Quantification of thermal ring flexibilities of aromatic and heteroaromatic compounds

The consequences of thermal fluctuations occurring at room temperatures on the aromatic character of a broad group of compounds were analyzed in three distinct ways. First of all, the ring deformations were modeled along normal coordinates coming from quantum thermo-chemistry computations. The amplitudes of vibrations were estimated according to absorbed energies at room temperature. Alternatively, in-plane and out-of-plane ring deformations were modeled via scanning procedure with partial relaxation of the molecular geometry. The influence of ring deformations on π–electron delocalization was expressed in terms of HOMA values. Besides, the ring deformability was defined as the averaged change of bond angles or dihedral angles constituting the ring that was associated with 1.5 kcal mol-1 increase of the system energy. The molecules structures adopted during vibrations at room temperature can lead to significant heterogeneity of structural index of aromaticity. The broad span of HOMA values was obtained for analyzed five- or six-membered aromatic and heteroaromatic rings. However, the averaged values obtained for such fluctuations almost perfectly match HOMA values of molecule in the ground state. It has been demonstrated that the ring deformability imposed by bond angle changes is much smaller than for dihedral angles with the same rise of system energy. Interestingly in the case of out-of-plane vibrations modeled by scanning procedure there is observed linear correlation between ring deformability and HOMA values. Proposed method for inclusion of thermal vibrations in the framework of π–electron delocalization provides natural shift of the way of thinking about aromaticity from a static quantity to a dynamic and heterogeneous one due to inclusion of a more realistic object of analysis – thermally deformed structures. From this perspective the thermal fluctuations are supposed to be non-negligible contributions to aromaticity phenomenon

Synthesis, Characterization and Biological Evaluation of New Manganese Metal Carbonyl Compounds That Contain Sulfur and Selenium Ligands as a Promising New Class of CORMs

Three new manganese carbonyl compounds with heavy atom donors were synthesized and their potential use as photoCORMS was evaluated. Interestingly, all compounds had an elusive binding mode, in which the ligands adopted a κ2-X coordination (where X = S or Se), confirmed both by X-ray crystallography and IR spectroscopy. The stability of the title compounds in the dark was determined by monitoring the changes in the UV spectra of the compounds in both dichloromethane and acetonitrile. These studies show that in coordinating solvents there is an exchange of the bromide bonded to the metal centre by a solvent molecule, which is evidenced by the changes in the UV and IR spectra and by DFT analysis. EDA and natural bond order analyses were conducted to evaluate the influence of the heavy atom donors in the first coordination sphere of the compounds. Photoexcitation at 380 nm demonstrated that all compounds showed release of all three COs, as seen in the photoproducts detected by IR spectroscopy. Furthermore, CO release was observed when the photoCORMs were incubated with living cells, and we observed a CO-dependent inhibition of cell viability

Synthesis, characterization and photoinduced CO-release by manganese(i) complexes

Herein, we report the CO-release activity of three new photoCORMs, two with nonbonding pyridine moieties and one with a benzyl group. The compounds [MnBr(CO)3(bpa-κ2)] (2, where bpa = N-benzyl(2-pyridylmethyl)amine); [MnBr(CO)3(pmpeaκ2)] (3, where pmpea = N-(2-pyridylmethyl)-N’-(2-pyridylethyl)amine) and [MnBr(CO)3(bpea-κ2)] (4, where bpea = N-bis(2- pyridylethyl)amine) were synthesized and characterized by common spectroscopic techniques (UV-Vis, IR). Density functional theory studies were also performed to provide new insights into the M–C bond and to assume the orbitals involved in the absorption transitions. Their CO-release activities were measured both in organic and in physiological media and compared to that of a previously published compound [Mn(CO)3(dpa-κ3)]Br (1, where dpa = N-bis(2- pyridylmethyl)amine). An increase in the number of members of the chelate from five to six, influenced the release of CO, affecting both the binding mode of the ligand and the CO-release process and affecting their potential use as potentials CO release carriers as therapeutic agents

Sesquiterpene lactones from Vernonia scorpioides and their in vitro cytotoxicity

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Fresh leaves of Vernonia scorpioides are widely used in Brazil to treat a variety of skin disorders. Previous in vivo studies with extracts of this species had also demonstrated a high antitumor potential. This paper reports isolation of four sesquiterpene lactones (hirsutinolides and glaucolides), together with diacetylpiptocarphol, 8-acetyl-13-etoxypiptocarphol, luteolin, apigenin, and ethyl caffeate from fresh leaves and flowers of Vernonia scorpioides. The hypothesis that hirsutinolide 3 is formed during extraction was verified theoretically using Density Functional Theory. The effects of isolated compounds on in vitro tumor cells were investigated, as well as their genotoxicity by means of an in vitro comet assay. The results indicate that glaucolide 2 and hirsutinolide 4 are toxic to HeLa cells. These compounds were genotoxic in vitro, a property that appears to be related to the presence of their epoxy groups, which has been a more reliable indication of toxicity than substitution on C-13 or the presence of alpha,beta-unsaturated keto-groups. These results need to be replicated in vivo in order to ascertain their toxicity. (C) 2010 Elsevier Ltd. All rights reserved.711315391544Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES

Platinum-triggered Bond-cleavage of Pentynoyl amide and N-propargyl handles for Drug-Activation

The ability to create ways to control drug activation at specific tissues while sparing healthy tissues remains a major challenge. The administration of exogenous target-specific triggers offers the potential for traceless release of active drugs on tumor sites from antibody-drug conjugates (ADCs) and caged prodrugs. We have developed a metal-mediated bond-cleavage reaction that uses platinum complexes[K2PtCl4 or Cisplatin (CisPt)] for drug activation. Key to the success of the reaction is a water-promoted activation process that triggers the reactivity of the platinum com-plexes. Under these conditions the decaging of pentynoyl tertiary amides and N-propargyls occurs rapidly in aqueous systems. In cells, the protected analogues of cytotoxic drugs 5-fluorouracil (5-FU) and monomethyl auristatin E (MMAE) are partially activated by non-toxic amounts of platinum salts. Additionally, a non-internalizing ADC built with a pentynoyl traceless linker that features a tertiary amide protected MMAE was also decaged in the presence of platinum salts for extracellular drug release in cancer cells. Finally, CisPt-mediated prodrug activation of a propargyl derivative of 5-FU was shown in a colorectal zebrafish xenograft model that led to significant reductions in tumor size. Overall, our results reveal a new metal-based cleavable reaction that expands the application of platinum complexes beyond those in catalysis and cancer therapy