Organocatalyzed Enantioselective Amination for Quaternized Serines as Tertiary Amides.

Herein, we describe a -aminocatalyzed enantioselective α-hydrazination of an α-formyl amide for the production of protected quaternized serines as tertiary amides with 's of generally >98% and ≤99% yields. The proposed TS model supported by density functional theory calculations involves a quinuclidinium ion Brønsted acid-assisted delivery of DBAD, which occurs from the face of an H-bonded enaminone when using a 9-cinchonamine catalyst, resulting in a hydrazide with the -configuration as determined by X-ray analysis.

The application of marine polysaccharides to antitumor nanocarriers.

Nanotechnology has revolutionized the diagnosis, monitoring and treatment of biomedical diseases, in which nanocarriers have greatly improved the targeting and bioavailability of antitumor drugs. The marine natural polysaccharides fucoidan, chitosan, alginate, carrageenan and porphyran have broad-spectrum bioactivities and unique physicochemical properties such as excellent non-toxicity, biocompatibility, biodegradability and reproducibility, which have placed them as a principal focus in the nanocarrier field. Nanocarriers based on different types of marine polysaccharides are distinctive in addressing antitumor therapeutic challenges such as targeting, environmental responsiveness, drug resistance, tissue toxicity, enhancing diagnostic imaging, overcoming the first-pass effect and innovative 3D binding.

An Investigation into the In Vitro Targeted Killing of CD44-Expressing Triple-Negative Breast Cancer Cells Using Recombinant Photoimmunotherapeutics Compared to Auristatin-F-Based Antibody-Drug Conjugates.

Triple-negative breast cancer (TNBC) is the deadliest form of breast cancer with limited treatment options. The persistence of highly tumorigenic CD44-expressing subpopulation referred to as cancer stem cells (CSCs), endowed with the self-renewal capacity, has been associated with therapeutic resistance, hence clinical relapses. To mitigate these undesired events, targeted immunotherapies using antibody-photoconjugate (APC) or antibody-drug conjugate (ADC), were developed to specifically release cytotoxic payloads within targeted cells overexpressing cognate antigen receptors.

Finding the Ajoene Sweet-Spot: Structure-Activity Relations that Govern its Blood Stability and Cancer Cytotoxicity.

Ajoene is an organosulfur compound found in crushed garlic that exerts its anti-cancer activity by S-thiolating cysteine residues on proteins. Its development is hampered due to limited bioavailability, so in this study, we synthesised analogues of ajoene to probe the significance of the ajoene vinyl disulfide/sulfoxide core with respect to cytotoxicity and blood stability. Polar side groups were also incorporated to improve aqueous solubility.

CSPG4 as a target for the specific killing of triple-negative breast cancer cells by a recombinant SNAP-tag-based antibody-auristatin F drug conjugate.

Purpose: Triple-negative breast cancer (TNBC) is phenotypic of breast tumors lacking expression of the estrogen receptor (ER), the progesterone receptor (PgR), and the human epidermal growth factor receptor 2 (HER2). The paucity of well-defined molecular targets in TNBC, coupled with the increasing burden of breast cancer-related mortality, emphasizes the need to develop targeted diagnostics and therapeutics. While antibody-drug conjugates (ADCs) have emerged as revolutionary tools in the selective delivery of drugs to malignant cells, their widespread clinical use has been hampered by traditional strategies which often give rise to heterogeneous mixtures of ADC products.

Click Chemistry-Generated Auristatin F-Linker-Benzylguanine for a SNAP-Tag-Based Recombinant Antibody-Drug Conjugate Demonstrating Selective Cytotoxicity toward EGFR-Overexpressing Tumor Cells.

Antibody-drug conjugates (ADCs) are bifunctional molecules combining the targeting potential of monoclonal antibodies with the cancer-killing ability of cytotoxic drugs. This simple yet intelligently designed system directly addresses the lack of specificity encountered with conventional anti-cancer treatment regimes. However, despite their initial success, the generation of clinically sustainable and effective ADCs has been plagued by poor tumor penetration, undefined chemical linkages, unpredictable pharmacokinetic profiles, and heterogeneous mixtures of products.

The Evolution of SNAP-Tag Labels.

The conjugation of proteins with synthetic molecules can be conducted in many different ways. In this Perspective, we focus on tag-based techniques and specifically on the SNAP-tag technology. The SNAP-tag technology makes use of a fusion protein between a protein of interest and an enzyme tag that enables the actual conjugation reaction.

Activity-Based Proteomic Identification of the -Thiolation Targets of Ajoene in MDA-MB-231 Breast Cancer Cells.

Garlic is a medicinal plant and spice that has been used for millennia for its health-promoting effects. These medicinal properties are associated with low molecular weight organosulfur compounds, produced following the crushing of garlic cloves. One of these compounds, ajoene, is proposed to act by -thioallylating cysteine residues on target proteins whose identification in cancer cells holds great promise for understanding mechanistic aspects of ajoene's cancer cell cytotoxicity.

The structures of the C146A variant of the amidase from Pyrococcus horikoshii bound to glutaramide and acetamide suggest the basis of amide recognition.

The nitrilase superfamily enzymes from Pyrococcus abyssi and Pyrococcus horikoshii hydrolyze several different amides. No nitriles that we tested were hydrolyzed by either enzyme. Propionamide and acetamide were the most rapidly hydrolyzed of all the substrates tested.

Opposing Roles of GSK3α and GSK3β Phosphorylation in Platelet Function and Thrombosis.

One of the mechanisms by which PI3 kinase can regulate platelet function is through phosphorylation of downstream substrates, including glycogen synthase kinase-3 (GSK3)α and GSK3β. Platelet activation results in the phosphorylation of an N-terminal serine residue in GSK3α (Ser21) and GSK3β (Ser9), which competitively inhibits substrate phosphorylation. However, the role of phosphorylation of these paralogs is still largely unknown.

Towards the development of a targeted albumin-binding radioligand: Synthesis, radiolabelling and preliminary in vivo studies.

Introduction: The compound named 4-[10-(4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)butanamido)decyl]-11-[10-(β,d-glucopyranos-1-yl)-1-oxodecyl]-1,4,8,11-tetraazacyclotetradecane-1,8-diacetic acid is a newly synthesised molecule capable of binding in vivo to albumin to form a bioconjugate. This compound was given the name, GluCAB(glucose-chelator-albumin-binder)-maleimide-1. Radiolabelled GluCAB-maleimide-1 and subsequent bioconjugate is proposed for prospective oncological applications and works on the theoretical dual-targeting principle of tumour localization through the "enhanced permeability and retention (EPR) effect" and glucose metabolism.

A Diverse Range of Hemozoin Inhibiting Scaffolds Act on as Heme Complexes.

A diverse series of hemozoin-inhibiting quinolines, benzamides, triarylimidazoles, quinazolines, benzimidazoles, benzoxazoles, and benzothiazoles have been found to lead to exchangeable heme levels in cultured (NF54) that ranged over an order of magnitude at the IC. Surprisingly, less active compounds often exhibited higher levels of exchangeable heme than more active ones. Quantities of intracellular inhibitor measured using the inoculum effect exhibited a linear correlation with exchangeable heme, suggesting formation of heme-inhibitor complexes in the parasite.

The Garlic Compound Z-Ajoene, S-Thiolates COX2 and STAT3 and Dampens the Inflammatory Response in RAW264.7 Macrophages.

Scope: Garlic (Allium sativum) has been used for centuries as a prophylactic and therapeutic medicinal agent to control inflammation-associated pathologies. To investigate the underlying mechanisms, an in vitro inflammatory model is established using RAW264.7 murine macrophages exposed to low-doses of lipopolysaccharide (LPS) in the presence of garlic compounds allicin and Z-ajoene (ZA), mimicking regular garlic consumption.

Rapamycin restrains platelet procoagulant responses via FKBP-mediated protection of mitochondrial integrity.

Background And Purpose: Rapamycin is a potent immunosuppressant and anti-proliferative agent used clinically to prevent organ transplant rejection and for coating coronary stents to counteract restenosis. Rapamycin complexes with the immunophilin FKBP12, which subsequently binds and inhibits mTORC1. Despite several reports demonstrating that rapamycin affects platelet-mediated responses, the underlying mechanism of how it alters platelet function is poorly characterised.

Redundant role of ASK1-mediated p38MAPK activation in human platelet function.

Apoptosis signal-regulating kinase 1 (ASK1) is a member of mitogen-activated protein kinase kinase kinase (MAP3K) family, which recently has been implicated in the regulation of p38 MAPK/PLA2/thromboxane (TxA) generation, as well as P2Y signalling in murine platelets. ASK1 has therefore been proposed as a potential target for anti-thrombotic therapy. At present it is unknown whether ASK1 also contributes to TxA formation and platelet function in human.

Synthesis of (+)-Tacamonine via Stereoselective Radical Cyclization.

A concise, asymmetric synthesis of the indole alkaloid (+)-tacamonine is reported involving a stereoselective radical cyclization of a 1-phenylsulfanyl tetrahydro-β-carboline bearing a pendant enoate ester side chain as a key step. In this process, a single stereocenter in the side chain allows for the formation of two stereocenters of the natural product in a highly diastereoselective fashion. Computational investigations of this key cyclization support the experimentally observed outcome and shed light on the factors impacting its stereoselectivity.

The garlic compound ajoene covalently binds vimentin, disrupts the vimentin network and exerts anti-metastatic activity in cancer cells.

Background: Garlic has been used for centuries for its flavour and health promoting properties that include protection against cancer. The vinyl disulfide-sulfoxide ajoene is one of the phytochemicals found in crushed cloves, hypothesised to act by S-thiolating reactive cysteines in target proteins.

Methods: Using our fluorescently labelled ajoene analogue called dansyl-ajoene, ajoene's protein targets in MDA-MB-231 breast cancer cells were tagged and separated by 2D electrophoresis.

Unsymmetrical Organotrisulfide Formation via Low-Temperature Disulfanyl Anion Transfer to an Organothiosulfonate.

New methodology is presented for the formation of unsymmetrical organotrisulfides in a high yield and purity, relatively free of polysulfide byproducts. The highlight of the method is the low-temperature (-78 °C) deprotection of a disulfanyl acetate with sodium methoxide in THF to form a disulfanyl anion, which reacts rapidly in situ with an organothiosulfonate ( S-aryl or S-alkyl) within 30 seconds followed by quenching. The discovery of these new reaction conditions together with the relative greenness of the chemistry overall makes for an efficient protocol, from which a range of organotrisulfides covering aliphatic, aromatic, as well as cysteine and sugar groups can be accessed in a high yield and purity.

Hemozoin inhibiting 2-phenylbenzimidazoles active against malaria parasites.

The 2-phenylbenzimidazole scaffold has recently been discovered to inhibit β-hematin (synthetic hemozoin) formation by high throughput screening. Here, a library of 325,728 N-4-(1H-benzo[d]imidazol-2-yl)aryl)benzamides was enumerated, and Bayesian statistics used to predict β-hematin and Plasmodium falciparum growth inhibition. Filtering predicted inactives and compounds with negligible aqueous solubility reduced the library to 35,124.

Chemical Proteomics and Super-resolution Imaging Reveal That Chloroquine Interacts with Plasmodium falciparum Multidrug Resistance-Associated Protein and Lipids.

It is well established that chloroquine, a quinoline antimalarial, inhibits hemozoin formation in the malaria parasite. Counterintuitively, this archetypal antimalarial is also used in the treatment of diseases in which hemozoin biocrystallization does not play a role. Hence, we decided to investigate whether chloroquine possesses binding targets other than Fe(III) protoporphyrin IX in blood stage Plasmodium falciparum parasites and whether these are related to sites of accumulation within the parasite other than the digestive vacuole.

Metformin reduces liver glucose production by inhibition of fructose-1-6-bisphosphatase.

Metformin is a first-line drug for the treatment of individuals with type 2 diabetes, yet its precise mechanism of action remains unclear. Metformin exerts its antihyperglycemic action primarily through lowering hepatic glucose production (HGP). This suppression is thought to be mediated through inhibition of mitochondrial respiratory complex I, and thus elevation of 5'-adenosine monophosphate (AMP) levels and the activation of AMP-activated protein kinase (AMPK), though this proposition has been challenged given results in mice lacking hepatic AMPK.

4-Aminoquinoline Antimalarials Containing a Benzylmethylpyridylmethylamine Group Are Active against Drug Resistant Plasmodium falciparum and Exhibit Oral Activity in Mice.

Emergence of drug resistant Plasmodium falciparum including artemisinin-tolerant parasites highlights the need for new antimalarials. We have previously shown that dibemequines, 4-amino-7-chloroquinolines with dibenzylmethylamine (dibemethin) side chains, are efficacious. In this study, analogues in which the terminal phenyl group of the dibemethin was replaced with a 2-pyridyl group and in which the 4-amino-7-chloroquinoline was either maintained or replaced with a 4-aminoquinoline-7-carbonitrile were synthesized in an effort to improve druglikeness.

Quaternized α,α'-Amino Acids via Curtius Rearrangement of Substituted Malonate-Imidazolidinones.

An efficient synthesis protocol is presented for accessing quaternized α-amino acids in chiral, nonracemic form via diastereoselective malonate alkylation followed by C- to N-transposition. The key stereodifferentiating step involves a diastereoselective alkylation of an α-monosubstituted malonate-imidazolidinone, which is followed first by a chemoselective malonate PMB ester removal and then a Curtius rearrangement to provide the transposition. The method demonstrates a high product ee (89-99% for eight cases) for quaternizing a range of proteinogenic α-amino acids.

The Cytotoxicity of the Ajoene Analogue BisPMB in WHCO1 Oesophageal Cancer Cells Is Mediated by CHOP/GADD153.

Garlic is a food and medicinal plant that has been used in folk medicine since ancient times for its beneficial health effects, which include protection against cancer. Crushed garlic cloves contain an array of small sulfur-rich compounds such as ajoene. Ajoene is able to interfere with biological processes and is cytotoxic to cancer cells in the low micromolar range.

Identification and Mechanistic Evaluation of Hemozoin-Inhibiting Triarylimidazoles Active against .

In a previous study, target based screening was carried out for inhibitors of β-hematin (synthetic hemozoin) formation, and a series of triarylimidazoles were identified as active against . Here, we report the subsequent synthesis and testing of derivatives with varying substituents on the three phenyl rings for this series. The results indicated that a 2-hydroxy-1,3-dimethoxy substitution pattern on ring A is required for submicromolar parasite activity.