The Clar aromatic sextet theory can provide a qualitative description of the dominant modes of cyclic π-electron conjugation in benzenoid molecules and of the relative stability among a series of isomeric benzenoid systems. In a series of nonplanar fully benzenoid hydrocarbons, the predictions of the Clar theory were tested by means of several different theoretical approaches: topological resonance energy (TRE), energy effect (ef), harmonic oscillator model of aromaticity (HOMA) index, six center delocalization index (SCI), and nucleus-independent chemical shifts (NICS). To assess deviations from planarity in the examined molecules, four different planarity descriptors were employed. It was shown how the planarity indices can be used to quantify the effect of nonplanarity on the local and global aromaticity of the studied systems.

The effect of benzo-annelation on the local aromaticity of the central ring of acridine (1), 9H-carbazole (2), dibenzofuran (3), and dibenzothiophene (4) was analyzed by means of the energy effects (ef), pairwise energy effects (pef), multicenter delocalization index (MCI), electron density at ring critical points (ρ(r(C))), harmonic oscillator model of aromaticity (HOMA), and nucleus independent chemical shifts (NICS). According to energetic, electron delocalization, and geometrical indices, angular benzo-annelation increases, whereas linear benzo-annelation decreases, the extent of the local aromaticity of the central ring containing heteroatoms. The local aromaticity of the central heterocyclic ring in the examined molecules can significantly vary by applying different modes of benzo-annelation. The NICS values do not always support the results obtained by the other aromaticity indices and, in some cases, lead to completely opposite conclusions.

Gold(III) complexes with 1,7- and 4,7-phenanthroline ligands, [AuCl(1,7-phen-κN7)] (1) and [AuCl(4,7-phen-κN4)] (2) were synthesized and structurally characterized by spectroscopic (NMR, IR and UV-vis) and single-crystal X-ray diffraction techniques. In these complexes, 1,7- and 4,7-phenanthrolines are monodentatedly coordinated to the Au(III) ion through the N7 and N4 nitrogen atoms, respectively. In comparison to the clinically relevant anti-angiogenic compounds auranofin and sunitinib, gold(III)-phenanthroline complexes showed from 1.5- to 20-fold higher anti-angiogenic potential, and 13- and 118-fold lower toxicity. Among the tested compounds, complex 1 was the most potent and may be an excellent anti-angiogenic drug candidate, since it showed strong anti-angiogenic activity in zebrafish embryos achieving IC value (concentration resulting in an anti-angiogenic phenotype at 50% of embryos) of 2.89μM, while had low toxicity with LC value (the concentration inducing the lethal effect of 50% embryos) of 128μM. Molecular docking study revealed that both complexes and ligands could suppress angiogenesis targeting the multiple major regulators of angiogenesis, such as the vascular endothelial growth factor receptor (VEGFR-2), the matrix metalloproteases (MMP-2 and MMP-9), and thioredoxin reductase (TrxR1), where the complexes showed higher binding affinity in comparison to ligands, and particularly to auranofin, but comparable to sunitinib, an anti-angiogenic drug of clinical relevance.

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The Clar aromatic sextet theory predicts that the intensity of cyclic conjugation in chevron-type benzenoid hydrocarbons monotonically decreases along the central chain. This regularity has been tested by means of several independent theoretical methods (by the energy effects of the respective sixmembered rings, as well as by their HOMA, NICS, and SCI values, calculated at the B3LYP/6-311G(d,p) level of DFT theory). Our results show that the predictions of Clar theory are correct only for the first few members of the chevron homologous series, and are violated at the higher members. This indicates that Clar theory is not universally applicable, even in the case of fully conjugated benzenoid molecules.