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Bioorganic & Medicinal Chemistry Letters (v.16, #9)

Editorial board (pp. co2).
Graphical contents list (pp. 2313-2326).
David W. Robertson, In Memoriam by Albert J. Robichaud (pp. 2327-2328).

Heteroaromatic side-chain analogs of pregabalin by Robert M. Schelkun; Po-wai Yuen; David J. Wustrow; Jack Kinsora; Ti-Zhi Su; Mark G. Vartanian (pp. 2329-2332).
As part of a program to identify the scope of substituents recognized by the α2-δ protein, a series of heteroaromatic analogs,2, of pregabalin,1, has been identified that possess anticonvulsant activity in the DBA/2 mouse model. The methods of synthesis and preliminary pharmacology are discussed herein.A series of heteroaromatic analogs of pregabalin has been identified that possess anticonvulsant activity in the DBA/2 mouse model. The methods of synthesis and preliminary pharmacology are discussed herein.

Carboxylate bioisosteres of gabapentin by Carmen E. Burgos-Lepley; Lisa R. Thompson; Clare O. Kneen; Simon A. Osborne; Justin S. Bryans; Thomas Capiris; Nirmala Suman-Chauhan; David J. Dooley; Cindy M. Donovan; Mark J. Field; Mark G. Vartanian; Jack J. Kinsora; Susan M. Lotarski; Ayman El-Kattan; Karen Walters; Madhu Cherukury; Charles P. Taylor; David J. Wustrow; Jacob B. Schwarz (pp. 2333-2336).
Ring expansion and acid replacement with tetrazole furnished a compound with a similar pattern of activity to gabapentin.A series of carboxylate bioisosteres of structures related to gabapentin1 have been prepared. When the carboxylate was replaced by a tetrazole, this group was recognized by the α2-δ protein. Further characterization of α2-δ binding compounds14a and14b revealed a similar pattern of functional in vitro and in vivo activity to gabapentin1.

Keywords: Gabapentin; α; 2; -δ subunit


The design and synthesis of human branched-chain amino acid aminotransferase inhibitors for treatment of neurodegenerative diseases by Lain-Yen Hu; Peter A. Boxer; Suzanne R. Kesten; Huangshu J. Lei; David J. Wustrow; David W. Moreland; Liming Zhang; Kay Ahn; Todd R. Ryder; Xiaohong Liu; John R. Rubin; Kelly Fahnoe; Richard T. Carroll; Satavisha Dutta; Douglass C. Fahnoe; Albert W. Probert; Robin L. Roof; Michael F. Rafferty; Catherine R. Kostlan; Jeffrey D. Scholten; Molly Hood; Xiao-Dan Ren; Gerald P. Schielke; Ti-Zhi Su; Charles P. Taylor; Anil Mistry; Patrick McConnell; Charles Hasemann; Jeffrey Ohren (pp. 2337-2340).
The SAR and pharmacological profile of a series of BCATc inhibitors is described.The inhibition of the cytosolic isoenzyme BCAT that is expressed specifically in neuronal tissue is likely to be useful for the treatment of neurodegenerative and other neurological disorders where glutamatergic mechanisms are implicated. Compound2 exhibited an IC50 of 0.8μM in the hBCATc assays; it is an active and selective inhibitor. Inhibitor2 also blocked calcium influx into neuronal cells following inhibition of glutamate uptake, and demonstrated neuroprotective efficacy in vivo. SAR, pharmacology, and the crystal structure of hBCATc with inhibitor2 are described.

Synthesis and structure–activity relationships of novel dipeptides and reduced dipeptides as ligands for melanocortin subtype-4 receptor by Qing Shi; Paul L. Ornstein; Karin Briner; Timothy I. Richardson; Macklin B. Arnold; Ryan T. Backer; Jennifer L. Buckmaster; Emily J. Canada; Christopher W. Doecke; Larry W. Hertel; Nick Honigschmidt; Hansen M. Hsiung; Saba Husain; Steve L. Kuklish; Michael J. Martinelli; Jeffrey T. Mullaney; Thomas P. O’Brien; Matt R. Reinhard; Roger Rothhaar; Jikesh Shah; Zhipei Wu; Chaoyu Xie; John M. Zgombick; Matthew J. Fisher (pp. 2341-2346).
The synthesis and SAR studies on the N-terminal residue of the ‘address element’ are reported.A series of benzylic piperazines (e.g.,4 and5) attached to an ‘address element’, the dipeptide H-d-Tic-d- p-Cl-Phe-OH,3 has been identified as ligands for the melanocortin subtype-4 receptor (MC4R). We describe herein the structure–activity relationship (SAR) studies on the N-terminal residue of the ‘address element’. Several novel dipeptides and reduced dipeptides with high MC4R binding affinities and selectivity emerged from this SAR study.

Keywords: Melanocortin subtype-4 receptor ligands; MC4R


Advances toward new antidepressants beyond SSRIs: 1-Aryloxy-3-piperidinylpropan-2-ols with dual 5-HT1A receptor antagonism/SSRI activities. Part 5 by Kumiko Takeuchi; Todd J. Kohn; Nicholas A. Honigschmidt; Vincent P. Rocco; Patrick G. Spinazze; Susan K. Hemrick-Luecke; Linda K. Thompson; David C. Evans; Kurt Rasmussen; Deanna Koger; David Lodge; Laura J. Martin; Janice Shaw; Penny G. Threlkeld; David T. Wong (pp. 2347-2351).
A series of 1-aryloxy-3-piperidinylpropan-2-ols possessing potent dual 5-HT1A receptor antagonism and serotonin reuptake inhibition was discovered. 1-(1 H-Indol-4-yloxy)-3-(4-benzo[ b]thiophen-2-ylpiperidinyl)propan-2-ols exhibited selective and high affinities at the 5-HT1A receptor and serotonin reuptake site in vitro. In vivo evaluation of this series of compounds demonstrated elevated extracellular serotonin levels from the basal and quick recovery of neuron firing that was presumably suppressed by the initial acute activation of 5-HT1A somatodendritic autoreceptors.A series of 1-aryloxy-3-piperidinylpropan-2-ols possessing potent dual 5-HT1A receptor antagonism and serotonin reuptake inhibition was discovered. 1-(1 H-Indol-4-yloxy)-3-(4-benzo[ b]thiophen-2-ylpiperidinyl)propan-2-ols exhibited selective and high affinities at the 5-HT1A receptor and serotonin reuptake site in vitro. In vivo evaluation of this series of compounds demonstrated elevated extracellular serotonin levels from the basal and quick recovery of neuron firing that was presumably suppressed by the initial acute activation of 5-HT1A somatodendritic autoreceptors.

Keywords: 5-HT; 1A; /SSRI; Serotonin; 5- HT; 1A; receptor antagonist; Selective serotonin reuptake inhibitor; Antidepressants; 1-Aryloxy-3-piperidinylpropan-2-ols


Aza-retinoids as novel retinoid X receptor-specific agonists by Luc J. Farmer; Kristen S. Marron; Stacie S. Canan Koch; C.K. Hwang; E Adam Kallel; Lin Zhi; Alex M. Nadzan; Dave W. Robertson; Youssef L. Bennani (pp. 2352-2356).
A new structurally simple series of potent lipophilic aza-retinoid RXR agonists has been developed. SAR studies for the N-alkyl-azadienoic acids described here demonstrate that the RXR activity profile is sensitive to the N-alkyl chain length. Further, we have expanded the work to include azadienoic acids, which exhibited many accessible conformations leading to a better understanding of the SAR around the series.A new structurally simple series of potent lipophilic aza-retinoids RXR agonists has been developed. SAR studies for the N-alkyl-azadienoic acids described here demonstrate that the RXR activity profile is sensitive to the N-alkyl chain length. Further, we have expanded the work to include azadienoic acids, which exhibited many accessible conformations leading to a better understanding of the SAR around the series.

Keywords: RXR selective retinoids; RXR-agonists


Synthesis and evaluation of succinoyl-caprolactam γ-secretase inhibitors by Lorin A. Thompson; Ann Y. Liauw; Mercy M. Ramanjulu; Padmaja Kasireddy-Polam; Stephen E. Mercer; Thomas P. Maduskuie; Marcie Glicksman; Arthur H. Roach; Jere E. Meredith; Rui-Qin Liu; Andrew P. Combs; Jeffrey N. Higaki; Barbara Cordell; Dietmar Seiffert; Robert C. Zaczek; David W. Robertson; Richard E. Olson (pp. 2357-2363).
The synthesis, evaluation, and structure–activity relationships of a series of succinoyl lactam inhibitors of the Alzheimer’s disease γ-secretase are described.The synthesis, evaluation, and structure–activity relationships of a series of succinoyl lactam inhibitors of the Alzheimer’s disease γ-secretase are described. Beginning with a screening hit with broad proteinase activity, optimization provided compounds with both high selectivity for inhibition of γ-secretase and high potency in cellular assays of Aβ reduction. The SAR and early in vivo properties of this series of inhibitors will be presented.

Keywords: γ-Secretase inhibitors; Alzheimer’s disease; β-Amyloid production inhibitors


RNA specific molecules: Cytotoxic plant alkaloid palmatine binds strongly to poly(A) by Prabal Giri; Maidul Hossain; Gopinatha Suresh Kumar (pp. 2364-2368).
Palmatine, the plant alkaloid, binds strongly to single stranded (ss) poly(A) by mechanism of partial intercalation, leading to its usefulness in inhibition of gene expression in eukaryotic cells.The cytotoxic plant alkaloid palmatine was found to bind strongly by partial intercalation to single stranded poly(A) structure with binding affinity ( Ka) of (8.36±0.26)×105M−1. The binding of palmatine was characterized to be exothermic and enthalpy driven with one palmatine for every two adenine residues. On the other hand, the binding to the double stranded poly(A) has been found to be significantly weak. This study identifies poly(A) as a potential bio-target for the alkaloid palmatine and its use as a lead compound in antitumor drug screening.

Keywords: Palmatine; RNA; Poly(A); Binding; Spectroscopy; ITC


Cespitulactones A and B, new diterpenoids from Cespitularia taeniata by Ya-Ching Shen; Ching-Jen Ho; Yao-Haur Kuo; Yun-Sheng Lin (pp. 2369-2372).
Two new diterpenoids, designated cespitulactones A (1) and B, were isolated from Cespitularia taeniata collected in Taiwan.Two new diterpenoids, designated cespitulactones A (1) and B (2), were isolated from a sample of the soft coral Cespitularia taeniata collected in Taiwan. Compound1 possesses a novel structure with a bond cleavage between C-10 and C-11, and having a 14-membered lactone ring junction between C-10 and C-12. Their structures were elucidated on the basis of extensive spectroscopic analysis and chemical derivatization. The isolated compounds were also evaluated for cytotoxicity toward human cancer cell lines.

Keywords: Cespitulactones; Cespitularia taeniata; Cytotoxicity


Synthesis of phospholipase A2 inhibitory biflavonoids by Jianjun Chen; Hyeun Wook Chang; Hyun Pyo Kim; Haeil Park (pp. 2373-2375).
A series of C–C biflavones was designed to investigate the relationship between structural array of a different flavone–flavone subunit linkage and the inhibitory activity against phospholipase A2 (PLA2). Among six classes of C–C biflavones designed, four classes of C–C biflavones, which have flavone–flavone subunit linkages at A ring–A ring, A ring–B ring, B ring–B ring, and B ring–C ring, were synthesized. The synthetic biflavones exhibited somewhat different inhibitory activities against sPLA2-IIA. Among them, the biflavonea having a C–C 4′–4′ linkage showed comparable inhibitory activity with that of the natural biflavonoid, ochnaflavone, and 7-fold stronger activity than that of amentoflavone. Further chemical modification is being carried out in order to obtain the chemically optimized biflavonoids.A series of C–C biflavones was designed to investigate the relationship between structural array of different flavone–flavone subunit linkage and the inhibitory activity against phospholipase A2 (PLA2). Among six classes of C–C biflavones designed, four classes of C–C biflavones, which have flavone–flavone subunit linkages at A ring–A ring, A ring–B ring, B ring–B ring, and B ring–C ring, were synthesized. The synthetic biflavones exhibited somewhat different inhibitory activities against sPLA2-IIA. Among them, the biflavonea having a C–C 4′–4′ linkage showed comparable inhibitory activity with that of the natural biflavonoid, ochnaflavone, and 7-fold stronger activity than that of amentoflavone. Further chemical modification is being carried out in order to obtain the chemically optimized biflavonoids.

Keywords: Biflavonoids; C–C cross-coupling reaction; Phospholipase A; 2; inhibition


Hispidin analogs from the mushroom Inonotus xeranticus and their free radical scavenging activity by In-Kyoung Lee; Bong-Sik Yun (pp. 2376-2379).
Three new free radical scavengers (1,2, and4) were isolated from the methanolic extract of the fruiting bodies of Inonotus xeranticus (Hymenochaetaceae), along with the known compound davallialactone (3). Their structures were established as hispidin analogs by extensive NMR spectral data. Compounds3 and4 displayed significant scavenging activity against the superoxide radical anion, ABTS radical cation, and DPPH radical, while1 and2 exhibited potent antioxidant effect only against ABTS radical cation.Three new free radical scavengers were isolated from the methanolic extract of the fruiting bodies of Inonotus xeranticus (Hymenochaetaceae), along with the known compound davallialactone. Their structures were established as hispidin analogs by extensive NMR spectral data. Compounds3 and4 displayed significant scavenging activity against the superoxide radical anion, ABTS radical cation, and DPPH radical, while1 and2 exhibited potent antioxidative activity only against ABTS radical cation.

Keywords: Antioxidant; Free radical scavenger; Mushroom; Inonotus xeranticus; Hispidin analog


Design and synthesis of potent β-secretase (BACE1) inhibitors withP1′ carboxylic acid bioisosteres by Tooru Kimura; Yoshio Hamada; Monika Stochaj; Hayato Ikari; Ayaka Nagamine; Hamdy Abdel-Rahman; Naoto Igawa; Koushi Hidaka; Jeffrey-Tri Nguyen; Kazuki Saito; Yoshio Hayashi; Yoshiaki Kiso (pp. 2380-2386).
Recently, we reported potent and small-sized β-secretase (BACE1) inhibitors KMI-420 and KMI-429 in which we replaced the Glu residue at the P4 position of KMI-260 and KMI-360, respectively, with a 1 H-tetrazole-5-carbonyl DAP (l-α,β-diaminopropionic acid) residue. At theP1′ position, these compounds contain one or two carboxylic acid groups, which are unfavorable for crossing the blood–brain barrier. Herein, we report BACE1 inhibitors withP1′ carboxylic acid bioisosteres in order to develop practical anti-Alzheimer’s disease drugs. Among them, tetrazole ring-containing compounds, KMI-570 (IC50=4.8nM) and KMI-684 (IC50=1.2nM), exhibited significantly potent BACE1 inhibitory activities.

Keywords: Alzheimer’s disease; BACE1 inhibitor; β-Secretase; Bioisostere


Bradykinin antagonists modified with dipeptide mimetic β-turn inducers by Maria C. Alcaro; Valerio Vinci; Anna M. D’Ursi; Mario Scrima; Mario Chelli; Sandro Giuliani; Stefania Meini; Marcello Di Giacomo; Lino Colombo; Anna Maria Papini (pp. 2387-2390).
A structure–activity relationship study of Icatibant analogues modified with dipeptide mimetic β-turn inducers is reported.Bradykinin (BK) is involved in a wide variety of pathophysiological processes. Potent BK peptide antagonists can be developed introducing constrained unnatural amino acids, necessary to force the secondary structure of the molecule. In this paper, we report a structure–activity relationship study of two peptide analogues of the potent B2 antagonist HOE 140 by replacing the D-Tic-Oic dipeptide with conformationally constrained dipeptide mimetic β-turn inducers.

Keywords: Bradykinin; Antagonist; Constrained amino acid; β-Turn inducer


Synthesis and antibacterial activity of novel oxazolidinones bearing N-hydroxyacetamidine substituent by Mohamed Takhi; C. Murugan; M. Munikumar; K.M. Bhaskarreddy; Gurpreet Singh; K. Sreenivas; M. Sitaramkumar; N. Selvakumar; J. Das; Sanjay Trehan; Javed Iqbal (pp. 2391-2395).
The synthesis of oxazolidinones possessing N-hydroxyacetamidine group on piperazine scaffold and their in vitro antibacterial activity profile are disclosed herein.Novel oxazolidinone antibacterials containing N-hydroxyacetamidine moiety are synthesized with the diversity at C-5 terminus. These compounds have been evaluated against a panel of clinically relevant Gram-positive and Gram-negative pathogens. Most of the analogs in this series displayed activity superior to Linezolid and in vivo efficacies of selected oxazolidinones are also disclosed herein.

Keywords: Oxazolidinone; Antibacterial; Linezolid; Acetamidine


Anti- Plasmodium activity of imidazole–dioxolane compounds by Jason Z. Vlahakis; Robert T. Kinobe; Kanji Nakatsu; Walter A. Szarek; Ian E. Crandall (pp. 2396-2406).
A series of imidazole–dioxolane compounds were assayed for inhibitory activity in Plasmodium falciparum cultures.A series of imidazole–dioxolane compounds, which we hypothesize should bind to heme and thus interfere with heme catabolism in the parasite, were assayed for inhibitory activity in Plasmodium falciparum cultures and the results were compared to those obtained with Chinese hamster ovary (CHO) cells. The majority of the compounds displayed a similar ratio of inhibitory activity in the two culture systems; however, a number of the compounds tested showed promising anti- Plasmodium activity. The mechanism of action of these compounds remains unclear, however their inability to act synergistically with chloroquine suggests that, if they are inhibiting heme detoxification, they do so in a manner that does not complement the action of chloroquine.

Keywords: Antimalarial; Plasmodium falciparum; Imidazole–dioxolane compounds


Rapid high-throughput detection of peroxide with an acridinium-9-carboxamide: A homogeneous chemiluminescent assay for plasma choline by Maciej Adamczyk; R. Jeffrey Brashear; Phillip G. Mattingly (pp. 2407-2410).
Hydrogen peroxide generated from the enzymatic oxidation of choline was detected using a chemiluminescent acridinium-9-carboxamide. The dose–response for choline (0–50μM) was established in buffer and was applicable to the quantification of choline in human plasma. This homogeneous assay was performed in a 96-well microplate format and required minimal sample volume (1μL) and analysis time (<5s per well).

Keywords: Choline; Chemiluminescence; Homogeneous assay; Acridinium-9-carboxamide


Discovery and SAR of 2-amino-5-[(thiomethyl)aryl]thiazoles as potent and selective Itk inhibitors by Jagabandhu Das; Chunjian Liu; Robert V. Moquin; James Lin; Joseph A. Furch; Steven H. Spergel; Kim W. McIntyre; David J. Shuster; Kathleen D. O’Day; Becky Penhallow; Chen-Yi Hung; Steven B. Kanner; Tai-An Lin; John H. Dodd; Joel C. Barrish; John Wityak (pp. 2411-2415).
A series of structurally novel aminothiazole based small molecule inhibitors of Itk were prepared to elucidate their structure–activity relationships (SARs), selectivity, and cell activity in inhibiting IL-2 secretion in a Jurkat T-cell assay. Compound2 is identified as a potent and selective Itk inhibitor which inhibits anti-TCR antibody induced IL-2 production in mice in vivo.A series of structurally novel aminothiazole based small molecule inhibitors of Itk were prepared to elucidate their structure–activity relationships (SARs), selectivity and cell activity in inhibiting IL-2 secretion in a Jurkat T-cell assay. Compound2 is identified as a potent and selective Itk inhibitor which inhibits anti-TCR antibody induced IL-2 production in mice in vivo.

Keywords: Selective Itk inhibitors; Thiazoles


N6-Ethyl-2-alkynyl NECAs, selective human A3 adenosine receptor agonists by Ran Zhu; Cynthia R. Frazier; Joel Linden; Timothy L. Macdonald (pp. 2416-2418).
A new adenosine analogue ZR1121 is reported. Compared with currently widely used hA3 agonists IB MECA and Cl-IB MECA, this compound has similar activity and about 100 times higher hA3/hA1 selectivity.A series of N6-ethyl-2-alkynyl NECA (5′- N-ethylcarboxamidoadenosine) analogs were synthesized and their binding affinity with the four human adenosine receptors was evaluated. One of the compounds ZR1121 shows high affinity with hA3 receptor and its selectivity over hA1 receptor is 1–2 log orders greater than IB-MECA or Cl-IB-MECA, the currently employed selective A3 agonists.

Keywords: Keyword; A; 3; adenosine agonist human NECA; N; 6; -ethyl


Alkynyl pyrimidines as dual EGFR/ErbB2 kinase inhibitors by Alex G. Waterson; Kirk L. Stevens; Michael J. Reno; Yue-Mei Zhang; Eric E. Boros; Frederic Bouvier; Abdullah Rastagar; David E. Uehling; Scott H. Dickerson; Bryan Reep; Octerloney B. McDonald; Edgar R. Wood; David W. Rusnak; Krystal J. Alligood; Sharon K. Rudolph (pp. 2419-2422).
Anilinoalkynylpyrimidines were prepared and evaluated as dual EGFR/ErbB2 kinase inhibitors. A preference was found for substituted phenyl and heteroaromatic rings attached to the alkyne. In addition, the presence of a potential hydrogen bond donor appended to this ring was favored. Selected molecules in the series demonstrated some activity against human tumor cell lines.Anilinoalkynylpyrimidines were prepared and evaluated as dual EGFR/ErbB2 kinase inhibitors. A preference was found for substituted phenyl and heteroaromatic rings attached to the alkyne. In addition, the presence of a potential hydrogen bond donor appended to this ring was favored. Selected molecules in the series demonstrated some activity against human tumor cell lines.

Keywords: Receptor tyrosine kinase; Kinase inhibition; EGFR; ErbB2; Medicinal chemistry


Identification of cytotoxic, T-cell-selective 1,4-benzodiazepine-2,5-diones by Tasha M. Francis; Thomas B. Sundberg; Joanne Cleary; Todd Groendyke; Anthony W. Opipari Jr.; Gary D. Glick (pp. 2423-2427).
A 1,4-benzodiazepine-2,5-dione (BZD) library was evaluated for lymphotoxic members. When the C3 substituent contains an electron-rich heterocycle, the resulting BZDs have sub-micromolar potency and are selective for T-cells.A family of 1,4-benzodiazepine-2,5-diones (BZDs) has been synthesized and evaluated against transformed B- and T-cells for lymphotoxic members. A large aromatic group on the C3 position is critical for cytotoxicity. When the C3 moiety contains an electron-rich heterocycle, the resulting BZDs have sub-micromolar potency and are selective for T-cells. Cell death is consistent with apoptosis and does not result from inhibition of the mitochondrial FoF1-ATPase, which is the molecular target of recently reported cytotoxic 1,4-benzodiazepines. Collectively, these studies begin to characterize some of the structural elements required for the activity of a novel family of T-cell-selective lymphotoxic agents.

Keywords: Apoptosis; Autoimmunity benzodiazepine; Cancer; Mitochondria


Synthesis of lipopolyhydroxylalkyleneamines for gene delivery by Qun Li; Guisheng Zhang; Joie Marhefka; Marina V. Kameneva; Dexi Liu (pp. 2428-2432).
A series of new lipopolyhydroxylalkyleneamines was synthesized and their activity in gene delivery was characterized.Various bis(2-hydroxy-3-chloropropyl)alkylamines were synthesized by coupling primary amine with epichlorohydrin and utilized as a monomer to react with ethylenediamine (EDA), N, N′-dimethylethylenediamine (DMEDA), or tetramethylethylenediamine (TMEDA) to generate a series of lipopolyhydroxylalkyleneamines. The number- and weight-average molecular weight ( M n and M w) and polydispersity index ( M w/ M n) of the lipopolyhydroxylalkyleneamines were dependent on reactant solvent and reaction temperature. The compounds with EDA as backbone have better transfection activity and lower toxicity than those with DMEDA and TMEDA as backbone.

Keywords: Keyword; Gene delivery


Synthesis of a bis-azido analogue of acromelic acid for radioisotope-free photoaffinity labeling and biochemical studies by Pi Sun; Guang Xing Wang; Kyoji Furuta; Masaaki Suzuki (pp. 2433-2436).
A novel bis-azido-containing acromelic acid analogue with the aromatic N3 acting as a photoaffinity group and the alkyl N3 group acting as a detecting group was designed and synthesized as a potential radioisotope-free biochemical probe for studies on kainoid receptors.A novel acromelic acid analogue containing a phenyl group possessing two different types of azido functional groups, of which one is the aromatic N3 acting as a photoaffinity group to bind to a target protein by photoirradiation and the other is alkyl N3 group which survives photolysis acting as a detecting group through the Staudinger–Bertozzi reaction to identify the ligated product, was designed and synthesized as a radioisotope-free biochemical probe potentially for studies on kainoid receptors.

Keywords: Acromelic acid; Radioisotopic free; Molecular probe; Bis-azodo analogue; Staudinger–Bertozzi reaction; Photoaffinity


α-Methylated derivatives of 2-arachidonoyl glycerol: Synthesis, CB1 receptor activity, and enzymatic stability by Teija Parkkari; Mikko Myllymki; Juha R. Savinainen; Susanna M. Saario; Joel A. Castillo-Melndez; Jarmo T. Laitinen; Tapio Nevalainen; Ari M.P. Koskinen; Tomi Jrvinen (pp. 2437-2440).
α-Methylated analogues of the endogenous cannabinoid, 2-arachidonoyl glycerol (2-AG), were synthesized aiming to the improved enzymatic stability of 2-AG. In addition, the CB1 activity properties of fluoro derivatives of 2-AG were studied. The CB1 receptor activity was determined by the [35S]GTPγS binding assay, and the enzymatic stability of α-methylated analogues was determined in rat cerebellar membranes. The results indicate that even if the α-methylated 2-AG derivatives are slightly weaker CB1 receptor agonists than 2-AG, they are clearly more stable than 2-AG. In addition, the results showed that the replacement of the hydroxyl group(s) of 2-AG by fluorine does not improve the CB1 activity of 2-AG.

Keywords: Cannabinoid; CB1 receptor; 2-AG; Enzymatic stability; Stereoselective synthesis


In vitro antioxidant activity of acetylated and benzoylated derivatives of polysaccharide extracted from Ulva pertusa (Chlorophyta) by Huimin Qi; Quanbin Zhang; Tingting Zhao; Rugui Hu; Kun Zhang; Zhien Li (pp. 2441-2445).
Acetylated and benzoylated ulvans were prepared and their in vitro antioxidant activities were determined.The antioxidant activity of natural ulvan and its derivatives (acetylated and benzoylated ulvans) in vitro was determined, including scavenging activity against superoxide and hydroxyl radicals, reducing power, and chelating ability. Obvious differences in antioxidant activity between natural ulvan and its derivatives were observed, moreover, the antioxidant activity of acetylated and benzoylated ulvans was stronger than that of natural ulvan.

Keywords: Abbreviations; DMAc; N; ,; N; -dimethylacetamide; LiCl; lithium chloride; p; -TsCl; p; -toluenesulfonyl chloride; Ac; 2; O; acetic anhydride; NBT; nitro blue tetrazolium; PMS; phenazine methosulfate; NADH; nicotinamide adenine dinucleotide reduced; EDTA; ethylenediaminetetraacetic acid; H; 2; O; 2; hydrogen peroxide; TCA; trichloroacetic acid; TBA; thiobarbituric acid; Vc; Vitamin CUlvan; Antioxidant activity; Acetylated and benzoylated ulvans


Taxoid from the needles of the Himalayan yew Taxus wallichiana with cytotoxic and immunomodulatory activities by Sunil K. Chattopadhyay; Anirban Pal; Prakas R. Maulik; Tanpreet Kaur; Ankur Garg; Suman Preet S. Khanuja (pp. 2446-2449).
From the needles of Taxus wallichiana, a taxoid was isolated, characterized and its cytotoxic and immunomodulatory activities were evaluated.The needles of Taxus wallichiana gave a taxoid 1-hydroxy- 2-deacetoxy-5-decinnamoyl-taxinine j, whose structure has been established by spectroscopic data and confirmed by X-ray crystallography. The taxoid possesses significant cytotoxic and immunomodulatory activity.

Keywords: Taxus wallichiana; Taxaceae; Taxoid; Structure determination; X-ray analysis; Cytotoxic; Immunomodulatory


Preparation and in vitro photodynamic activities of novel axially substituted silicon (IV) phthalocyanines and their bovine serum albumin conjugates by Xiong-Jie Jiang; Jian-Dong Huang; Yu-Jiao Zhu; Fen-Xiang Tang; Dennis K.P. Ng; Jian-Cheng Sun (pp. 2450-2453).
The new silicon (IV) phthalocyanine2 was found to be essentially non-aggregated and strongly fluorescent in water. The compound and its non-covalent bovine serum albumin conjugate (2-BSA) exhibited extremely high photodynamic activities toward B16 melanoma cancer cell line with IC50 values down to 33 and 38nM, respectively.Two novel axially substituted phthalocyanines, namely bis(4-(4-acetylpiperazine)phenoxy)phthalocyaninatosilicon (IV) (1) and its N-methylated derivative2, have been synthesized. The dicationic phthalocyanine2 is non-aggregated in water and exhibits good photophysical properties. The non-covalent BSA conjugates of these compounds have also been prepared. Compound2 and the conjugate2-BSA show extremely high photodynamic activities toward B16 melanoma cancer cell lines. The corresponding 50% growth-inhibitory (IC50) ratios are 33 and 38nM, respectively.

Keywords: Phthalocyanines; Silicon; Albumin; Photodynamic therapy; Photosensitizers


Synthesis and antitumor activity of icogenin and its analogue by Shujie Hou; Peng Xu; Liang Zhou; Dequan Yu; Pingsheng Lei (pp. 2454-2458).
Icogenin: R=α-l-rhamnopyranosyl-(1→2)-[ β-d-glucopyranosyl(1→3)]-β-d-glucopyranosyl (1). The designed analogue of icogenin: R=α-l-rhamnopyranosyl-(1→2)-[β-d-glucopyranosyl(1→3)]-α-d-glucopyranosyl (2).Natural saponin icogenin, namely 25( S)-22- O-methyl-furost-5-en-3β,26-dio-3- O-α-l-rhamnopyranosyl-(1→2)-[β-d-glucopyranosyl-(1→3)]-β-d-glucopyranoside, and one of its analogues, 25( S)-22- O-methyl-furost-5-en-3β,26-dio-3- O-α-l-rhamnopyranosyl-(1→2)-[β-d-glucopyranosyl-(1→3)]-α-d-glucopyranoside, were first synthesized via line strategy and convergent approach, respectively. It was observed that icogenin and its analogue show potent antitumor activity in vitro.

Keywords: Saponin; Icogenin; Glycosylation; Cytotoxicity


Radanamycin, a macrocyclic chimera of radicicol and geldanamycin by Mingwen Wang; Gang Shen; Brian S.J. Blagg (pp. 2459-2462).
A chimera of radicicol and geldanamycin has been prepared and evaluated against MCF-7 breast cancer cells.Radicicol and geldanamycin are potent inhibitors of the Hsp90 protein folding machinery, which is an emerging target for the development of cancer chemotherapeutics. However, radicicol is inactive in vivo and geldanamycin suffers from its redox-active behavior that produces toxicity unrelated to Hsp90 inhibition. It was proposed that a chimeric molecule containing the resorcinol ring of radicicol and the quinone of geldanamycin could provide an opportunity to elucidate structure–activity relationships for both natural products and serve as a starting point for the development of more potent inhibitors. Synthesis of the macrocyclic chimera named radanamycin is reported along with the biological activity exhibited by this compound in MCF-7 breast cancer cells.

Keywords: Hsp90; Inhibitors; Geldanamycin; Radicicol; Cancer


A practical and green approach towards synthesis of dihydropyrimidinones: Using heteropoly acids as efficient catalysts by Ezzat Rafiee; Hadi Jafari (pp. 2463-2466).
One-pot synthesis of dihydropyrimidones catalyzed by heteropoly acids as efficient, inexpensive, easily available and environmentally friendly catalysts. High to excellent yields, short reaction times and compatibility with various functional groups are features of this new procedure.A simple and green chemistry procedure for the synthesis of dihydropyrimidinones using heteropoly acid mediated cyclocondensation reaction is described. This method provides an efficient and much improved modification of the original Biginelli reaction reported in 1893, in terms of high yields, and short reaction times. It has the ability to allow a wide variety of substitutions in all three components.

Keywords: Dihydropyrimidinones or thiones (DHPMs); Heteropoly acid; Multicomponent reactions (MCR); Biginelli reaction


Structure–activity relationship of thiopyrimidines as mGluR5 antagonists by Lance G. Hammerland; Martin Johansson; Jonas Malmstrm; Jan P. Mattsson; Alexander B.E. Minidis; Karolina Nilsson; Alecia Peterson; David Wensbo; Andreas Wllberg; Krister sterlund (pp. 2467-2469).
Structure–activity relationship investigation of thiopyrimidines as mGluR5 antagonists.Structure–activity relationship investigations of the thiopyrimidine (1), an HTS hit with micromolar activity as a metabotropic glutamate receptor 5 (mGluR5) antagonist, led to compounds with sub-micromolar activity.

Keywords: Thiopyrimidine; Metabotropic glutamate receptor; mGluR5


Caged gene-inducer spatially and temporally controls gene expression and plant development in transgenic Arabidopsis plant by Ken-ichiro Hayashi; Kazuya Hashimoto; Naoyuki Kusaka; Atsushi Yamazoe; Hidehiro Fukaki; Masao Tasaka; Hiroshi Nozaki (pp. 2470-2474).
Two caged steroids were synthesized as caged gene-inducers and applied to transgenic plants harboring steroid-inducible gene activation systems. Light could control the spatial and temporal expression of transgene and plant development.Two new types of caged gene-inducers, caged 17β-estradiol and caged dexamethazone, were synthesized. Caged gene-inducers were applied to transgenic Arabidopsis plants carrying a steroid hormone-inducible transactivation system. Light uncaged caged gene-inducers and controlled spatial and temporal expression of transgene in the transgenic plant. Furthermore, caged gene-inducers enabled the control of root development by light.

Keywords: Caged hormone; Gene expression; Light


Substrate specificity of strictosidine synthase by Elizabeth McCoy; M. Carmen Galan; Sarah E. O’Connor (pp. 2475-2478).
The substrate requirements for strictosidine synthase are systematically and quantitatively examined and the enzymatically generated compounds are processed by the second enzyme in this natural product biosynthetic pathway.Strictosidine synthase catalyzes a Pictet–Spengler reaction in the first step in the biosynthesis of terpene indole alkaloids to generate strictosidine. The substrate requirements for strictosidine synthase are systematically and quantitatively examined and the enzymatically generated compounds are processed by the second enzyme in this biosynthetic pathway.

Keywords: Alkaloids; Biosynthesis; Enzyme catalysis; Glycosidase; Pictet–Spengler


Synthesis and SAR studies of very potent imidazopyridine antiprotozoal agents by Tesfaye Biftu; Dennis Feng; Michael Fisher; Gui-Bai Liang; Xiaoxia Qian; Andrew Scribner; Richard Dennis; Shuliang Lee; Paul A. Liberator; Chris Brown; Anne Gurnett; Penny S. Leavitt; Donald Thompson; John Mathew; Andrew Misura; Samantha Samaras; Tamas Tamas; Joseph F. Sina; Kathleen A. McNulty; Crystal G. McKnight; Dennis M. Schmatz; Matthew Wyvratt (pp. 2479-2483).
Compounds10a (IC50 110pM) and21 (IC50 40pM) are the most potent inhibitors of Eimeria tenella cGMP-dependent protein kinase activity reported to date and are efficacious in the in vivo antiparasitic assay when administered to chickens at 12.5 and 6.25ppm levels in the feed. However, both compounds are positive in the Ames microbial mutagenesis assay which precludes them from further development as antiprotozoal agents in the absence of negative lifetime rodent carcinogenicity studies.Compounds10a (IC50 110pM) and21 (IC50 40pM) are the most potent inhibitors of Eimeria tenella cGMP-dependent protein kinase activity reported to date and are efficacious in the in vivo antiparasitic assay when administered to chickens at 12.5 and 6.25ppm levels in the feed. However, both compounds are positive in the Ames microbial mutagenesis assay which precludes them from further development as antiprotozoal agents in the absence of negative lifetime rodent carcinogenicity studies.

Keywords: Protein kinase G; Antiprotozoan; Anticoccidial; Imidazopyridine


Studies on synthesis and evaluation of quantitative structure–activity relationship of 10-methyl-6-oxo-5-arylazo-6,7-dihydro-5 H-[1,3]azaphospholo[1,5- d][1,4]benzodiazepin-2-phospha-3-ethoxycarbonyl-1-phosphorus dichlorides by Ashok Kumar; Pratibha Sharma; V.K. Gurram; Nilesh Rane (pp. 2484-2491).
A series of [1,3]azaphospholo [1,5- d][1,4] benzodiazepin-3-ethoxycarbonyl-1-phosphorus dichlorides have been synthesized. Their chemical structures are confirmed by spectral and elemental analysis data. These synthesized compounds are subjected to antimicrobial activity using ampicillin and clotrimazole as reference antibiotic drugs. Quantitative structure–activity relationship (QSAR) investigations are applied to find the correlation between evaluated biological activities and physicochemical descriptors. Significant correlations are obtained between biological activity and the polarizability parameter (MR) of the compounds studied.A new series of 10-methyl-6-oxo-5-arylazo-6,7-dihydro-5 H-[1,3]azaphospholo[1,5- d][1,4]benzodiazepin-2-phospha-3-ethoxycarbonyl-1-phosphorus dichlorides11ap has been synthesized and evaluated as antimicrobial agents. Structures of all the synthesized compounds were established on the basis of elemental analysis and spectroscopic data. Quantitative structure–activity relationship (QSAR) investigations were applied to find out the correlation between the experimentally evaluated activity with various parameters of the compounds studied. QSAR equations showed that the molecular refractivity correlates significantly with the antimicrobial activity.

Keywords: 1,4-Benzodiazepine; Azaphohole; Intramolecular cyclocondensation; Antimicrobial activity; QSAR; Molecular refractive index (MR)


Investigation of the mechanism of action of 3-(4-bromophenyl)-5-acyloxymethyl-2,5-dihydrofuran-2-one against Candida albicans by flow cytometry by Lus A. Vale-Silva; Vladimr Buchta; Doris Vokurkov; Milan Pour (pp. 2492-2495).
Preliminary investigations on the mechanism of action of 3-(4-bromophenyl)-5-acyloxymethyl-2,5-dihydrofuran-2-one against Candida albicans by flow cytometry, using PI, DiBAC4 (3), and FUN-1, and determination of the kinetics of growth inhibition are reported.The mechanism of action of the antifungal agent 3-(4-bromophenyl)-5-acyloxymethyl-2,5-dihydrofuran-2-one against Candida albicans was investigated by flow cytometry, using propidium iodide, DiBAC4(3), and FUN-1 as the fluorescent dyes. A related but less active agent, together with amphotericin B and fluconazole, was tested in parallel for comparison of the results. The incrustoporine derivative was found to have a potent fungicidal activity on C. albicans, resulting in damage of cell membrane.

Keywords: Incrustoporine; Furanones; Antifungal; Mechanism of action; Flow cytometry; Candida


Three-dimensional solution structure of EM703 with potent promoting activity of monocyte-to-macrophage differentiation by Hiroaki Gouda; Toshiaki Sunazuka; Kiminari Yoshida; Akihiro Sugawara; Yusuke Sakoh; Satoshi Ōmura; Shuichi Hirono (pp. 2496-2499).
The three-dimensional structural features of EM703, which might be important for its potent promoting activity of monocyte-to-macrophage differentiation, are reported.EM703, which is an erythromycin derivative synthesized by our group, has a potent promoting activity of monocyte-to-macrophage differentiation in vitro. Its activity is approximately 300 times higher than that of erythromycin A (EM-A). In this study, we determined three-dimensional (3D) solution structures of EM703 and EM-A, and compared them using a superposition method, in order to investigate the 3D structure–activity relationship. We found a distinct difference between the 3D structures of these molecules, which might be an important factor in their divergent activities.

Keywords: Erythromycin A; Erythromycin derivative; Immunomodulatory activity; NMR; Molecular dynamics; Three-dimensional solution structure; Alignment; QSAR


Ketopiperazine-based renin inhibitors: Optimization of the “C? ring by Daniel D. Holsworth; Cuiman Cai; Xue-Min Cheng; Wayne L. Cody; Dennis M. Downing; Noe Erasga; Chitase Lee; Noel A. Powell; Jeremy J. Edmunds; Michael Stier; Mehran Jalaie; Erli Zhang; Pat McConnell; Michael J. Ryan; John Bryant; Tingsheng Li; Aparna Kasani; Eric Hall; Rajendra Subedi; Mohammad Rahim; Samarendra Maiti (pp. 2500-2504).
A series of ketopiperazine-based renin inhibitors designed to interact in the S3 sub-pocket of the renin protein were evaluated for renin inhibitory activity. The investigation revealed that linear and sterically small side chain substituents are preferred in the S3 sub-pocket for optimal renin inhibition. Polar groups in the S3 sub-pocket were not well tolerated and caused a reduction in renin inhibitory activity. Further, compounds with clog P’s⩽3 demonstrated a dramatic reduction in CYP3A4 inhibitory activity.A systematic investigation of the S3 sub-pocket activity requirements was conducted. It was observed that linear and sterically small side chain substituents are preferred in the S3 sub-pocket for optimal renin inhibition. Polar groups in the S3-sub-pocket were not well tolerated and caused a reduction in renin inhibitory activity. Further, compounds with clog P’s⩽3 demonstrated a dramatic reduction in CYP3A4 inhibitory activity.

Keywords: Renin inhibitor; Hypertension; Ketopiperazine; CYP3A4


Identification of potent phenyl imidazoles as opioid receptor agonists by Henry J. Breslin; Chaozhong Cai; Tamara A. Miskowski; Santosh V. Coutinho; Sui-Po Zhang; Pamela Hornby; Wei He (pp. 2505-2508).
Using previously reported opioid receptor (OR) agonist analogs4ac as starting points, the structure–activity relationship (SAR) for their related series has been further refined. This SAR study has led to the identification of 2,6-di-Me-Tyr (DMT) analogs4h and4j as the most potent OR agonist within the series. In addition, it was discovered that 4-(aminocarbonyl)-2,6-dimethyl-Phe is a reasonable bioisostere surrogate for the DMT moiety, as supported by the OR activities of compounds4x and4y.

Keywords: Opioid receptor ligands; Opioid receptor agonist; DMT; 2,6-Dimethyl-Tyr; 4-(Aminocarbonyl)-2,6-dimethyl-Phe; 2,6-Di-Me-4-carboxamido-Phe; Phenyl imidazole


The spermicidal and antitrichomonas activities of SSRI antidepressants by V.S. Kiran Kumar S.T.; Vishnu Lal Sharma; Pratibha Tiwari; Divya Singh; Jagdamba Prasad Maikhuri; Gopal Gupta; Man Mohan Singh (pp. 2509-2512).
The study investigated spermicidal and antitrichomonas activities of selective serotonin reuptake inhibitor (SSRI) antidepressants with a view to generate new lead for development of dual-function spermicidal microbicides, which is an urgent global need. FluoxetineHCl (1) was found to be most promising among the SSRIs studied.The study investigated spermicidal and antitrichomonas activities of selective serotonin reuptake inhibitor (SSRI) antidepressants with a view to generate new lead for development of dual-function spermicidal microbicides, which is an urgent global need. Fluoxetine, Sertraline, and Fluvoxamine exhibited both spermicidal and anti-STI (antitrichomonas) activities in vitro, whereas Paroxetine and Citalopram showed only the spermicidal activity. Fluoxetine exhibited better activity profile than the other antidepressant drugs with its spermicidal and antitrichomonas activities being comparable to that of the OTC contraceptive Nonoxynol-9. The non-detergent nature of Fluoxetine and a much lower spermicidal ED50 value (than N-9) may add considerably to its merit as a candidate for microbicidal contraceptive. Thus, the antidepressants exhibiting both spermicidal and antitrichomonas activities might provide useful lead for the development of novel, dual-function spermicidal contraceptives.

Keywords: Spermicidal activity; Antitrichomonas activity; SSRI; Antidepressant


Development of siRNA for therapeutics: Efficient synthesis of phosphorothioate RNA utilizing phenylacetyl disulfide (PADS) by Vasulinga T. Ravikumar; Mark Andrade; Recaldo L. Carty; Amy Dan; Steve Barone (pp. 2513-2517).
Efficient synthesis of phosphorothioate RNA (PS-RNA) is demonstrated by using phenylacetyl disulfide (PADS) in a mixture of pyridine and acetonitrile (1:1, v/v) for 3min. Sulfurization is achieved with >99.8% stepwise efficiency. This reagent also performs well during synthesis of RNA containing PS:PO mixed backbone.Efficient synthesis of phosphorothioate RNA (PS-RNA) is demonstrated by using phenylacetyl disulfide (PADS) in a mixture of pyridine and acetonitrile (1:1, v/v) for 3min. Sulfurization is achieved with >99.8% stepwise efficiency. This reagent also performs efficiently during synthesis of RNA containing PS:PO mixed backbone.

Keywords: siRNA; Oligonucleotide; Phosphorothioates; PADS; Sulfurization; Solid-support synthesis


Synthesis of fluorescent derivatives of wortmannin and demethoxyviridin as probes for phosphatidylinositol 3-kinase by Jos-Luis Giner; Karen A Kehbein; James A. Cook; Michele C. Smith; Chris J. Vlahos; John A. Badwey (pp. 2518-2521).
Fluorescent analogs were synthesized of the potent PI 3-kinase inhibitors, wortmannin and demethoxyviridin. The esterification of 11-deacetylwortmannin, 17-hydroxywortmannin, and demethoxyviridin with the fluorescent carboxylic acids NBD-sarcosine and 7-dimethylaminocoumarin-4-acetic acid generated six novel fluorescent esters. Potent inhibition of PI 3-kinase-α was observed for the derivatives of 11-desacetylwortmannin and demethoxyviridin.

Keywords: Enzyme inhibitors; Fluorescent probes; Phosphoinositol 3-kinase; Steroidal drugs


Antibacterial activity of (−)-deoxypseudophrynaminol versus its racemate and derivatives by Andrew V. Dix; Carly M. Meseck; Adam J. Lowe; Miguel O. Mitchell (pp. 2522-2524).
(−)-(3a S,8a S)-Deoxypseudophrynaminol (R1=CH3, R2=H) has 43-fold greater antibacterial potency than the racemate at 40μg/mL against Staphylococcus aureus. When R1=CO2CH3 and R2=prenyl, there is no antibacterial activity, but there is weak antibacterial activity when R1=CH3 and R2=prenyl.(−)-Deoxypseudophrynaminol1 possesses 43-fold greater antibacterial potency than the racemate toward Staphylococcus aureus, indicating that the (−)-enantiomer is the biologically active isomer in this assay. Comparison of the percent growth inhibition by derivatives of1 indicates that prenylation of N8 and replacement of N1-methyl by methyl carbamate are detrimental to antibacterial potency. (−)-1 is a promising lead structure for the development of the novel hexahydropyrrolo[2,3- b]indole class of antibacterial agents.

Keywords: Indoles; Hexahydropyrrolo[2,3-; b; ]indoles; Antibacterial; Deoxypseudophrynaminol; Debromoflustramine


The synthesis of highly potent, selective, and water-soluble agonists at the human adenosine A3 receptor by Michael P. DeNinno; Hiroko Masamune; Lois K. Chenard; Kenneth J. DiRico; Cynthia Eller; John B. Etienne; Jeanene E. Tickner; Scott P. Kennedy; Delvin R. Knight; Jimmy Kong; Joseph J. Oleynek; W. Ross Tracey; Roger J. Hill (pp. 2525-2527).
Using a combination of parallel and directed synthesis, the discovery of a highly potent and selective series of adenosine A3 agonists was achieved. High aqueous solubility, required for the intended parenteral route of administration, was achieved by the presence of one or two basic amine functional groups.

Keywords: Adenosine; Agonist; A; 3; Cardioprotection


Substituted coumarins as potent 5-lipoxygenase inhibitors by Erich L. Grimm; Christine Brideau; Nathalie Chauret; Chi-Chung Chan; Daniel Delorme; Yves Ducharme; Diane Ethier; Jean-Pierre Falgueyret; Richard W. Friesen; Jocelyne Guay; Pierre Hamel; Denis Riendeau; Chantal Soucy-Breau; Philip Tagari; Yves Girard (pp. 2528-2531).
A novel series of substituted coumarin derivatives has been synthesized. SAR studies in this series led to the identification of inhibitor1.Leukotriene biosynthesis inhibitors have potential as therapeutic agents for asthma and inflammatory diseases. A novel series of substituted coumarin derivatives has been synthesized and the structure–activity relationship was evaluated with respect to their ability to inhibit the formation of leukotrienes via the human 5-lipoxygenase enzyme.

Keywords: 5-Lipoxygenase; Leukotrienene inhibitor; Coumarin; Structure–activity relationship


Design and synthesis of 2,3,4,9-tetrahydro-1 H-carbazole and 1,2,3,4-tetrahydro-cyclopenta[ b]indole derivatives as non-nucleoside inhibitors of hepatitis C virus NS5B RNA-dependent RNA polymerase by Ariamala Gopalsamy; Mengxiao Shi; Gregory Ciszewski; Kaapjoo Park; John W. Ellingboe; Mark Orlowski; Boris Feld; Anita Y.M. Howe (pp. 2532-2534).
A novel class of HCV NS5B RNA dependent RNA polymerase inhibitors containing 2,3,4,9-tetrahydro-1 H-carbazole and 1,2,3,4-tetrahydro-cyclopenta[ b]indole scaffolds and their structure–activity relationship are described.A novel class of HCV NS5B RNA dependent RNA polymerase inhibitors containing 2,3,4,9-tetrahydro-1 H-carbazole and 1,2,3,4-tetrahydro-cyclopenta[ b]indole scaffolds were designed and synthesized. Optimization of the aromatic region showed preference for 5,8-disubstitution pattern in both the scaffolds examined while favoring the n-propyl moiety for the C-1 position. 1,2,3,4-tetrahydro-cyclopenta[ b]indole scaffold was slightly more potent than the corresponding 2,3,4,9-tetrahydro-1 H-carbazole and analogue36 displayed an IC50 of 550nM against HCV NS5B enzyme.

Keywords: Tetrahydro-1; H; -carbazole; Tetrahydro-cyclopenta[; b; ]indole; NS5B RNA-dependent RNA polymerase inhibitor; HCV inhibitor


Low molecular weight indole fragments as IMPDH inhibitors by Rebekah E. Beevers; George M. Buckley; Natasha Davies; Joanne L. Fraser; Francis C. Galvin; Duncan R. Hannah; Alan F. Haughan; Kerry Jenkins; Stephen R. Mack; William R. Pitt; Andrew J. Ratcliffe; Marianna D. Richard; Verity Sabin; Andrew Sharpe; Sophie C. Williams (pp. 2535-2538).
The study of non-oxazole containing indole fragments as inhibitors of inosine monophosphate dehydrogenase (IMPDH) is described. The synthesis and in vitro inhibitory values for IMPDH II are discussed.The study of non-oxazole containing indole fragments as inhibitors of inosine monophosphate dehydrogenase (IMPDH) is described. The synthesis and in vitro inhibitory values for IMPDH II are discussed.

Keywords: IMPDH; Inosine monophosphate dehydrogenase; Fragment


Novel indole inhibitors of IMPDH from fragments: Synthesis and initial structure–activity relationships by Rebekah E. Beevers; George M. Buckley; Natasha Davies; Joanne L. Fraser; Francis C. Galvin; Duncan R. Hannah; Alan F. Haughan; Kerry Jenkins; Stephen R. Mack; William R. Pitt; Andrew J. Ratcliffe; Marianna D. Richard; Verity Sabin; Andrew Sharpe; Sophie C. Williams (pp. 2539-2542).
The elaboration of previously reported indole fragments as inhibitors of inosine monophosphate dehydrogenase (IMPDH) is described. The synthesis, in vitro inhibitory values for IMPDH II, PBMC proliferation and physicochemical properties are discussed.The elaboration of previously reported indole fragments as inhibitors of inosine monophosphate dehydrogenase (IMPDH) is described. The synthesis, in vitro inhibitory values for IMPDH II, PBMC proliferation and physicochemical properties are discussed.

Keywords: IMPDH; Inosine monophosphate dehydrogenase; Fragment elaboration


4-Amino derivatives of the Hsp90 inhibitor CCT018159 by Xavier Barril; Mandy C. Beswick; Adam Collier; Martin J. Drysdale; Brian W. Dymock; Alexandra Fink; Kate Grant; Robert Howes; Allan M. Jordan; Andrew Massey; Allan Surgenor; Joanne Wayne; Paul Workman; Lisa Wright (pp. 2543-2548).
Novel piperazinyl, morpholino and piperidyl derivatives of the pyrazole-based Hsp90 inhibitor CCT018159 have been prepared and the observed SAR explained by X-ray co-crystallography with Human Hsp90. The most potent of the new compounds has an IC50 of less than 600nM against the enzyme and demonstrates low micromolar inhibition of tumour cell proliferation.Novel piperazinyl, morpholino and piperidyl derivatives of the pyrazole-based Hsp90 inhibitor CCT018159 are described. Structure–activity relationships have been elucidated by X-ray co-crystal analysis of the new compounds bound to the N-terminal domain of human Hsp90. Key features of the binding mode are essentially identical to the recently reported potent analogue VER-49009. The most potent of the new compounds has a methylsulfonylbenzyl substituent appended to the piperazine nitrogen, possesses an IC50 of less than 600nM binding against the enzyme and demonstrates low micromolar inhibition of tumour cell proliferation.

Keywords: Hsp90; Cancer; Structure-based drug design; Pyrazole; X-ray crystallography


Dipeptide nitrile inhibitors of cathepsin K by Eva Altmann; Reiner Aichholz; Claudia Betschart; Thomas Buhl; Jonathan Green; Ren Lattmann; Martin Missbach (pp. 2549-2554).
A series of dipeptidyl nitriles as inhibitors of cathepsin K have been explored starting from lead structure1 (Cbz–Leu–NH–CH2–CN, IC50=39nM). Attachment of non-natural amino acid side chains in P1 and modification of the P3 subunit led to inhibitors with higher potency and improved pharmacokinetic properties.A series of dipeptidyl nitriles as inhibitors of cathepsin K have been explored starting from lead structure1 (Cbz–Leu–NH–CH2–CN, IC50=39nM). Attachment of non-natural amino acid side chains in P1 and modification of the P3 subunit led to inhibitors with higher potency and improved pharmacokinetic properties.

( R)-Sila-venlafaxine: A selective noradrenaline reuptake inhibitor for the treatment of emesis by Graham A. Showell; Matthew J. Barnes; Jrgen O. Daiss; John S. Mills; John G. Montana; Reinhold Tacke; Julie B.H. Warneck (pp. 2555-2558).
The in vitro profile and in vivo anti-emetic activity of the selective noradrenaline reuptake inhibitor ( R)-2 are reported.Sila-substitution of drugs (the carbon/silicon switch) is a concept that is being successfully used for the development of new chemical entities. The ( R)-sila-analogue of the antidepressant venlafaxine is devoid of the serotonin reuptake inhibition observed with the marketed drug, leading to a selective noradrenaline reuptake inhibitor displaying anti-emetic properties.

Keywords: Sila-substitution; Noradrenaline reuptake inhibitor; Anti-emetic

Corrigendum to “Hetaryl imidazoles: Novel dual inhibitors of VEGF receptors I and II? [Bioorg. Med. Chem. Lett. 16 (2006) 1440–1444] by Alexander S. Kiselyov; Marina Semenova; Victor V. Semenov; Evgueni Piatnitski; Shawn Ouyang (pp. 2559-2559).
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