Stability and Reactivity of the Phenalene and Olympicene Isomers.

The phenalene (triangulene) and olympicene molecules belong to the polycyclic aromatic hydrocarbon class, which have attracted substantial technological interest due to their unique electronic properties. Electronic structure calculations serve as a valuable tool in investigating the stability and reactivity of these molecular systems. In the present work, the multireference calculations, namely, the complete active space second-order perturbation theory and multireference averaged quadratic coupled cluster (MR-AQCC), were employed to study the reactivity and stability of phenalene and olympicene isomers, as well as their modified structures where the sp3-carbon at the borders were removed. The harmonic oscillator model of aromaticity (HOMA) and the nucleus-independent chemical shift as geometric and magnetic indexes calculated with density functional theory were utilized to assess the aromaticity of the studied molecules. These indexes were compared with properties such as the excitation energy and natural orbitals occupation. The reactivity analyzed using the HOMA index combined with MR-AQCC revealed the radical character of certain structures as well as the weakening of their aromaticity. Moreover, the results suggest that the removal of sp3-carbon atoms and the addition of hydrogen atoms did not alter the π network and the excitation energies of the phenalene molecules.

Competition Between Phenothiazines and BH3 Peptide for the Binding Site of the Antiapoptotic BCL-2 Protein.

The study of proteins and mechanisms involved in the apoptosis and new knowledge about cancer's biology are essential for planning new drugs. Tumor cells develop several strategies to gain proliferative advantages, including molecular alterations to evade from apoptosis. Failures in apoptosis could contribute to cancer pathogenesis, since these defects can cause the accumulation of dividing cells and do not remove genetic variants that have malignant potential. The apoptosis mechanism is composed by proteins that are members of BCL-2 and cysteine-protease families. BH3-only peptides are the "natural" intracellular ligands of BCL-2 family proteins. On the other hand, studies have proved that phenothiazine compounds influence the induction of cellular death. To understand the characteristics of phenothiazines and their effects on tumoral cells and organelles involved in the apoptosis, as well as evaluating their pharmacologic potential, we have carried out computational simulation with the purpose of relating the structures of the phenothiazines with their biological activity. Since the tridimensional (3D) structure of the target protein is known, we have employed the molecular docking approach to study the interactions between compounds and the protein's active site. Hereafter, the molecular dynamics technique was used to verify the temporal evolution of the BCL-2 complexes with phenothiazinic compounds and the BH3 peptide, the stability and the mobility of these molecules in the BCL-2 binding site. From these results, the calculation of binding free energy between the compounds and the biological target was carried out. Thus, it was possible to verify that thioridazine and trifluoperazine tend to increase the stability of the BCL-2 protein and can compete for the binding site with the BH3 peptide.

How to efficiently tune the biradicaloid nature of acenes by chemical doping with boron and nitrogen.

Acenes are fascinating polyaromatic compounds that combine impressive semiconductor properties with an open-shell character by varying their molecular sizes. However, the increasing chemical instabilities related to their biradicaloid structures pose a great challenge for synthetic chemistry. Modifying the π-bond topology through chemical doping allows modulation of the electronic properties of graphene-related materials. In spite of the practical importance of these techniques, remarkably little is known about the basic question - the extent of the radical character created or quenched thereby. In this work, we report a high-level computational study on two acene oligomers doubly-doped with boron and nitrogen, respectively. These calculations demonstrate precisely which the chemical route is in order to either quench or enhance the radical character. Moving the dopants from the terminal rings to the central ones leads to a remarkable variation in the biradicaloid character (and thereby also in the chemical stability). This effect is related to a π-charge transfer involving the dopants and the radical carbon centers at the zigzag edges. This study also provides specific guidelines for a rational design of large polyaromatic compounds with enhanced chemical stability.

Singlet La and Lb Bands for N-Acenes (N = 2-7): A CASSCF/CASPT2 Study.

In this work CASPT2 calculations of polyacenes (from naphthalene to heptacene) were performed to find a methodology suitable for calculations of the absorption spectra, in particular of the La (B2u state) and Lb (B3u state) bands, of more extended systems. The effect of the extension of the active space and of freezing σ orbitals was investigated. The MCSCF excitation energy of the B2u state is not sensitive to the size of the active space used. However, the CASPT2 results depend strongly on the amount of σ orbitals frozen reflecting the ionic character of the B2u state. On the other hand, the excitation energies of the B3u state are much more sensitive to the size of the active space used in the calculations reflecting its multiconfigurational character. We found a good agreement with experimental data for both bands by including 14 electrons in 14 π orbitals in the active space followed by the CASPT2(14,14) perturbation scheme in which both σ and π orbitals are included.

Quantum-chemistry descriptors for photosensitizers based on macrocycles.

Phthalocyanines, porphyrins, and chlorins have been widely studied as photosensitizers. Both experimental and computational strategies are employed in order to propose new and more active molecules derived from those macrocycles. In this context, there are two main strategies used: (i) the addition of different substituents and (ii) the complexation of the macrocycle with different metallic ions. In this work, we present selected descriptors based on quantum chemistry calculations for forty macrocycles, including some approved drugs. We have found that density functional theory is a suitable methodology to study the large sets of molecules when applying the B3LYP/LanL2DZ methodology for geometry optimization and TD-OLYP/6-31G(d) for absorption spectrum. The inclusion of solvent effects by means of continuum model is important in order to obtain the accurate electronic data. We have verified that by bonding charged or polar substituents to the macrocycle, it is possible to enhance water solvation as well as to improve spectroscopic properties because molecular orbital contributions for Q band can be affected by some substituents. Selected descriptors, electronic and steric, were pointed out as important to propose the new photosensitizers.

Cytotoxicity of phenothiazine derivatives associated with mitochondrial dysfunction: a structure-activity investigation.

Phenothiazine derivatives are neuroleptic drugs used in the treatment of schizophrenia and anxiety. Several side effects are described for these drugs, including hepatotoxicity, which may be related to their cytotoxic activity. Working with isolated rat liver mitochondria, we previously showed that phenothiazine derivatives induced the mitochondrial permeability transition associated with cytochrome c release. Since the mitochondrial permeabilization process plays a central role in cell death, the aim of this work was to evaluate the effects of five phenothiazine derivatives (chlorpromazine, fluphenazine, thioridazine, trifluoperazine, and triflupromazine) on the viability of hepatoma tissue culture (HTC) cells to establish the structural requirements for cytotoxicity. All phenothiazine derivatives decreased the viability of the HTC cells in a concentration-dependent manner and exhibited different cytotoxic potencies. The EC50 values ranged from 45 to 125 µM, with the piperidinic derivative thioridazine displaying the most cytotoxicity, followed by the piperazinic and aliphatic derivatives. The addition of the phenothiazine derivatives to cell suspensions resulted in significant morphological changes and plasma membrane permeabilization. Octanol/water partition studies revealed that these drugs partitioned preferentially to the apolar phase, even at low pH values (≤4.5). Also, structural and electronic properties were calculated employing density functional theory. Interestingly, the phenothiazine derivatives promoted an immediate dissipation of the mitochondrial transmembrane potential in HTC cells, and the EC50 values were closely correlated with those obtained in cell viability assays, as well as the EC50 for swelling in isolated mitochondria. These results significantly contribute to improving our understanding of the specific structural requirements of the phenothiazine derivatives to induce cell death and suggest the involvement of the mitochondrial permeability transition in phenothiazine-induced cytotoxicity in HTC cells.