Potential C-terminal-domain inhibitors of heat shock protein 90 derived from a C-terminal peptide helix

August 6, 2014, 1:58 am

≫ Next: Selective inhibition of human carbonic anhydrases by novel amide derivatives of probenecid: Synthesis, biological evaluation and molecular modelling studies

≪ Previous: Effect of p-aminophenols on tyrosinase activity

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Publication date: 1 August 2014
Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 15
Author(s): Jason Gavenonis , Nicholas E. Jonas , Joshua A. Kritzer
Hsp90 is a molecular chaperone implicated in many diseases including cancer and neurodegenerative disease. Most inhibitors target the ATPase site in Hsp90’s N-terminal domain, with relatively few inhibitors of other domains reported to date. Here, we show that peptides derived from a short helix at the C-terminus of Hsp90 show micromolar activity as Hsp90 inhibitors in vitro. These inhibitors do not block the N-terminal domain’s ATP-binding site, and thus are likely to bind at the C-terminal domain. Substitutions and helix stapling were applied to demonstrate structure–activity relationships and improve activity. These helical peptides will help guide the design of a new class of inhibitors of Hsp90’s C-terminal domain.

Graphical abstract

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Selective inhibition of human carbonic anhydrases by novel amide derivatives of probenecid: Synthesis, biological evaluation and molecular modelling studies

August 6, 2014, 1:58 am

≫ Next: Benzoquinones as inhibitors of botulinum neurotoxin serotype A

≪ Previous: Potential C-terminal-domain inhibitors of heat shock protein 90 derived from a C-terminal peptide helix

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Publication date: 1 August 2014
Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 15
Author(s): Melissa D’Ascenzio , Simone Carradori , Daniela Secci , Daniela Vullo , Mariangela Ceruso , Atilla Akdemir , Claudiu T. Supuran
Novel amide derivatives of probenecid, a well-known uricosuric agent, were synthesized and evaluated as inhibitors of human carbonic anhydrases (hCAs, EC 4.2.1.1). The transmembrane isoforms (hCA IX and XII) were potently and selectively inhibited by some of them. The proposed chemical modification led to a complete loss of hCA II inhibition (K is>10,000nM) and enhanced the inhibitory activity against the tumour-associated hCA XII (compound 4 showed a K i value of 15.3nM). The enzyme inhibitory data have also been validated by docking studies of the compounds within the active site of hCA XII.

Graphical abstract

Benzoquinones as inhibitors of botulinum neurotoxin serotype A

August 6, 2014, 1:58 am

≫ Next: 2,2′-Dihydroxybenzophenones and their carbonyl N-analogues as inhibitor scaffolds for MDR-involved human glutathione transferase isoenzyme A1-1

≪ Previous: Selective inhibition of human carbonic anhydrases by novel amide derivatives of probenecid: Synthesis, biological evaluation and molecular modelling studies

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Publication date: 1 August 2014
Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 15
Author(s): Paul T. Bremer , Mark S. Hixon , Kim D. Janda
Although botulinum neurotoxin serotype A (BoNT/A) is known for its use in cosmetics, it causes a potentially fatal illness, botulism, and can be used as a bioterror weapon. Many compounds have been developed that inhibit the BoNTA zinc-metalloprotease light chain (LC), however, none of these inhibitors have advanced to clinical trials. In this study, a fragment-based approach was implemented to develop novel covalent inhibitors of BoNT/A LC. First, electrophilic fragments were screened against BoNT/A LC, and benzoquinone (BQ) derivatives were found to be active. In kinetic studies, BQ compounds acted as irreversible inhibitors that presumably covalently modify cysteine 165 of BoNT/A LC. Although most BQ derivatives were highly reactive toward glutathione in vitro, a few compounds such as natural product naphthazarin displayed low thiol reactivity and good BoNT/A inhibition. In order to increase the potency of the BQ fragment, computational docking studies were employed to elucidate a scaffold that could bind to sites adjacent to Cys165 while positioning a BQ fragment at Cys165 for covalent modification; 2-amino-N-arylacetamides met these criteria and when linked to BQ displayed at least a 20-fold increase in activity to low μM IC50 values. Unlike BQ alone, the linked-BQ compounds demonstrated only weak irreversible inhibition and therefore acted mainly as non-covalent inhibitors. Further kinetic studies revealed a mutual exclusivity of BQ covalent inactivation and competitive inhibitor binding to sites adjacent to Cys165, refuting the viability of the current strategy for developing more potent irreversible BoNT/A inhibitors. The highlights of this study include the discovery of BQ compounds as irreversible BoNT/A inhibitors and the rational design of low μM IC50 competitive inhibitors that depend on the BQ moiety for activity.

Graphical abstract

2,2′-Dihydroxybenzophenones and their carbonyl N-analogues as inhibitor scaffolds for MDR-involved human glutathione transferase isoenzyme A1-1

August 6, 2014, 1:58 am

≫ Next: Straightforward entry to pyrido[2,3-d]pyrimidine-2,4(1H,3H)-diones and their ADME properties

≪ Previous: Benzoquinones as inhibitors of botulinum neurotoxin serotype A

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Publication date: 1 August 2014
Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 15
Author(s): Fereniki D. Perperopoulou , Petros G. Tsoungas , Trias N. Thireou , Vagelis E. Rinotas , Eleni K. Douni , Elias E. Eliopoulos , Nikolaos E. Labrou , Yannis D. Clonis
The MDR-involved human GSTA1-1, an important isoenzyme overexpressed in several tumors leading to chemotherapeutic-resistant tumour cells, has been targeted by 2,2′-dihydroxybenzophenones and some of their carbonyl N-analogues, as its potential inhibitors. A structure-based library of the latter was built-up by a nucleophilic cleavage of suitably substituted xanthones to 2,2′-dihydroxy-benzophenones (5–9) and subsequent formation of their N-derivatives (oximes 11–13 and N-acyl hydrazones 14–16). Screening against hGSTA1-1 led to benzophenones 6 and 8, and hydrazones 14 and 16, having the highest inhibition potency (IC50 values in the range 0.18±0.02 to 1.77±0.10μM). Enzyme inhibition kinetics, molecular modeling and docking studies showed that they interact primarily at the CDNB-binding catalytic site of the enzyme. In addition, the results from cytotoxicity studies with human colon adenocarcinoma cells showed low LC50 values for benzophenone 6 and its N-acyl hydrazone analogue 14 (31.4±0.4μM and 87±1.9μM, respectively), in addition to the strong enzyme inhibition profile (IC50( 6 ) =1,77±0.10μM; IC50( 14 ) =0.33±0.05μM). These structures may serve as leads for the design of new potent mono- and bi-functional inhibitors and pro-drugs against human GTSs.

Graphical abstract

Straightforward entry to pyrido[2,3-d]pyrimidine-2,4(1H,3H)-diones and their ADME properties

August 6, 2014, 1:58 am

≫ Next: Synthesis and biological evaluation of bivalent cannabinoid receptor ligands based on hCB2R selective benzimidazoles reveal unexpected intrinsic properties

≪ Previous: 2,2′-Dihydroxybenzophenones and their carbonyl N-analogues as inhibitor scaffolds for MDR-involved human glutathione transferase isoenzyme A1-1

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Publication date: 1 August 2014
Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 15
Author(s): Martyna Jatczak , Koen Muylaert , Laurens M. De Coen , Janneke Keemink , Benjamin Wuyts , Patrick Augustijns , Christian V. Stevens
A straightforward synthesis of pyrido[2,3-d]pyrimidine-2,4(1H,3H)-diones was developed starting from 2-chloropyridine-3-carboxylic acid by esterification, nucleophilic aromatic substitution and amide formation in one step, and ring closure allowing their synthesis with two identical or two different group attached to nitrogen. The structural diversity of these [2,3-d]pyrimidine-2,4(1H,3H)-diones resulted in significant variation in the biopharmaceutical properties. This was reflected by the broad range in fasted state simulated intestinal fluid solubility values (12.6μM to 13.8mM), Caco-2 permeability coefficients (1.2×10⁻⁶ cm/s to 90.7×10⁻⁶ cm/s) and in vitro-predicted human in vivo intrinsic clearance values (0 to 159ml/min/kg).

Graphical abstract

Synthesis and biological evaluation of bivalent cannabinoid receptor ligands based on hCB2R selective benzimidazoles reveal unexpected intrinsic properties

August 6, 2014, 1:58 am

≫ Next: Synthesis and evaluation of the novel 2-[18F]fluoro-3-propoxy-triazole-pyridine-substituted losartan for imaging AT1 receptors

≪ Previous: Straightforward entry to pyrido[2,3-d]pyrimidine-2,4(1H,3H)-diones and their ADME properties

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Publication date: 1 August 2014
Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 15
Author(s): Martin Nimczick , Daniela Pemp , Fouad H. Darras , Xinyu Chen , Jörg Heilmann , Michael Decker
The design of bivalent ligands targeting G protein-coupled receptors (GPCRs) often leads to the development of new, highly selective and potent compounds. To date, no bivalent ligands for the human cannabinoid receptor type 2 (hCB2R) of the endocannabinoid system (ECS) are described. Therefore, two sets of homobivalent ligands containing as parent structure the hCB2R selective agonist 13a and coupled at different attachment positions were synthesized. Changes of the parent structure at these positions have a crucial effect on the potency and efficacy of the ligands. However, we discovered that bivalency has an influence on the effect at both cannabinoid receptors. Moreover, we found out that the spacer length and the attachment position altered the efficacy of the bivalent ligands at the receptors by turning agonists into antagonists and inverse agonists.

Graphical abstract

Synthesis and evaluation of the novel 2-[18F]fluoro-3-propoxy-triazole-pyridine-substituted losartan for imaging AT1 receptors

August 6, 2014, 1:58 am

≫ Next: Synthesis and fungicidal activity of quinolin-6-yloxyacetamides, a novel class of tubulin polymerization inhibitors

≪ Previous: Synthesis and biological evaluation of bivalent cannabinoid receptor ligands based on hCB2R selective benzimidazoles reveal unexpected intrinsic properties

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Publication date: 1 August 2014
Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 15
Author(s): Natasha Arksey , Tayebeh Hadizad , Basma Ismail , Maryam Hachem , Ana C. Valdivia , Rob S. Beanlands , Robert A. deKemp , Jean N. DaSilva
The 2-[¹⁸F]fluoro-3-pent-4-yn-1-yloxypyridine ([¹⁸F]FPyKYNE) analog of the potent non-peptide angiotensin II type 1 receptor (AT1R) blocker losartan was produced via click chemistry linking [¹⁸F]FPyKYNE to azide-modified tetrazole-protected losartan followed by TFA deprotection. Preliminary small animal imaging with positron emission tomography (PET) in rats displayed high uptake in the kidneys with good contrast to surrounding tissue. Rat metabolism displayed the presence of 23% unchanged tracer in plasma at 30min. Upon co-administration with AT1R blocker candesartan (2.5, 5 and 10mg/kg), a dose-dependent reduction (47–65%) in tracer uptake was observed in the kidney, while no difference was observed following AT2R blocker PD123,319 (5mg/kg), indicating binding selectivity for AT1R over AT2R and potential for imaging AT1R using PET.

Graphical abstract

Synthesis and fungicidal activity of quinolin-6-yloxyacetamides, a novel class of tubulin polymerization inhibitors

August 6, 2014, 1:58 am

≫ Next: Furazan and furoxan sulfonamides are strong α-carbonic anhydrase inhibitors and potential antiglaucoma agents

≪ Previous: Synthesis and evaluation of the novel 2-[18F]fluoro-3-propoxy-triazole-pyridine-substituted losartan for imaging AT1 receptors

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Publication date: 1 August 2014
Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 15
Author(s): Clemens Lamberth , Fiona Murphy Kessabi , Renaud Beaudegnies , Laura Quaranta , Stephan Trah , Guillaume Berthon , Fredrik Cederbaum , Gertrud Knauf-Beiter , Valeria Grasso , Stephane Bieri , Andy Corran , Urvashi Thacker
A novel class of experimental fungicides has been discovered, which consists of special quinolin-6-yloxyacetamides. They are highly active against important phytopathogens, such as Phytophthora infestans (potato and tomato late blight), Mycosphaerella graminicola (wheat leaf blotch) and Uncinula necator (grape powdery mildew). Their fungicidal activity is due to their ability to inhibit fungal tubulin polymerization, leading to microtubule destabilization. An efficient synthesis route has been worked out, which allows the diverse substitution of four identified key positions across the molecular scaffold.

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Furazan and furoxan sulfonamides are strong α-carbonic anhydrase inhibitors and potential antiglaucoma agents

August 6, 2014, 1:58 am

≫ Next: Synthesis, reactivity and biological activity of N(4)-boronated derivatives of 2′-deoxycytidine

≪ Previous: Synthesis and fungicidal activity of quinolin-6-yloxyacetamides, a novel class of tubulin polymerization inhibitors

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Publication date: 1 August 2014
Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 15
Author(s): Konstantin Chegaev , Loretta Lazzarato , Yasinalli Tamboli , Donatella Boschi , Marco Blangetti , Andrea Scozzafava , Fabrizio Carta , Emanuela Masini , Roberta Fruttero , Claudiu T. Supuran , Alberto Gasco
A series of furazan and furoxan sulfonamides were prepared and studied for their ability to inhibit human carbonic anhydrase (CA, EC 4.2.1.1) isoforms hCA I, hCA II, hCA IX, and hCA XII. The simple methyl substituted products 3–5 were potent inhibitors. Differing structural modifications of these leads had differing effects on potency and selectivity. In particular, products in which the sulfonamide group is separated from the hetero ring by a phenylene bridge retained high potency only on the hCA XII isoform. The sulfonamides 3–5 exerted intraocular pressure (IOP) lowering effects in vivo in hypertensive rabbits more efficiently than dorzolamide. Some other products (39–42), although less effective in vitro hCA II/XII inhibitors, also effectively lowered IOP in two different animal models of glaucoma.

Graphical abstract

Synthesis, reactivity and biological activity of N(4)-boronated derivatives of 2′-deoxycytidine

August 6, 2014, 1:58 am

≫ Next: Design and synthesis of 8-hydroxyquinoline-based radioprotective agents

≪ Previous: Furazan and furoxan sulfonamides are strong α-carbonic anhydrase inhibitors and potential antiglaucoma agents

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Publication date: 1 August 2014
Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 15
Author(s): Joanna Nizioł , Zbigniew Zieliński , Andrzej Leś , Magdalena Dąbrowska , Wojciech Rode , Tomasz Ruman
By seeking new stable boron-containing nucleoside derivatives, potential BNCT boron delivery agents, a novel synthetic approach was tested, aimed at a boron attachment via a single bond to an aliphatic carbon of sp³ hybridization. The latter allowed successful modification of deoxycytidine in the reaction with 2-(iodomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane of the deoxynucleoside amino group. For new compounds, detailed NMR, LDI HRMS (Laser Desorption/Ionization High-Resolution Mass Spectrometry) analyses along with in vivo phosphorylation studies, toxicity assays and DFT modelling are presented.

Graphical abstract

Design and synthesis of 8-hydroxyquinoline-based radioprotective agents

August 6, 2014, 1:58 am

≫ Next: Dual-stage triterpenoids from an African medicinal plant targeting the malaria parasite

≪ Previous: Synthesis, reactivity and biological activity of N(4)-boronated derivatives of 2′-deoxycytidine

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Publication date: 1 August 2014
Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 15
Author(s): Shinya Ariyasu , Akiko Sawa , Akinori Morita , Kengo Hanaya , Misato Hoshi , Ippei Takahashi , Bing Wang , Shin Aoki
In radiation therapy, adverse side effects are often induced due to the excessive cell death that occurs in radiosensitive normal cells. The radiation-induced cell death of normal cells is caused, at least in part, by apoptosis, which undergoes via activation of p53 and increase in the p53 protein, a zinc-containing transcriptional factor, in response to cellular damage. Therefore, radioprotective drugs that can protect normal cells from radiation and thus suppress adverse side effects would be highly desirable. We report herein on the radioprotective activity of 8-hydroxyquinoline (8HQ) derivatives that were initially designed so as to interact with the Zn²⁺ in p53. Indeed, the 5,7-bis(methylaminosulfonyl)-8HQ and 8-methoxyquinoline derivatives considerably protected MOLT-4 cells against γ-ray radiation (10Gy), accompanied by a low cytotoxicity. However, mechanistic studies revealed that the interaction of these drugs with p53 is weak and the mechanism for inhibiting apoptosis appears to be different from that of previously reported radioprotectors such as bispicen, which inhibits apoptosis via the denaturation of p53 as well as by blocking both transcription-dependent and -independent apoptotic pathways.

Graphical abstract

Dual-stage triterpenoids from an African medicinal plant targeting the malaria parasite

August 6, 2014, 1:58 am

≫ Next: Synthesis and biological evaluation of 2-anilino-4-substituted-7H-pyrrolopyrimidines as PDK1 inhibitors

≪ Previous: Design and synthesis of 8-hydroxyquinoline-based radioprotective agents

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Publication date: 1 August 2014
Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 15
Author(s): Cátia Ramalhete , Filipa P. da Cruz , Silva Mulhovo , Inês J. Sousa , Miguel X. Fernandes , Miguel Prudêncio , Maria-José U. Ferreira
Sixteen triterpenoids (1–16), previously isolated from the aerial parts of the African medicinal plant Momordica balsamina or obtained by derivatization, were evaluated for their activity against liver stages of Plasmodium berghei, measuring the luminescence intensity in Huh-7 cells infected with a firefly luciferase-expressing P. berghei line, PbGFP-Luccon. Toxicity of compounds (1–16) was assessed on the same cell line through the fluorescence measurement of cell confluency. The highest activity was displayed by a derivative bearing two acetyl residues, karavoate B (7), which led to a dose-dependent decrease in the P. berghei infection rate, exhibiting a very significant activity at the lowest concentration employed (1μM) and no toxicity towards the Huh-7 cells. It is noteworthy that, in previous studies, this compound was found to be a strong inhibitor of blood-stages of Plasmodium falciparum, thus displaying a dual-stage antimalarial activity.

Graphical abstract

Synthesis and biological evaluation of 2-anilino-4-substituted-7H-pyrrolopyrimidines as PDK1 inhibitors

August 6, 2014, 1:58 am

≫ Next: Structure-based optimization and biological evaluation of trisubstituted pyrazole as a core structure of potent ROS1 kinase inhibitors

≪ Previous: Dual-stage triterpenoids from an African medicinal plant targeting the malaria parasite

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Publication date: 1 August 2014
Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 15
Author(s): Nathan J. O’Brien , Martin Brzozowski , Melissa J. Buskes , Leslie W. Deady , Belinda M. Abbott
PDK1, a biological target that has attracted a large amount of attention recently, is responsible for the positive regulation of the PI3K/Akt pathway that is often activated in a large number of human cancers. A series of second-generation 2-anilino-4-substituted-7H-pyrrolopyrimidines were synthesised by installation of various functions at the 4-position of the 7H-pyrrolopyrimidine scaffold. All compounds were screened against the isolated PDK1 enzyme and dose response analysis was obtained on the best compounds of the series.

Graphical abstract

Structure-based optimization and biological evaluation of trisubstituted pyrazole as a core structure of potent ROS1 kinase inhibitors

August 6, 2014, 1:58 am

≫ Next: Bicyclic tetrapeptides as potent HDAC inhibitors: Effect of aliphatic loop position and hydrophobicity on inhibitory activity

≪ Previous: Synthesis and biological evaluation of 2-anilino-4-substituted-7H-pyrrolopyrimidines as PDK1 inhibitors

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Publication date: 1 August 2014
Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 15
Author(s): Byung Sun Park , Mohammad M. Al-Sanea , Ahmed Z. Abdelazem , Hye Mi Park , Eun Joo Roh , Hyun-Mee Park , Kyung Ho Yoo , Taebo Sim , Jin Sung Tae , So Ha Lee
Recently inhibition of ROS1 kinase has proven to be a promising strategy for several indications such as glioblastoma, non-small cell lung cancer (NSCLC), and cholangiocarcinoma. Our team reported trisubstituted pyrazole-based ROS1 inhibitors by which two inhibitors showed good IC50 values in enzyme-based screening. To develop more advanced ROS1 inhibitors through SAR this trisubstituted pyrazole-based scaffold has been built. Consequently, 16 compounds have been designed, synthesized and shown potent IC50 values in the enzymatic assay, which are from 13.6 to 283nM. Molecular modeling studies explain how these ROS1 kinase inhibitors revealed effectively the key interactions with ROS1 ATP binding site. Among these compounds, compound 9a (IC50 =13.6nM) has exerted 5 fold potency than crizotinib and exhibited high degree of selectivity (selectivity score value=0.028) representing the number of non-mutant kinases with biological activity over 90% at 10μM.

Graphical abstract

Bicyclic tetrapeptides as potent HDAC inhibitors: Effect of aliphatic loop position and hydrophobicity on inhibitory activity

August 6, 2014, 1:58 am

≫ Next: Melleolides induce rapid cell death in human primary monocytes and cancer cells

≪ Previous: Structure-based optimization and biological evaluation of trisubstituted pyrazole as a core structure of potent ROS1 kinase inhibitors

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Publication date: 1 August 2014
Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 15
Author(s): Md. Nurul Islam , Md. Shahidul Islam , Md. Ashraful Hoque , Tamaki Kato , Norikazu Nishino , Akihiro Ito , Minoru Yoshida
Several histone deacetylase (HDAC) inhibiting bicyclic tetrapeptides have been designed and synthesized through intramolecular ring-closing metathesis (RCM) reaction and peptide cyclization. We designed bicyclic tetrapeptides based on CHAP31, trapoxin B and HC-toxin I. The HDAC inhibitory and p21 promoter assay results showed that the aliphatic loop position as well as the hydrophobicity plays an important role toward the activity of the bicyclic tetrapeptide HDAC inhibitors.

Graphical abstract

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Melleolides induce rapid cell death in human primary monocytes and cancer cells

August 6, 2014, 1:58 am

≫ Next: Design and synthesis of CHAP31, trapoxin B and HC-toxin based bicyclic tetrapeptides disulfide as potent histone deacetylase inhibitors

≪ Previous: Bicyclic tetrapeptides as potent HDAC inhibitors: Effect of aliphatic loop position and hydrophobicity on inhibitory activity

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Publication date: 1 August 2014
Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 15
Author(s): Markus Bohnert , Olga Scherer , Katja Wiechmann , Stefanie König , Hans-Martin Dahse , Dirk Hoffmeister , Oliver Werz
The melleolides are structurally unique and bioactive natural products of the basidiomycete genus Armillaria. Here, we report on cytotoxic effects of melleolides from Armillaria mellea towards non-transformed human primary monocytes and human cancer cell lines, respectively. In contrast to staurosporine or pretubulysin that are less cytotoxic for monocytes, the cytotoxic potency of the active melleolides in primary monocytes is comparable to that in cancer cells. The onset of the cytotoxic effects of melleolides was rapid (within <1h), as compared to the apoptosis inducer staurosporine, the protein biosynthesis inhibitor cycloheximide, and the DNA transcription inhibitor actinomycin D (>5h, each). Side-by-side comparison with the detergent triton X-100 and staurosporine in microscopic and flow cytometric analysis studies as well as analysis of the viability of mitochondria exclude cell lysis and apoptosis as relevant or primary mechanisms. Our results rather point to necrotic features of cell death mediated by an as yet elusive but rapid mechanism.

Graphical abstract

Design and synthesis of CHAP31, trapoxin B and HC-toxin based bicyclic tetrapeptides disulfide as potent histone deacetylase inhibitors

August 6, 2014, 1:58 am

≫ Next: Synthesis and cholinesterase inhibition of cativic acid derivatives

≪ Previous: Melleolides induce rapid cell death in human primary monocytes and cancer cells

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Publication date: 1 August 2014
Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 15
Author(s): Md. Ashraful Hoque , Md. Nurul Islam , Md. Shahidul Islam , Tamaki Kato , Norikazu Nishino , Akihiro Ito , Minoru Yoshida
The naturally occurring cyclic depsipeptide, FK228 inhibits histone deacetylase (HDAC) enzymes after reductive cleavage of intra-molecular disulfide bond. One of the sulfhydryl groups produced in the reduction interacts with zinc atom that involved in the catalytic mechanism of type 1 and 2 HDACs such as HDAC1, HDAC4, and HDAC6. In the present study, we describe the development of CHAP31, trapoxin B and HC-toxin based cyclic tetrapeptides with intra-molecular disulfide bond as HDAC inhibitors. The bicyclic tetrapeptides disulfide showed potent HDAC1 and HDAC4 inhibition and p21 promoting activity.

Graphical abstract

Synthesis and cholinesterase inhibition of cativic acid derivatives

August 6, 2014, 1:58 am

≫ Next: The development of new molecular tools containing a chemically synthesized carbohydrate ligand for the elucidation of carbohydrate roles via photoaffinity labeling: Carbohydrate–protein interactions are affected by the structures of the glycosidic bonds and the reducing-end sugar

≪ Previous: Design and synthesis of CHAP31, trapoxin B and HC-toxin based bicyclic tetrapeptides disulfide as potent histone deacetylase inhibitors

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Publication date: 1 August 2014
Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 15
Author(s): Natalia P. Alza , Victoria Richmond , Carlos J. Baier , Eleonora Freire , Ricardo Baggio , Ana Paula Murray
Alzheimer’s disease (AD) is a neurodegenerative disorder associated with memory impairment and cognitive deficit. Most of the drugs currently available for the treatment of AD are acetylcholinesterase (AChE) inhibitors. In a preliminary study, significant AChE inhibition was observed for the ethanolic extract of Grindelia ventanensis (IC50 =0.79mg/mL). This result prompted us to isolate the active constituent, a normal labdane diterpenoid identified as 17-hydroxycativic acid (1), through a bioassay guided fractionation. Taking into account that 1 showed moderate inhibition of AChE (IC50 =21.1μM), selectivity over butyrylcholinesterase (BChE) (IC50 =171.1μM) and that it was easily obtained from the plant extract in a very good yield (0.15% w/w), we decided to prepare semisynthetic derivatives of this natural diterpenoid through simple structural modifications. A set of twenty new cativic acid derivatives (3–6) was prepared from 1 through transformations on the carboxylic group at C-15, introducing a C2–C6 linker and a tertiary amine group. They were tested for their inhibitory activity against AChE and BChE and some structure–activity relationships were outlined. The most active derivative was compound 3c, with an IC50 value of 3.2μM for AChE. Enzyme kinetic studies and docking modeling revealed that this inhibitor targeted both the catalytic active site and the peripheral anionic site of this enzyme. Furthermore, 3c showed significant inhibition of AChE activity in SH-SY5Y human neuroblastoma cells, and was non-cytotoxic.

Graphical abstract

The development of new molecular tools containing a chemically synthesized carbohydrate ligand for the elucidation of carbohydrate roles via photoaffinity labeling: Carbohydrate–protein interactions are affected by the structures of the glycosidic bonds and the reducing-end sugar

August 6, 2014, 1:58 am

≫ Next: Development of potent antagonists for formyl peptide receptor 1 based on Boc-Phe-d-Leu-Phe-d-Leu-Phe-OH

≪ Previous: Synthesis and cholinesterase inhibition of cativic acid derivatives

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Publication date: 1 August 2014
Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 15
Author(s): Isao Ohtsuka , Yutaka Sadakane , Noriyasu Hada , Mari Higuchi , Toshiyuki Atsumi , Nobuko Kakiuchi
Photoaffinity labeling technology is a highly efficient method for cloning carbohydrate-binding proteins. When the carbohydrate probes are synthesized according to conventional methods, however, the reducing terminus of the sugar is opened to provide an acyclic structure. Our continued efforts to solve this problem led to the development of new molecular tools with an oligosaccharide structure that contains a phenyldiazirine group for the elucidation of carbohydrate–protein interactions. We investigated whether carbohydrate–lectin interactions are affected by differences in the glycosidic formation and synthesized three types of molecular tools containing Galp–GlcpNAc disaccharide ligands and a photoreactive group (1, 2, 3). Photoaffinity labeling validated the recognition of the new ligand by different glycosidic bonds. Photoaffinity labeling also demonstrated that both the reducing end sugar and non-reducing end sugar recognized the Erythrina cristagalli agglutinin.

Graphical abstract

Development of potent antagonists for formyl peptide receptor 1 based on Boc-Phe-d-Leu-Phe-d-Leu-Phe-OH

August 6, 2014, 1:58 am

≫ Next: Bradykinin antagonists and thiazolidinone derivatives as new potential anti-cancer compounds

≪ Previous: The development of new molecular tools containing a chemically synthesized carbohydrate ligand for the elucidation of carbohydrate roles via photoaffinity labeling: Carbohydrate–protein interactions are affected by the structures of the glycosidic bonds and the reducing-end sugar

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Publication date: 1 August 2014
Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 15
Author(s): Ryo Hayashi , Toshiki Kitajima , Hikaru Mizuguchi , Miki Fujimoto , Aya Yamaguchi , Shuichiro Koga , Yuya Koga , Satoshi Osada , Hiroaki Kodama
While stimulation of formyl peptide receptors (FPRs) on the surface of human neutrophils induces several immune responses, under conditions of continuous activation of the receptor by agonists such as formyl-Met-Leu-Phe-OH (fMLP), neutrophil-dependent tissue damage ensues. Thus, FPR antagonists could be anticipated as drugs for FPR-related disease. In this study, Boc-Phe-d-Leu-Phe-d-Leu-Phe-OH (Boc-FlFlF), one of several FPR subtype selective antagonists, was chosen and the positions at the Phe residues were optimized. We found that substitution with unnatural amino acids resulted in an improvement of two orders of magnitude. The most potent antagonist indicated FPR subtype selectivity at 1μM. In addition to finding a potent antagonist, the structure–activity trends observed in this study should be valuable in designing a new type of FPR subtype selective antagonist.

Graphical abstract