On the instability of iodides of heavy main group atoms in their higher oxidation state.

The inert pair effect-the tendency of the s orbital of heavy atoms to stay unreactive, is a consequence of the relativistic contraction of the s orbitals. While the manifestations of this on the reactivity depend on the nature of the substituents, this aspect is often overlooked. Divalent Pb prefers inorganic substituents, whereas tetravalent Pb prefers organic substituents. Among the inorganic substituents, again there are specific preferences-tetravalent Pb prefers F and Cl more than Br and I. It is as though the relativistic contraction of the s orbital of Pb is more significant with Br and I substituents than with Cl, F, and alkyl substituents. Herein, we address this problem using the molecular orbital approach and support it with quasi-relativistic density functional computations. We explain why typical hypervalent systems, like 12-X-6, and 10-X-5 (X is a heavy atom, the number preceding X is the number of valence electrons surrounding X, and the number after X is the coordination number) with less electronegative substituents carrying a lone pair (such as iodine), and Lewis octet molecules like PbI4 are unstable, but their dianions (14-X-6, 12-X-5, PbI42-) are not. For heavy atoms, the relativistic contraction of the s orbital renders the antibonding combination of s with ligand orbitals (σ1*) very low-lying, making it a good acceptor of electrons. Thus, compounds where σ1* is empty are kinetically unstable when an electron donor with appropriate energy (such as the lone pair on iodine or bromine) is present in the vicinity. Donor-acceptor interaction between σ1* and the lone pair on I or Br (F and Cl lone pairs are energetically far away from σ1*) is responsible for the instability of such compounds. The kinetic stability of tetraalkyl lead compounds is due to the absence of lone pairs on the alkyl substituents. This work illustrates the key factor responsible for the instability of heavy element iodides by taking into consideration the covalent nature of the bonds, while the existing explanations assume a purely ionic bonding, which is an oversimplification.

SERS and MD simulation studies of a kinase inhibitor demonstrate the emergence of a potential drug discovery tool.

We demonstrate the use of surface-enhanced Raman spectroscopy (SERS) as an excellent tool for identifying the binding site of small molecules on a therapeutically important protein. As an example, we show the specific binding of the common antihypertension drug felodipine to the oncogenic Aurora A kinase protein via hydrogen bonding interactions with Tyr-212 residue to specifically inhibit its activity. Based on SERS studies, molecular docking, molecular dynamics simulation, biochemical assays, and point mutation-based validation, we demonstrate the surface-binding mode of this molecule in two similar hydrophobic pockets in the Aurora A kinase. These binding pockets comprise the same unique hydrophobic patches that may aid in distinguishing human Aurora A versus human Aurora B kinase in vivo. The application of SERS to identify the specific interactions between small molecules and therapeutically important proteins by differentiating competitive and noncompetitive inhibition demonstrates its ability as a complementary technique. We also present felodipine as a specific inhibitor for oncogenic Aurora A kinase. Felodipine retards the rate of tumor progression in a xenografted nude mice model. This study reveals a potential surface pocket that may be useful for developing small molecules by selectively targeting the Aurora family kinases.