Asymmetric Chemoenzymatic Synthesis of (−)‐Podophyllotoxin and Related Aryltetralin Lignans

(?)‐Podophyllotoxin is one of the most potent microtubule depolymerizing agents and has served as an important lead compound in antineoplastic drug discovery. Reported here is a short chemoenzymatic total synthesis of (?)‐podophyllotoxin and related aryltetralin lignans. Vital to this approach is the use of an enzymatic oxidative C?C coupling reaction to construct the tetracyclic core of the natural product in a diastereoselective fashion. This strategy allows gram‐scale access to (?)‐deoxypodophyllotoxin and is readily adaptable to the preparation of related aryltetralin lignans.     

Synthesis and Antimycobacterial Activity of 3-Phenyl-1H-indoles

Tuberculosis has been described as a global health crisis since the 1990s, with an estimated 1.4 million deaths in the last year. Herein, a series of 20 1H-indoles were synthesized and evaluated as in vitro inhibitors of Mycobacterium tuberculosis (Mtb) growth. Furthermore, the top hit compounds were active against multidrug-resistant strains, without cross-resistance with first-line drugs. Exposing HepG2 and Vero cells to the molecules for 72 h showed that one of the evaluated structures was devoid of apparent toxicity. In addition, this 3-phenyl-1H-indole showed no genotoxicity signals. Finally, time-kill and pharmacodynamic model analyses demonstrated that this compound has bactericidal activity at concentrations close to the Minimum Inhibitory Concentration, coupled with a strong time-dependent behavior. To the best of our knowledge, this study describes the activity of 3-phenyl-1H-indole against Mtb for the first time.     

Computational insights into the mechanism of radical generation in B12-dependent methylmalonyl-CoA mutase

ONIOM calculations have provided novel insights into the mechanism of homolytic Co-C5' bond cleavage in the 5'-deoxyadenosylcobalamin cofactor catalyzed by methylmalonyl-CoA mutase. We have shown that it is a stepwise process in which conformational changes in the 5'-deoxyadenosine moiety precede the actual homolysis step. In the transition state structure for homolysis, the Co-C5' bond elongates by approximately 0.5 Angstroms from the value found in the substrate-bound reactant complex. The overall barrier to homolysis is approximately 10 kcal/mol, and the radical products are approximately 2.5 kcal/mol less stable than the initial ternary complex of enzyme, substrate, and cofactor. The movement of the deoxyadenosine moiety during the homolysis step positions the resulting 5'-deoxyadenosyl radical for the subsequent hydrogen atom transfer from the substrate, methylmalonyl-CoA.     

Synthesis, cytotoxic effect, and structure-activity relationship of Pd(II) complexes with coumarin derivatives

We report the influence of the substituent at the N atom of the ligands on the synthesis, biological activity, and stability of Pd(II) complexes of the general formula PdL(2). The compounds adopt a cis or trans configuration with respect to the substituent at the nitrogen atom. Sterically hindered substituents promote the formation of trans isomers, whereas when the nitrogen atom is unsubstituted, cis isomers are formed. The compounds were characterized by elemental analysis, infrared and 1H NMR spectroscopies, and electrospray mass spectrometry. The complexes were also studied using X-ray diffraction and computational DFT methods. Both complexes cis-3a and trans-3c exhibit square-planar geometries around the Pd(II) atom. The cytotoxic effects of these complexes were examined on two human leukemia cell lines, HL-60 and NALM-6. Pd complex cis-3a showed significant cytotoxic activity. The effects exhibited by this complex were comparable to those reported for carboplatin. Loigand 2a was not cytotoxic. Computational analysis carried out at the PB/B3LYP/LACVP**//mPW1PW91/LanL2DZ level showed excellent correlation between the energy difference of the cis and trans isomers and the cytotoxic activity, rendering computations a useful predictive tool for the design of new drugs.     

Structural basis for the interaction of a vascular endothelial growth factor mimic peptide motif and its corresponding receptors

Vascular endothelial growth factor (VEGF) is central to the survival and development of the vascular and nervous systems. We screened phage display libraries and built a peptide-based ligand-receptor map of binding sites within the VEGF family. We then validated a cyclic peptide, CPQPRPLC, as a VEGF-mimic that binds specifically to neuropilin-1 and VEGF receptor-1. Here, we use NMR spectroscopy to understand the structural basis of the interaction between our mimic peptide and the VEGF receptors. We show that: (1) CPQPRPLC has multiple interactive conformations; (2) receptor binding is mediated by the motif Arg-Pro-Leu; and (3) the Pro residue within Arg-Pro-Leu participates in binding to neuropilin-1 but not to VEGF receptor-1, perhaps representing an evolutionary gain-of-function. Therefore, Arg-Pro-Leu is a differential ligand motif to VEGF receptors and a candidate peptidomimetic lead for VEGF pathway modulation.     

Renormalization in non-Abelian gauge theories

The renormalization is performed in a manifestly covariant approach. The simplest form of the Ward identities z₁=z₂=…=z_n=… is fulfilled automatically in every gauge. In the Yang-Mills theory the counter-terms are gauge-invariant and depend on the charge renormalization constant only. In pure gravitation the analysis of all divergences is reduced in the present approach to some special classification of the kth order scalar densities in a Riemannian space.     

Photoelectrochemical oxidation of water at transparent ferric oxide film electrodes

The fabrication of thin-film Fe(2)O(3) photoanodes from the spray pyrolysis of Fe(III)-containing solutions is reported along with their structural characterization and application to the photoelectrolysis of water. These films combine good performance, measured in terms of photocurrent density, with excellent mechanical stability. A full investigation into the effects that modifications of the spray-pyrolysis method, such as the addition of dopants or structure-directing agents and changes in precursor species or carrier solvent, have on the performance of the photoanodes has been realized. The largest photocurrents were obtained from photoanodes prepared from ferric chloride precursor solutions, simultaneously doped with Ti(4+) (5%) and Al(3+) (1%). Doping with Zn(2+) also shows promise, cathodically shifting the onset potential by approximately 0.22 V.     

Identification of compounds in wine by HPLC-tandem mass spectrometry

In this work several compounds were detected in wines by HPLC-tandem mass spectrometry. In particular cinnamic and benzoic acids, tyrosol, apigenin-7-glucoside and luteolin-7-glucoside were identified and quantified in Italian wines. Red wines show bigger amount of cinnamic and benzoic acids than white wines. tyrosol is in bigger amount with respect to two flavones: luteolin-7-glucoside and apigenin-7-glucoside. These last two flavones are only in some wine, but it can be important to detect the presence of different substances in small amount to be able to characterize a wine.     

Enhanced delivery of 5-aminolevulinic acid esters by iontophoresis in vitro

The goals of this study were to quantitatively evaluate the iontophoretic delivery of a homologous series of cationic aminolevulinic acid (ALA) esters and to determine the contributions of electromigration and electroosmosis to their overall electrotransport in vitro. Anodal iontophoretic transport of ALA esters through porcine skin in vitro was followed for 2 h at a constant current of 0.5 mA/cm2. To deduce the mechanism, the concomitant transport of an electroosmotic marker, mannitol, was also assessed. Positively charged ALA esters of moderate lipophilicity showed increased iontophoretic flux through the skin. A more than 50-fold enhancement as compared with the zwitterionic parent ALA was observed for the methyl ester. As the size and lipophilicity of the ester increased, the efficiency of electrotransport decreased. The most lipophilic esters reduced the electroosmotic flow presumably because of the association of these cations with negative charges in the skin. Iontophoresis of methyl-ALA and hexyl-ALA also increased the amount of prodrug delivered into the skin. In summary, significant topical delivery of ALA esters can be achieved by iontophoresis, and transport into and across the skin was greatly enhanced compared with that of ALA itself. It remains to be seen whether this enhanced local bioavailability of the protoporphyrin prodrug can allow improved photodynamic therapy for the treatment of skin cancer.     

Novel twin corannulene: synthesis and crystal structure determination of a dicorannulenobarrelene dicarboxylate

[reaction: see text] The dicorannulenobarrelene 1 was synthesized with the final step achieved by a nickel-mediated fourfold intramolecular coupling of dibromomethyl with bromomethyl groups. Low-temperature (1)H NMR spectra of 1 show a presence of three conformers with approximate populations of 0.82:0.13:0.05, in good agreement with theoretical predictions. In the crystal, 1 incorporates two CCl(4) molecules and adopts the bis-exo conformation.