Synthesis of a Double-Spanned Resorc[4]arene via Ring-Closing Metathesis and Calculation of Aggregation Propensity

Ring-closing metathesis (RCM) catalyzed by a second-generation Grubbs catalyst has been used to synthesize resorc[4]­arenes <b>2b</b>–<b>5b</b> starting from undecenyl resorc[4]­arene <b>1b</b> fixed in the cone conformation. X-ray diffraction analysis of the major metathesis product, <b>3b</b> (50% yield), revealed a cavity-shaped architecture resembling a basket, endowed with a large intramolecular space (∼10 Å) and a strong propensity to self-assemble as a supramolecular trio of heterochiral dimers. This prompted us to investigate the aggregation propensity of basket <b>3b</b> in THF/water solution by UV–visible spectroscopy. The cavitation Gibbs free-energy change (ΔΔ<i>G</i>_cav = 4.78 kcal mol^–1) associated with the self-assembly of macrocycle <b>3b</b> was calculated as a measure of the solvophobic interactions involved in the process

Design, Palladium-Catalyzed Synthesis, and Biological Investigation of 2‑Substituted 3‑Aroylquinolin-4(1<i>H</i>)‑ones as Inhibitors of the Hedgehog Signaling Pathway

2-Substituted 3-aroylquinolin-4­(1<i>H</i>)-ones, prepared through a palladium-catalyzed carbonylative cyclization of <i>N</i>-(2-iodoaryl)­enaminones, proved to inhibit efficiently the Hedgehog pathway through direct antagonism of the wild-type and drug-resistant form of the Smoothened receptor. Notably, these compounds repressed the Hh-dependent growth events and the proliferation of tumor cells with aberrant activation of the Hh pathway, which plays a crucial role in development and tumorigenesis

Reaction of Nitrosonium Cation with Resorc[4]arenes Activated by Supramolecular Control: Covalent Bond Formation

Resorc­[4]­arenes <b>1</b> and <b>2</b>, which previously proved to entrap NO⁺ cation within their cavities under conditions of host-to-guest excess, were treated with a 10-fold excess of NOBF₄ salt in chloroform. Kinetic and spectral UV–visible analyses revealed the formation of isomeric 1:2 complexes as a direct evolution of the previously observed event. Accordingly, three-body <b>1</b>–(NO⁺)₂ and <b>2</b>–(NO⁺)₂ adducts were built by MM and fully optimized by DFT calculations at the B3LYP/6-31G­(d) level of theory. Notably, covalent nitration products <b>4</b>,<b> 5</b> and <b>6</b>,<b> 7</b> were obtained by reaction of NOBF₄ salt with host <b>1</b> and <b>2</b>, respectively, involving macrocycle ring-opening and insertion of a nitro group in one of the four aromatic rings. In particular, compounds <b>4</b> and <b>6</b>, both containing a trans-double bond in the place of the methine bridge, were oxidized to aldehydes <b>5</b> and <b>7</b>, respectively, after addition of water to the reaction mixture. Calculation of the charge and frontier orbitals of the aromatic donor (HOMO) and the NO⁺ acceptor (LUMO) clearly suggests an ipso electrophilic attack by a first NO⁺ unit on the resorcinol ring, mediated by the second NO⁺ unit

DataSheet1_Inhibition of adenovirus transport from the endosome to the cell nucleus by rotenone.pdf

Regardless of the clinical impact of human adenovirus (HAdV) infections in the healthy population and its high morbidity in immunosuppressed patients, a specific treatment is still not yet available. In this study, we screened the CM1407 COST Action’s chemical library, comprising 1,233 natural products to identify compounds that restrict HAdV infection. Among them, we identified rotenolone, a compound that significantly inhibited HAdV infection. Next, we selected four isoflavonoid-type compounds (e.g., rotenone, deguelin, millettone, and tephrosin), namely rotenoids, structurally related to rotenolone in order to evaluate and characterized in vitro their antiviral activities against HAdV and human cytomegalovirus (HCMV). Their IC50 values for HAdV ranged from 0.0039 µM for rotenone to 0.07 µM for tephrosin, with selective indices ranging from 164.1 for rotenone to 2,429.3 for deguelin. In addition, the inhibition of HCMV replication ranged from 50% to 92.1% at twice the IC50 concentrations obtained in the plaque assay for each compound against HAdV. Our results indicated that the mechanisms of action of rotenolone, deguelin, and tephrosin involve the late stages of the HAdV replication cycle. However, the antiviral mechanism of action of rotenone appears to involve the alteration of the microtubular polymerization, which prevents HAdV particles from reaching the nuclear membrane of the cell. These isoflavonoid-type compounds exert high antiviral activity against HAdV at nanomolar concentrations, and can be considered strong hit candidates for the development of a new class of broad-spectrum antiviral drugs.</p

Structures of PtpB inhibitors.

<p>Chemical structure of PtpB inhibitors showing an IC₅₀ < 100 µM. Below the line are the two common chemical scaffolds: Scaffold A present in KuwE, Ega1, M2 and M2H; Scaffold B present in PirIII, Δ3, 6016 and Ac3.</p

Peptide mass fingerprints.

<p>Peptide mass fingerprinting of PtpB recorded by MS in absence (A) and presence of 300 µM KuwE (B). The tryptic peptide <i>m/z</i> 2224 corresponds to the complete sequence of the catalytic site ((R145)VVTLLAAGRPVLT<u>HCFAGKDR</u>(T167)) and the tryptic peptide <i>m/z</i> 1953 corresponds to a part of the catalytic site ((R145)VVTLLAAGRPVLT<u>HCFAGK</u>(D165)), which include the His159 and the catalytic Cys160 residues.</p

Protection of PtpB proteolytic cleavage by KuwE.

<p>Schematic representation of the region protected by KuwE in PtpB structure. The amino acid sequence VVTLLAAGRPVLTHCFAGKDR (<i>m/z</i> 2224) identified by mass spectrometry is highlighted in blue sticks and cartoon. KuwE is showed as orange sticks while PtpB is represented as green (alpha-helix) and magenta (beta-chain) cartoon.</p

Differences between PtpB and PTP1B.

<p>Sequence alignment of Mtb PtpB (UniProtKB code: P96830, 276 aa complete sequence) and human PTP1B (UniProtKB code: P18031, 435 aa complete sequence). Not conserved amino acids of the PtpB active site motif, which may be exploited to design selective Mtb PtpB inhibitors, are highlighted by a red box. Sequence alignment was performed with ClustalX. Sequence numbering corresponds to human PTP1B. Bars below the sequence alignment correspond to the degree of amino acid conservation between the two sequence (full bar: residues identity; empty bar: completely different residues). </p

Synthesis, biological evaluation and molecular modeling studies on novel quinonoid inhibitors of CDC25 phosphatases

<p>The cell division cycle 25 phosphatases (CDC25A, B, and C; E.C. 3.1.3.48) are key regulator of the cell cycle in human cells. Their aberrant expression has been associated with the insurgence and development of various types of cancer, and with a poor clinical prognosis. Therefore, CDC25 phosphatases are a valuable target for the development of small molecule inhibitors of therapeutic relevance. Here, we used an integrated strategy mixing organic chemistry with biological investigation and molecular modeling to study novel quinonoid derivatives as CDC25 inhibitors. The most promising molecules proved to inhibit CDC25 isoforms at single digit micromolar concentration, becoming valuable tools in chemical biology investigations and profitable leads for further optimization.</p> <p></p

Kinetics measurements of PtpB inhibitors.

<p>Lineweaver-Burk double-reciprocal plots representing inhibitory profiles of compounds KuwE, PirIII, Ega1, 6016, Ac3 and ∆3 against PtpB. Kinetic experiments were conducted in the presence of increasing concentrations of inhibitors: 0 µM (), 1 µM (), 2 µM (), 3 µM (), 6 µM (), 10 µM (), 20 µM (), 25 µM (), 30 µM (), 35 µM (), 40 µM (), 45 µM (); <i>p</i>NPP was used as substrate in all experiments. For KuwE, Ac3 and 6016, all lines converged at the <i>y</i>-axis (1/<i>V</i>_max), whereas the slope (K_Mapp/<i>V</i>_max) and <i>x</i>-axis interception (1/<i>K</i>_Mapp) varies according to the inhibitor concentration; the constant value of <i>V</i>_max and the increased values of <i>K</i>_Mapp are consistent with a competitive inhibition mechanism. For PirIII, Ega1 and Δ3, all lines converge at the <i>x</i>-axis (1/<i>K</i>_Mapp) and the <i>y</i>-axis interception (1/<i>V</i>_max) varies as a function of the inhibitor concentration; the constant value of <i>K</i>_Mapp and the increased values of <i>V</i>_max indicate that these compounds are noncompetitive inhibitors. </p