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Abstract Chidamide is the first oral subtype-selective histone deacetylase inhibitor approved in China for the treatment of relapsed and refractory peripheral T cell lymphoma. Due to the existence of isomers, many articles or patents have mistaken its structure. Herein we explored the synthesis of the key intermediate (E)-4-((3-(pyridin-3-yl)acrylamido)methyl)benzoic acid (A-3) and chidamide, using the condensing agent HBTU, instead of the unstable N,N'-carbonyldiimidazole. The single crystal of chidamide was determined by X-ray diffraction study. The optimized preparation process was easy to operate, and the purity of the final product can be up to 99.76%. Moreover, the structure of chidamide was established to be (E)-N-(2-amino-4-fluorophenyl)-4-((3-(pyridin-3-yl)acrylamido)methyl)benzamide.

A series of β‐carboline amides has been synthesized in one‐pot reaction via coupling between an acid and an amine in the presence of HBTU/Et3N. This mild amidation reaction undergoes efficiently and chemoselectively. Bioactivity studies indicate that the β‐carboline amide derivatives exhibit neuroprotective activity and might be developed to be lead compounds for anti‐stroke agents. [ABSTRACT FROM AUTHOR]

In the present study, varying amounts of tetramethylguanidinium moiety have been conjugated to linear polyethylenimine to obtain linear polyethylenimine-tmg (LPTG) polymers. Incorporation of hydrophobic and highly basic moiety in the polymeric backbone resulted in the significant improvement in the antibacterial activity which was confirmed by zone of inhibition and MIC assays. Further, the results of transmission electron microscopy and confocal studies revealed that the projected LPTG polymers possessed higher antibacterial activity than the native polymer. In addition, these modified polyethylenimine (PEI) polymers were capable of reducing auric chloride into stable gold nanoparticles. These polyamine-stabilized gold nanoparticles can be used in various biomedical applications. [ABSTRACT FROM AUTHOR]

Abstract: A new synthesis of a bifunctional chelator possessing DOTAM-Gly-l-Phe-OH and DO3A chelating cages interconnected by an oligoamide chain has been achieved via HBTU-mediated coupling from easily accessible building blocks. Both homo- and heterobimetallic lanthanide(III) complexes derived from this bifunctional chelator have been prepared in moderate yields. The CEST spectrum acquired for homobimetallic Eu3+ complex showed this molecule to be a promising PARACEST MRI contrast agent whereas the Eu3+/Tm3+ heterobimetallic complex lacked a useful CEST signal. [Copyright &y& Elsevier]

We describe a case of anaphylaxis and allergic contact urticaria from occupational airborne exposure to HBTU (o-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate), which is a chemical used widely for solid and solution-phase peptide synthesis. Previously, the use of this chemical has been associated with occupational asthma, allergic contact urticaria and allergic contact dermatitis in individual cases, but not with anaphylaxis. Our diagnoses were based on the clinical symptoms, positive skin prick test (SPT) and positive skin provocation test to HBTU. The positive SPT indicates that the anaphylaxis reaction was IgE-mediated. We recommend that in the handling of HBTU, appropriate safety measures should be compulsory, and if work-related symptoms develop, the possibility of anaphylaxis should be considered in advising on appropriate work tasks. [ABSTRACT FROM AUTHOR]

Abstract: The reaction of a sulfonamide moiety with HBTU (O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate) during amide coupling, leading to the formation of tetramethylsulfonylguanidines, is described. Optimised conditions showed that HBTU was as a convenient agent for the synthesis of tetramethylsulfonylguanidines, in basic conditions. A panel of diverse sulfonamides was used to demonstrate the scope of this procedure. [Copyright &y& Elsevier]

Abstract: The properties and structure–activity relationships (SAR) of a macrocyclic analogue of porcine protegrin I (PG-I) have been investigated. The lead compound, having the sequence cyclo-(-Leu-Arg-Leu-Lys-Lys-Arg-Arg-Trp-Lys-Tyr-Arg-Val-d-Pro-Pro-), shows antimicrobial activity against Gram-positive and -negative bacteria, but a much lower haemolytic activity and a much reduced ability to induce dye release from phosphatidylcholine/phosphatidylglycerol liposomes, when compared to PG-I. The enantiomeric form of the lead peptide shows comparable antimicrobial activity, a property shared with other cationic antimicrobial peptides acting on cell membranes. SAR studies involving the synthesis and biological profiling of over 100 single site substituted analogues, showed that the antimicrobial activity was tolerant to a large number of the substitutions tested. Some analogues showed slightly improved antimicrobial activities (2–4-fold lowering of MICs), whereas other substitutions caused large increases in haemolytic activity on human red blood cells. [Copyright &y& Elsevier]

The IR studies for the preactivation step of N-protected iminodiacetic acid with different coupling reagents (TCFH,TFFH, HATU, HBTU, HSTU) were reported here and showed theformation of an anhydride as an active intermediate in caseof TCFH and TFFH. The formation of a mixture of an anhydrideand an active ester (-OBt, -OAt or -OSu) were observed forHBTU, HATU or HSTU coupling reagent. Dependent on the couplingconditions, acylation of N-protected iminodiacetic acid with amino acid ester or amide derivatives in solution phase gavemono- or di-substituted iminodiacetic acid derivatives. Couplingof N-protected iminodiacetic acid with an amino acid or peptideattached to a solid support (PAL-PEG-PS or Wang resin) gave onlythe monosubstituted iminodiacetic acid derivatives. [ABSTRACT FROM AUTHOR]

An efficient and generally applicable method for the synthesis of head-to-tail cyclic peptides with HBTU (2-(1 H-benzotriazol-1-yl)-1,1,3, 3-tetramethyluronium hexafluorophosphate) has been developed. The utility of this approach was exemplified with the multigram preparation of a potent endothelin receptor-selective (ET) antagonist BQ-123 ( cyclo[- d-Trp- d-Asp-Pro- d-Val-Leu-]). This methodology can be readily applied to the small-and largescale synthesis of other head-to-tail cyclic peptides. [ABSTRACT FROM AUTHOR]

Abstract: The HIV-1 nucleocapsid (NCp7), structurally defined by zinc-binding domains, participates in crucial stages of the HIV-1 lifecycle and is mutationally nonpermissive, making it an attractive anti-HIV target. Mode of action studies have shown that the secondary structure and activity of NCp7 can be disrupted by acyl transfer from N-2-mercaptobenzoyl-amino amides. We have developed an improved one-pot reaction that affords N-2-mercaptobenzoyl-amino acids on multi-gram scales. This synthetic route allows for rapid modular construction and has greatly expanded the scope of easily accessible potential NCp7 inhibitors. [Copyright &y& Elsevier]

Comments on the case of a 37-year-old male who presented with work-related dermatitis. Improvement of the dermatitis after application of corticosteroid creams; Detection of dermal lymphocytic and eosinophilic perivascular infiltration; Immediate immunological immunoglobulin E-mediated mechanism.

The article presents the case study of middle aged woman who was taken to the medical care center with hand dermatitis. The woman worked as a laboratory technician and suffered from dermatitis for the past 2 years. It mentions that her condition improved when she was given steroids and also when she was not working. She was diagnosed with allergic contact dermatitis to [( o-benzotriazole-10yl)- N,N,N'N',-tetramethyluronium hexafluorophosphate (HBTU).

G protein-coupled receptor kinase 2 (GRK2) is a relevant signaling node of the cellular transduction network, playing major roles in the physiology of various organs/tissues including the heart and blood vessels. Emerging evidence suggests that GRK2 is up regulated in pathological situations such as heart failure, hypertrophy and hypertension, and its inhibition offers a potential therapeutic solution to these diseases. We explored the GRK2 inhibitory activity of a library of cyclic peptides derived from the HJ loop of G protein-coupled receptor kinases 2 (GRK2). The design of these cyclic compounds was based on the conformation of the HJ loop within the X-ray structure of GRK2. One of these compounds, the cyclic peptide 7, inhibited potently and selectively the GRK2 activity, being more active than its linear precursor. In a cellular system, this peptide confirms the beneficial signaling properties of a potent GRK2 inhibitor. Preferred conformations of the most potent analog were investigated by NMR spectroscopy., (Copyright © 2013. Published by Elsevier Masson SAS.)

Inhibition of isoprenylcysteine Carboxylmethyltransferase (ICMT) is of particular interest as a potential target for the development of cancer chemotherapeutic agents. Screening for inhibitors of ICMT utilises a scintillation proximity assay (SPA) in which Biotin-S-Farnesyl-L-Cysteine (BFC) acts as a surrogate substrate. A solid-phase synthesis protocol for the preparation of BFC using 2-chlorotrityl chloride resin as a solid support has been developed to provide sufficient supply of BFC for high throughput screening (HTS) and subsequent chemistry campaigns to target inhibitors of ICMT. The BFC prepared by this method can be produced quickly on large scale and is stable when stored at -20 °C as a solid, in solution, or on the resin., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

A new α-conotoxin LsIA was isolated from the crude venom of Conus limpusi using assay-guided RP-HPLC fractionation. Synthetic LsIA was a potent antagonist of α3β2, α3α5β2 and α7 nAChRs, with half-maximal inhibitory concentrations of 10, 31 and 10 nM, respectively. The structure of LsIA determined by NMR spectroscopy comprised a characteristic disulfide bond-stabilized α-helical structure and disordered N-terminal region. Potency reductions of up to 9-fold were observed for N-terminally truncated analogues of LsIA at α7 and α3β2 nAChRs, whereas C-terminal carboxylation enhanced potency 3-fold at α3β2 nAChRs but reduced potency 3-fold at α7 nAChRs. This study gives further insight into α-conotoxin pharmacology and the molecular basis of nAChR selectivity, highlighting the influence of N-terminal residues and C-terminal amidation on conotoxin pharmacology., (Copyright © 2013. Published by Elsevier Inc.)

Derivatives of peptides of the TIPP (Tyr-Tic-Phe-Phe; Tic=1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) family containing a guanidino (Guan) function in place of the N-terminal amino group were synthesized in an effort to improve their blood-brain barrier permeability. Unexpectedly, N-terminal amidination significantly altered the in vitro opioid activity profiles. Guan-analogues of TIPP-related δ opioid antagonists showed δ partial agonist or mixed δ partial agonist/μ partial agonist activity. Guanidinylation of the mixed μ agonist/δ antagonists H-Dmt-Tic-Phe-Phe-NH2 (DIPP-NH2) and H-Dmt-TicΨ[CH2NH]Phe-Phe-NH2 (DIPP-NH2[Ψ]) converted them to mixed μ agonist/δ agonists. A docking study revealed distinct positioning of DIPP-NH2 and Guan-DIPP-NH2 in the δ receptor binding site. Lys(3)-analogues of DIPP-NH2 and DIPP-NH2[Ψ] (guanidinylated or non-guanidinylated) turned out to be mixed μ/κ agonists with δ antagonist-, δ partial agonist- or δ full agonist activity. Compounds with some of the observed mixed opioid activity profiles have therapeutic potential as analgesics with reduced side effects or for treatment of cocaine addiction., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

A whole organism high-throughput screen of approximately 87,000 compounds against Trypanosoma brucei brucei led to the recent discovery of several novel compound classes with low micromolar activity against this organism and without appreciable cytotoxicity to mammalian cells. Herein we report a structure-activity relationship (SAR) investigation around one of these hit classes, the 3-(oxazolo[4,5-b]pyridin-2-yl)anilides. Sharp SAR is revealed, with our most active compound (5) exhibiting an IC₅₀ of 91 nM against the human pathogenic strain T.b. rhodesiense and being more than 700 times less toxic towards the L6 mammalian cell line. Physicochemical properties are attractive for many compounds in this series. For the most potent representatives, we show that solubility and metabolic stability are key parameters to target during future optimisation., (Copyright © 2013. Published by Elsevier Masson SAS.)