Regioselective Preferential Nucleophilic Addition of <i>N</i>-Heterocycles onto Haloarylalkynes over <i>N</i>-Arylation of Aryl Halides

The study of preferential addition of heterocyclic amines onto halo-substituted arylalkynes over <i>N</i>-arylation under various catalytic conditions is described. The present work supports and confirms the mechanistic pathway of our recent work on the tandem synthesis of indolo- and pyrrolo-[2,1-<i>a</i>]isoquinolines via hydroamination followed by oxidative addition and not vice versa

Regioselective Preferential Nucleophilic Addition of <i>N</i>-Heterocycles onto Haloarylalkynes over <i>N</i>-Arylation of Aryl Halides

The study of preferential addition of heterocyclic amines onto halo-substituted arylalkynes over <i>N</i>-arylation under various catalytic conditions is described. The present work supports and confirms the mechanistic pathway of our recent work on the tandem synthesis of indolo- and pyrrolo-[2,1-<i>a</i>]isoquinolines via hydroamination followed by oxidative addition and not vice versa

Base-Mediated Selective Synthesis of Diversely Substituted <i>N</i>-Heterocyclic Enamines and Enaminones by the Hydroamination of Alkynes

Regio- and stereoselective alkynylation of various <i>N</i>-heterocycles <b>1a</b>–<b>l</b> using potassium and cesium salts in DMSO is described. Terminal alkynes <b>2a</b>–<b>k</b> and internal alkynes <b>4a</b>–<b>f</b> provided the kinetically stable <i>Z</i>-enamines <b>3a</b>–<b>l</b> and <b>5a</b>–<b>i</b> in good to excellent yields using KOH at 120 °C. Addition of heterocyclic amines to 1,3- and 1,4-diethynylbenzene <b>6a</b>–<b>b</b> provided the mixture of <i>E</i>/<i>Z</i> isomers with KOH; however, with Cs₂CO₃ selectively <i>Z</i>-isomers <b>7ab</b>–<b>db</b> were obtained by the hydroamination at one triple bond. This developed methodology also provides an easy and novel access for the synthesis of enaminones <b>10a</b>–<b>c</b>. The detailed work also supports the formation of <i>cis-</i>isomer by preferential addition of <i>o</i>-haloarylalkynes followed by intramolecular C2 arylation in the copper-catalyzed tandem synthesis of indolo and pyrrolo­[2,1-<i>a</i>]­isoquinolines

A Simple and Efficient Synthesis of 2,3-Diarylnaphthofurans Using Sequential Hydroarylation/Heck Oxyarylation

An efficient and simple strategy has been developed for the synthesis of 2,3-diarylnaphthofurans using sequential hydroarylation of naphthols and alkynes in the presence of In(OTf)₃ under microwave irradiation followed by one-pot Heck-oxyarylation of generated 1-substituted-α-hydroxy styrenes

Design and Biological Evaluation of Cell-Penetrating Peptide–Doxorubicin Conjugates as Prodrugs

Doxorubicin (Dox) is a hydrophilic anticancer drug that has short retention time due to the efficient efflux in some cancer cells (e.g., ovarian adenocarcinoma SK-OV-3). Cyclic [W­(RW)₄] and the corresponding linear peptide (RW)₄ were conjugated with Dox through an appropriate linker to afford cyclic [W­(RW)₄]–Dox and linear (RW)₄–Dox conjugates to enhance the cellular uptake and cellular retention of the parent drug for sustained anticancer activity. Comparative antiproliferative assays between covalent (cyclic [W­(RW)₄]–Dox and linear (RW)₄–Dox) and the corresponding noncovalent physical mixtures of the peptides and Dox were performed. Cyclic [W­(RW)₄]–Dox inhibited the cell proliferation of human leukemia (CCRF-CEM) (62–73%), ovarian adenocarcinoma (SK-OV-3) (51–74%), colorectal carcinoma (HCT-116) (50–67%), and breast carcinoma (MDA-MB-468) (60–79%) cells at a concentration of 1 μM after 72–120 h of incubation. Cyclic [W­(RW)₄]–Dox exhibited higher antiproliferative activity than linear (RW)₄–Dox in all cancer cells with the highest activity observed after 72 h. Flow cytometry analysis showed 3.6-fold higher cellular uptake of cyclic [W­(RW)₄]–Dox than Dox alone in SK-OV-3 cells after 24 h incubation. The cellular hydrolysis study showed that 99% of cyclic [W­(RW)₄]–Dox was hydrolyzed intracellularly within 72 h and released Dox. These data suggest that cyclic [W­(RW)₄]–Dox can be used as a potential prodrug for improving the cellular delivery and retention of Dox

Cationic cell-penetrating peptides tested as furin inhibitors.

<p>Cationic cell-penetrating peptides tested as furin inhibitors.</p

K_i values of the synthetic cyclic peptides tested as furin inhibitors.

<p>The data for hexa-D-arginine (D6R) and nona-D-arginine (D9R) are taken from [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0130417#pone.0130417.ref028" target="_blank">28</a>] and [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0130417#pone.0130417.ref015" target="_blank">15</a>] respectively.</p><p>K_i values of the synthetic cyclic peptides tested as furin inhibitors.</p

Inhibition of furin by the cationic peptides HIV-1 TAT_47-57 and Chariot.

<p>Soluble human furin, pre-incubated for 20 min at room temperature in the presence of (a) HIV-1 TAT (47–57) or (b) Chariot peptide, was tested at the specified concentrations. Furin activity was assessed by measuring the release of the fluorescent mca product from the fluorogenic substrate, pERTKR-mca. Results represent the mean ± S.D., N = 3. *P<0.01; **P<0.05.</p

Cyclic polyarginine peptides inhibit cellular convertase activity.

<p>(a) CHO cells were incubated with each compound at 1 μM for 24 h at 37°C, and cell viability was monitored by incubation for 4 h with WST-1. (b) CHO-GRAPfurin cells, expressing secreted alkaline phosphatase tethered to Golgi membranes by a transmembrane domain interrupted by a furin cleavage site, was incubated with 1 μM of each cyclic peptide for 20–24 h at 37 °C. Secreted alkaline phosphatase activity was measured in the medium. Results represent the mean ± S.D., N = 3.</p

Chemical structures of cyclic polyarginine peptides tested as furin inhibitors.

<p>Chemical structures of cyclic polyarginine peptides tested as furin inhibitors.</p