino-1,4-pyrazine derivatives 4 and 6, and related imidazolopyrazinones 7, has been synthesized, the aryl groups of which are catechol and/or phenol substituents. These compounds, tested against human keratinocyte cells stressed by UVB irradiation, showed high antioxidative prop...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Cavalier JF,Burton M,Dussart F,Marchand C,Rees JF,Marchand-Brynaert J

    更新日期:2001-04-01 00:00:00

  • Design, synthesis, and biological evaluation of water-soluble amino acid prodrug conjugates derived from combretastatin, dihydronaphthalene, and benzosuberene-based parent vascular disrupting agents.

    abstract::Targeting tumor vasculature represents an intriguing therapeutic strategy in the treatment of cancer. In an effort to discover new vascular disrupting agents with improved water solubility and potentially greater bioavailability, various amino acid prodrug conjugates (AAPCs) of potent amino combretastatin, amino dihyd...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Devkota L,Lin CM,Strecker TE,Wang Y,Tidmore JK,Chen Z,Guddneppanavar R,Jelinek CJ,Lopez R,Liu L,Hamel E,Mason RP,Chaplin DJ,Trawick ML,Pinney KG

    更新日期:2016-03-01 00:00:00

  • Large scale preparation of chiral building blocks for the P3 site of renin inhibitors.

    abstract::Racemic ethyl 2-benzyl-3-(tert-butylsulfonyl)propionate (1) and racemic ethyl 2-benzyl-3-[[1-methyl-1-((morpholin-4-yl)carbonyl)ethyl]sulfonyl] propionate (3) were enantioselectively hydrolyzed by subtilisin Carlsberg generating the respective (S)-acids used as building blocks for renin inhibitors. The esters were rea...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Doswald S,Estermann H,Kupfer E,Stadler H,Walther W,Weisbrod T,Wirz B,Wostl W

    更新日期:1994-06-01 00:00:00

  • Solution-phase parallel synthesis of substituted chalcones and their antiparasitary activity against Giardia lamblia.

    abstract::A library of 25-membered chalcones was prepared by parallel synthesis. Substituted acetophenones and benzaldehydes were condensed using the Claisen-Schmidt base-catalyzed aldol condensation. Several chalcones showed in vitro antiparasitic activity against Giardia lamblia. The highest activity observed for the IC(50) v...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Montes-Avila J,Díaz-Camacho SP,Sicairos-Félix J,Delgado-Vargas F,Rivero IA

    更新日期:2009-09-15 00:00:00

  • Novel anticancer agents, kayeassamins C-I from the flower of Kayea assamica of Myanmar.

    abstract::A CHCl3-soluble fraction of 70% EtOH extract of the flower of Kayea assamica from Myanmar exhibited 100% preferential cytotoxicity (PC(100)) against human pancreatic cancer PANC-1 cells under nutrient-deprived conditions at 1 microg/mL. Bioassay-guided fractionation and isolation afforded nine new coumarins, kayeassam...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Win NN,Awale S,Esumi H,Tezuka Y,Kadota S

    更新日期:2008-09-15 00:00:00

  • Construction of a chemically and conformationally self-replicating system of amyloid-like fibrils.

    abstract::The amyloid-like fibril is considered to be a macromolecular self-assemblage with a highly-ordered quaternary structure, in which numerous beta-stranded polypeptide chains align regularly. Therefore, this kind of fibril has the potential to be engineered into proteinaceous materials, although conformational alteration...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Takahashi Y,Mihara H

    更新日期:2004-02-15 00:00:00

  • A new opioid designed multiple ligand derived from the micro opioid agonist endomorphin-2 and the delta opioid antagonist pharmacophore Dmt-Tic.

    abstract::Opioid compounds with mixed micro agonist/delta antagonist properties could be used as analgesics with low propensity to induce tolerance and dependence. Here we report the synthesis of a new designed multiple ligand deriving from the micro selective agonist endomorphin-2 and the delta selective antagonist pharmacopho...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Salvadori S,Trapella C,Fiorini S,Negri L,Lattanzi R,Bryant SD,Jinsmaa Y,Lazarus LH,Balboni G

    更新日期:2007-11-15 00:00:00

  • Design, synthesis and preliminary biological evaluation of zatebradine analogues as potential blockers of the hyperpolarization-activated current.

    abstract::A series of zatebradine analogues, differing in the basic moiety and in the methylene spacer, have been synthesized; their negative chronotropic activity has been determined in guinea pig atria. The most active compounds have been studied for their blocking properties on the hyperpolarization-activated current If (whi...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Romanelli MN,Cerbai E,Dei S,Guandalini L,Martelli C,Martini E,Scapecchi S,Teodori E,Mugelli A

    更新日期:2005-02-15 00:00:00

  • Veratridine binding to a transmembrane helix of sodium channel Nav1.4 determined by solid-state NMR.

    abstract::The multi-step ligand action to a target protein is an important aspect when understanding mechanisms of ligand binding and discovering new drugs. However, structurally capturing such complex mechanisms is challenging. This is particularly true for interactions between large membrane proteins and small molecules. One ...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Niitsu A,Egawa A,Ikeda K,Tachibana K,Fujiwara T

    更新日期:2018-11-15 00:00:00

  • Synthesis of curcumin mimics with multidrug resistance reversal activities.

    abstract::In order to discover novel multidrug resistance (MDR) reversal agents for efficient cancer chemotherapy, the unsymmetrical curcumin mimics with various amide moieties (6-19) were synthesized and evaluated their MDR reversal activities in MDR cell line KBV20C. Among the tested compounds, 13, 16, and 17 showed potent MD...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Um Y,Cho S,Woo HB,Kim YK,Kim H,Ham J,Kim SN,Ahn CM,Lee S

    更新日期:2008-04-01 00:00:00

  • Covalent inhibition of SUMO and ubiquitin-specific cysteine proteases by an in situ thiol-alkyne addition.

    abstract::Posttranslational modification of proteins with ubiquitin and ubiquitin-like modifiers such as SUMO can be reverted by specific proteases, also referred to as deubiquitinases and isopeptidases, most of which are cysteine-dependent. We have found that the replacement of the conserved C-terminal glycine with propargylam...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Sommer S,Weikart ND,Linne U,Mootz HD

    更新日期:2013-05-01 00:00:00

  • Design and synthesis of spirotryprostatin-inspired diketopiperazine systems from prolyl spirooxoindolethiazolidine derivatives.

    abstract::Based on the spirotryprostatin-A structure, we designed, synthesized, and evaluated different series of compounds belonging to the diketopiperazine structural class as potential cell cycle modulators and cytotoxic agents. Starting from the spirooxoindolthiazolidine scaffold, amide coupling with Pro derivatives and int...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Bertamino A,Aquino C,Sala M,Simone Nd,Mattia CA,Erra L,Musella S,Iannelli P,Carotenuto A,Grieco P,Novellino E,Campiglia P,Gomez-Monterrey I

    更新日期:2010-06-15 00:00:00

  • Benzanilides with spasmolytic activity: chemistry, pharmacology, and SAR.

    abstract::The following study describes the synthesis of new benzanilide derivatives and their pharmacological investigation on smooth muscle preparations of guinea pigs. All compounds were synthesized in good yields and showed a spasmolytic activity without significant effect on vascular smooth muscles and heart muscle prepara...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Brunhofer G,Handler N,Leisser K,Studenik CR,Erker T

    更新日期:2008-06-01 00:00:00

  • Synthesis and structure-activity relationship studies on tryprostatin A, an inhibitor of breast cancer resistance protein.

    abstract::Tryprostatin A is an inhibitor of breast cancer resistance protein, consequently a series of structure-activity studies on the cell cycle inhibitory effects of tryprostatin A analogues as potential antitumor antimitotic agents have been carried out. These analogues were assayed for their growth inhibition properties a...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Jain HD,Zhang C,Zhou S,Zhou H,Ma J,Liu X,Liao X,Deveau AM,Dieckhaus CM,Johnson MA,Smith KS,Macdonald TL,Kakeya H,Osada H,Cook JM

    更新日期:2008-04-15 00:00:00

  • Toward the development of chemoprevention agents (III): synthesis and anti-inflammatory activities of a new class of 5-glycylamino-2-substituted-phenyl-1,3-dioxacycloalkanes.

    abstract::A new series of 5-glycylamino-2-substituted-phenyl-1,3-dioxacycloalkanes were designed and synthesized. The anti-inflammatory activities of these compounds were tested using the xylene-induced mouse ear edema model. Sixteen of these new compounds exhibited comparable or better anti-inflammatory activities than aspirin...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Bi L,Zhao M,Gu K,Wang C,Ju J,Peng S

    更新日期:2008-02-15 00:00:00

  • Aurine tricarboxylic acid, a potent metal-chelating inhibitor of NFkappaB-DNA binding.

    abstract::The metal-interaction of aurine tricarboxylic acid (ATA) and its inhibitory effect on the DNA binding of NFkappaB were studied. Chemical speciation and spectroscopic studies have shown the strong interaction of ATA with metal ions present in the biological systems. EPR, FTIR and electronic spectral studies indicated t...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Sharma RK,Garg BS,Kurosaki H,Goto M,Otsuka M,Yamamoto T,Inoue J

    更新日期:2000-07-01 00:00:00

  • Antimitotic and antivascular activity of heteroaroyl-2-hydroxy-3,4,5-trimethoxybenzenes.

    abstract::This study reports the synthesis of a series of heteroaroyl-2-hydroxy-3,4,5-trimethoxybenzenes, which are potent antitubulin agents. Compound 13, (2-hydroxy-3,4,5-trimethoxyphenyl)-(6-methoxy-1H-indol-3-yl)-methanone exhibits marked antiproliferative activity against KB and MKN45 cells with IC50 values of 8.8 and 10.5...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Lee HY,Chang CY,Lai MJ,Chuang HY,Kuo CC,Chang CY,Chang JY,Liou JP

    更新日期:2015-08-01 00:00:00

  • Actin-binding doliculide causes premature senescence in p53 wild type cells.

    abstract::Addressing the actin cytoskeleton as future anticancer target can be an innovative chemotherapeutic approach to combat malignancies. Doliculide is a potent stabilizer of actin filaments and can be used as tool and therapeutic lead in cancer research. Though a variety of molecules are known to bind to actin and lead to...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Foerster F,Chen T,Altmann KH,Vollmar AM

    更新日期:2016-01-15 00:00:00

  • Engineered production of cancer targeting peptide (CTP)-containing C-1027 in Streptomyces globisporus and biological evaluation.

    abstract::Conjugation of cancer targeting peptides (CTPs) with small molecular therapeutics has emerged as a promising strategy to deliver potent (but typically nonspecific) cytotoxic agents selectively to cancer cells. Here we report the engineered production of a CTP (NGR)-containing C-1027 and evaluation of its activity agai...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Li W,Li X,Huang T,Teng Q,Crnovcic I,Rader C,Shen B

    更新日期:2016-09-01 00:00:00

  • Multivalent presentation of a hydrolytically stable GM(3) lactone mimetic as modulator of melanoma cells motility and adhesion.

    abstract::A hydrolytically stable mimetic of the tumour antigen GM(3) lactone is used to decorate multivalent scaffolds. Two of them positively interfere on melanoma cell adhesion, migration and resistance to apoptosis (anoikis). Notably, their ability to hamper melanoma-cells adhesion and reduce the metastatic potential is enh...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Richichi B,Comito G,Cerofolini L,Gabrielli G,Marra A,Moni L,Pace A,Pasquato L,Chiarugi P,Dondoni A,Toma L,Nativi C

    更新日期:2013-05-15 00:00:00

  • Synthesis of brequinar analogue inhibitors of malaria parasite dihydroorotate dehydrogenase.

    abstract::A series of 2-phenyl quinoline-4-carboxylic acid derivatives related to brequinar, an inhibitor of human dihydroorotate dehydrogenase (DHODH), has been prepared and evaluated as inhibitors of DHODH from the malaria parasite Plasmodium falciparum. Brequinar was essentially inactive against PfDHODH (IC(50) 880 microM) w...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Boa AN,Canavan SP,Hirst PR,Ramsey C,Stead AM,McConkey GA

    更新日期:2005-03-15 00:00:00

  • Synthesis of heteroaromatic tropeines and heterogeneous binding to glycine receptors.

    abstract::Heteroaromatic carboxylic esters of (nor)tropine were synthesized. Tropine esters displaced [(3)H]strychnine binding to glycine receptors of rat spinal cord with low Hill slopes. Two-site displacement resulted in nanomolar IC(50,1) and micromolar IC(50,2) values, and IC(50,2)/IC(50,1) ratios up to 615 depending on the...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Maksay G,Vincze Z,Nemes P

    更新日期:2009-10-01 00:00:00

  • In-situ side-chain peptide cyclization as a breaker strategy against the amyloid aggregating peptide.

    abstract::Accumulation and deposition of misfolded amyloid β (Aβ) peptide outside the nerve cells are one of the major causes of Alzheimer's disease (AD). To date, one of the promising therapeutic strategies for AD is to block the early steps associated with the aggregation of Aβ peptide. We have developed synthetic breaker pep...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Ghosh N,Kundu LM

    更新日期:2021-01-16 00:00:00

  • Cyanocobalamin (vitamin B12) conjugates with enhanced solubility.

    abstract::Cyanocobalamin (vitamin B12) is an essential nutrient as well as a very useful carrier in drug delivery. Conjugates of vitamin B12 are investigated due to their wide range of therapeutic applications. We report the synthesis of six vitamin B12 conjugates, and the effect of conjugation on their solubilities and stabili...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Wang X,Wei L,Kotra LP

    更新日期:2007-02-15 00:00:00

  • Structure-activity relationship studies of manzamine A: amidation of positions 6 and 8 of the beta-carboline moiety.

    abstract::Twenty manzamine amides were synthesized and evaluated for in vitro antimalarial and antimicrobial activities. The amides of manzamine A (1) showed significantly reduced cytotoxicity against Vero cells, although were less active than 1. The structure-activity analysis showed that linear, short alkyl groups adjacent to...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Wahba AE,Peng J,Kudrimoti S,Tekwani BL,Hamann MT

    更新日期:2009-11-15 00:00:00

  • 1,3-Dimethyl-7-substituted-1,2,3,4-tetrahydroisoquinolines as probes for the binding orientation of tetrahydroisoquinoline at the active site of phenylethanolamine N-methyltransferase.

    abstract::In order to determine the function of epinephrine (Epi) in the central nervous system, we have targeted the enzyme that catalyzes the final step in the biosynthesis of Epi, phenylethanolamine N-methyltransferase (PNMT; EC 1,2,3,4-Tetrahydroisoquinolines (THIQs) are inhibitors of this enzyme, but also displa...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Grunewald GL,Caldwell TM,Li Q,Criscione KR

    更新日期:1999-05-01 00:00:00