Ring‐Opening of N‐tert‐Butanesulfinylethynylaziridines with Lithium Tris(dimethylphenylsilyl)zincate: Stereoselective Access to 4‐Amino‐1‐allenylsilanes

The ring‐opening of N‐tert‐butanesulfinylethynylaziridines with lithium tris(dimethylphenylsilyl)zincate is reported. The reaction is demonstrated to be both stereoselective and stereospecific and to proceed through an anti‐S_N2′ process. Further deprotection of the nitrogen atom under mild conditions allows access to 4‐amino‐1‐(dimethylphenylsilyl)allenes with high yields and levels of stereoselectivity.

     

Synthesis and Biological Activity of 10‐Aza‐narciclasine

The first active aza analogue of narciclasine was synthesized from a pentasubstituted derivative of nicotinic acid. The key features of the synthesis include a halogen dance of bromopyridine and an intramolecular Heck reaction with a conduramine derived chemoenzymatically from bromobenzene. 10‐Aza‐narciclasine was found to have reasonable activity against several cancer cell lines.

     

Alkylzinc‐Mediated Addition of Alkynes to N‐Tosylaldimines: Enantioselective Synthesis of (E)‐(2‐En‐3‐ynyl)‐amines

An alkylzinc‐mediated simple and efficient procedure for the catalytic enantioselective synthesis of N‐tosyl‐(E)‐(2‐en‐3‐ynyl)‐amines has been developed. The method works well with various N‐tosylaldimines and alkynes.     

Molecular Assembly of an Aptamer–Drug Conjugate for Targeted Drug Delivery to Tumor Cells

Special delivery! An aptamer‐directed anticancer drug was molecularly engineered to be delivered to target cells for efficient therapeutic application. The covalent conjugation of drug and aptamer creates alternative opportunities for targeted therapy, as multiple yet specific aptamers can be “generated” relatively easily by cell‐SELEX for any target cells; this demonstrates the full potential of cell‐SELEX as a molecular discovery tool for biomedical studies and drug development.

     

Antibodies against Mucin‐Based Glycopeptides Affect Trypanosoma cruzi Cell Invasion and Tumor Cell Viability

This study describes the synthesis of glycopeptides NHAc[βGal]‐(Thr)₂‐[αGalNAc]‐(Thr)₂‐[αGlcNAc]‐(Thr)₂Gly‐OVA ( 1 ‐OVA) and NHAc[βGal‐αGalNAc]‐(Thr)₃‐[αLacNAc]‐(Thr)₃‐Gly‐OVA ( 2 ‐OVA) as mimetics of both T. cruzi and tumor mucin glycoproteins. These glycopeptides were obtained by solid‐phase synthesis, which involved the prior preparation of the protected glycosyl amino acids αGlcNAc‐ThrOH ( 3 ), αGalNAc‐ThrOH ( 4 ), βGal‐ThrOH ( 5 ), αLacNAc‐ThrOH ( 6 ), and βGal‐αGalNAc‐ThrOH ( 7 ) through glycosylation reactions. Immunizations of mice with glycopeptides 1 ‐OVA and 2 ‐OVA induced high antibody titers (1:16 000), as verified by ELISA tests, whereas flow cytometry assays showed the capacity of the obtained anti‐glycopeptides 1 ‐OVA and 2 ‐OVA antibodies to recognize both T. cruzi and MCF‐7 tumor cells. In addition, antisera induced by glycopeptides 1 ‐OVA and 2 ‐OVA were also able to inhibit T. cruzi fibroblast cell invasion (70 %) and to induce antibody‐mediated cellular cytotoxicity (ADCC) against MCF‐7 cells, with 50 % reduction of cell viability.     

Gold‐Catalysis: Highly Efficient and Regio‐Selective Carbonyl Migration in Alkynyl‐Substituted Indole‐3‐Carboxamides Leading to Azepino[3,4‐b]indol‐1‐ones

An unprecedented rearrangement/anellation sequence allows the clean synthesis of azepino[3,4‐b]indol‐1‐ones from readily available starting materials. Alkyne‐substituted indole‐3‐carboxamides were prepared and converted to azepino[3,4‐b]indol‐1‐ones by the SPhosAuNTf₂ catalyst (SPhos=2‐dicyclohexylphosphino‐2′,6′‐dimethoxybiphenyl). The new connectivity, which involves an unprecedented 3,2‐shift of an acylamino group for the product formation, was proven by a crystal structure analysis.     

Enantioselective Diynylation of Cyclic N‐Acyl Ketimines: Access to Chiral Trifluoromethylated Tertiary Carbinamines

A novel enantioselective diynylation of cyclic N‐acyl trifluoromethylketimines with chloramphenicol‐amine derivatives as chiral additives has been successfully developed. A series of diynylated tertiary trifluoromethylcarbinamines were obtained in high yields with good to excellent enantioselectivities (with up to 99% ee).     

Carboxylate Analogues of Aryl‐Urea‐Substituted Fatty Acids That Target the Mitochondria in MDA‐MB‐231 Breast Cancer Cells to Promote Cell Death

Selective targeting of the tumor cell mitochondrion is a viable approach for the development of anticancer agents because the organelle is functionally different from the mitochondria of normal cells. We recently developed a novel aryl‐urea fatty acid, 16({[4‐chloro‐3‐(trifluoromethyl)phenyl]carbamoyl}amino)hexadecanoic acid ( 1 ) that was found to disrupt mitochondria and to activate apoptosis in MDA‐MB‐231 breast cancer cells. However, there is currently little information on the structural requirements for the activity of compound 1 analogues. The present study evaluated the role of the carboxylic acid group on the anticancer activity of 1 . Bioisosteric replacement of the carboxylate in 1 maintained activity. Thus, like 1 , the sulfonic acid analogue 1‐SA and the oxo‐thiadiazole analogue 1‐OT were also found to target the mitochondrion and to activate cell killing capacity. The hydroxamic acid analogue 1‐HA also killed MDA‐MB‐231 cells, but its onset of action was slower than that of 1‐SA and 1‐OT . In contrast, replacement of the carboxylate with non‐bioisosteric amido and methylamido groups produced analogues that minimally altered mitochondrial function and showed little capacity to decrease tumor cell viability. These findings suggest that the carboxylate moiety in the novel mitochondrially targeted agent 1 is an important determinant of the kinetics and efficacy of anticancer cell activities of compound 1 analogues. Further development of carboxylate‐modified analogues of aryl‐urea fatty acids as potential anticancer agents could now be warranted.     

Targeted Delivery of Proteasome Inhibitors to Somatostatin‐Receptor‐Expressing Cancer Cells by Octreotide Conjugation

Clinical application of proteasome inhibitors (PIs) is so far limited to peripheral blood cancers due to the pronounced cytotoxicity towards all cell types. Targeted delivery of PIs could permit the treatment of other cancers along with decreasing side effects. Herein we describe the first small‐molecule proteasome inhibitor conjugate for targeted delivery, created by fusing PIs to a synthetic ligand of somatostatin receptors, which are highly expressed in a variety of tumors. X‐ray crystallographic studies and in vitro IC₅₀ measurements demonstrated that addition of the cyclopeptide octreotide as a targeting vehicle does not affect the PI's binding mode. The cytotoxicity of the conjugate against somatostatin‐receptor‐expressing cells was up to 11‐fold higher than that of a non‐targeting surrogate. We have therefore established PIs as a new payload for drug conjugates and have shown that targeted delivery thereof could be a promising approach for the broader application of this FDA‐approved class of compounds.     

Ruthenium‐Catalyzed Asymmetric Hydrogenation of β‐Keto‐ enamines: An Efficient Approach to Chiral γ‐Amino Alcohols

A highly efficient and enantioselective hydrogenation of unprotected β‐ketoenamines catalyzed with ruthenium(II) dichloro{(S)‐(−)‐2,2′‐bis[di(3,5‐xylyl)phosphino]‐1,1′‐binaphthyl}[(2S)‐(+)‐1,1‐bis(4‐methoxyphenyl)‐3‐methyl‐1,2‐butanediamine] {Ru[(S)‐xylbinap][(S)‐daipen]Cl₂} has been successfully developed. This methodology provides a straightforward access to free γ‐secondary amino alcohols, which are key building blocks for a variety of pharmaceuticals and natural products, with high yields (>99%) and excellent enantioselectivities (up to 99% ee) in all cases.     

Chiral Bis(N‐sulfonylamino)phosphine‐ and TADDOL‐Phosphite‐Oxazoline Ligands: Synthesis and Application in Asymmetric Catalysis

A series of N,P‐ligands has been prepared, containing a chiral oxazoline ring and as a second chiral unit a bis(N‐sulfonylamino)phosphine group embedded in a diazaphospholidine ring or a cyclic phosphite group derived from TADDOL. These modular ligands are readily synthesized from chiral amino alcohols and chiral 1,2‐diamines or TADDOLs. Palladium and iridium complexes derived from these ligands were found to be efficient catalysts for enantioselective allylic alkylation and olefin hydrogenation, respectively.     

Stereocontrol in Palladium‐Catalyzed Propargylic Substitutions: Kinetic Resolution to give Enantioenriched 1,5‐Enynes and Propargyl Acetates

Kinetic resolution during the catalytic allyl‐propargyl cross‐coupling with chiral starting materials can be accomplished with a chiral palladium catalyst. These reactions offer ready access to enantiomerically enriched enyne products from simple, readily available starting materials.

     

α‐Bromoacrylamido N‐Substituted Isatin Derivatives as Potent Inducers of Apoptosis in Human Myeloid Leukemia Cells

A novel series of α‐bromoacryloyl N‐substituted isatin analogues were found to inhibit the growth and viability of human myeloid leukemia HL‐60 and U‐937 cells as well as human lymphoid leukemia MOLT‐3 cells. Cell death induced by these molecules was preceded by a rapid release of cytochrome c from mitochondria into the cytosol and subsequent caspase activation involving caspase‐3, to cleave poly(ADP‐ribose) polymerase (PARP). These findings suggest that these compounds present antiproliferative activity which may be mediated by apoptosis caused by cytochrome c release and caspase activation in human leukemia cells.     

One‐Pot Quinine‐Catalyzed Synthesis of α‐Chiral γ‐Keto Esters: Enantioenriched Precursors of cis‐α,γ‐Substituted‐γ‐Butyrolactones

A highly enantioselective one‐pot synthesis of important building blocks, α‐chiral γ‐keto esters, has been developed by combining a quinine‐catalyzed Michael addition of malononitrile to trans‐enones followed by magnesium monoperoxyphthalate (MMPP) oxidation. These synthons proved to be useful reagents for a simple access to challenging cis‐α,γ‐disubstituted γ‐butyrolactones in good diastereoselectivity and high enantiocontrol.

     

Short Chemoenzymatic Azide‐Free Synthesis of Oseltamivir (Tamiflu): Approaching the Potential for Process Efficiency

A short chemoenzymatic and azide‐free synthesis of oseltamivir was attained with the key steps consisting of a one‐pot Dauben–Michno oxidative transposition and amination and a reductive transposition of an acrylate.     

Copper (I) Iodide‐Catalyzed One‐Step Preparation of Functionalized Allenes from Terminal Alkynes: Amine Effect

An efficient one‐step synthesis of functionalized allenes from readily available functionalized terminal alkynes and aldehydes by applying the effect of a dialkylamine has been developed. The protocol is catalyzed by copper(I) iodide and the dialkylamine is believed to play a very important role in the transformation.     

Design and Synthesis of N‐Acylated Aza‐Goniothalamin Derivatives and Evaluation of Their in vitro and in vivo Antitumor Activity

Herein we describe the synthesis of a focused library of compounds based on the structure of goniothalamin ( 1 ) and the evaluation of the potential antitumor activity of the compounds. N‐Acylation of aza‐goniothalamin ( 2 ) restored the in vitro antiproliferative activity of this family of compounds. 1‐(E)‐But‐2‐enoyl‐6‐styryl‐5,6‐dihydropyridin‐2(1H)‐one ( 18 ) displayed enhanced antiproliferative activity. Both goniothalamin ( 1 ) and derivative 18 led to reactive oxygen species generation in PC‐3 cells, which was probably a signal for caspase‐dependent apoptosis. Treatment with derivative 18 promoted Annexin V/7‐aminoactinomycin D double staining, which indicated apoptosis, and also led to G₂/M cell‐cycle arrest. In vivo studies in Ehrlich ascitic and solid tumor models confirmed the antitumor activity of goniothalamin ( 1 ), without signs of toxicity. However, derivative 18 exhibited an unexpectedly lower in vivo antitumor activity, despite the treatments being administered at the same site of inoculation. Contrary to its in vitro profile, aza‐goniothalamin ( 2 ) inhibited Ehrlich tumor growth, both on the ascitic and solid forms. Our findings highlight the importance of in vivo studies in the search for new candidates for cancer treatment.     

Lectin‐Based Drug Design: Combined Strategy to Identify Lead Compounds using STD NMR Spectroscopy,Solid‐Phase Assays and Cell Binding for a Plant Toxin Model

The growing awareness of the sugar code—i.e. the biological functionality of glycans—is leading to increased interest in lectins as drug targets. The aim of this study was to establish a strategic combination of screening procedures with increased biorelevance. As a model, we used a potent plant toxin (viscumin) and lactosides synthetically modified at the C6/C6′ positions and the reducing end aglycan. Changes in the saturation transfer difference (STD) in NMR spectroscopy, applied in inhibition assays, yielded evidence for ligand activity and affinity differences. Inhibitory potency was confirmed by the blocking of lectin binding to a glycoprotein‐bearing matrix. In cell‐based assays, iodo/azido‐substituted lactose derivatives were comparatively active. Interestingly, cell‐type dependence was observed, indicating the potential of synthetic carbohydrate derivative to interact with lectins in a cell‐type (glycan profile)‐specific manner. These results are relevent to research into human lectins, glycosciences, and beyond.