Non-covalent interactions with aromatic rings pervade modern chemical research. The strength and orientation of these interactions can be tuned and controlled through substituent effects. Computational studies of model complexes have provided a detailed understanding of the origin and nature of these substituent effects, and pinpointed flaws in entrenched models of these interactions in the literature. Here, we provide a brief review of efforts over the last decade to unravel the origin of substituent effects in π-stacking, XH/π, and ion/π interactions through detailed computational studies. We highlight recent progress that has been made, while also uncovering areas where future studies are warranted.

Multi-drug chemoresistance remains one of the most common reasons for chemotherapy failure. The membrane transporter protein ABCG2/BCRP1 has been shown in vitro to effectively reduce the intracellular concentrations of several prominent anticancer chemotherapeutic agents such as mitoxantrone and doxorubicin. Intriguingly, cancer stem cells are known to be characterized by multi-drug chemoresistance. Taking into account that the ABCG2(+) subset of tumor cells are often enriched with cells with cancer stem-like phenotypes, it has been proposed that ABCG2 activity underlies the ability of cancer cells to regenerate post-chemotherapy. Furthermore, we also review evidence suggesting that tyrosine kinase inhibitors, including imatinib and gefitinib, are both direct and downstream inactivators of ABCG2 and, therefore, serve as candidates to reverse cancer stem cell chemoresistance and potentially target cancer stem cells.

The enantioselective propargylation of aromatic aldehydes with allenyltrichlorosilanes catalyzed by bipyridine N-oxides was explored using density functional theory. Low-lying transition states for a highly enantioselective helical bipyridine N-oxide catalyst [Org. Lett. 2011, 13, 1654] were characterized at the B97-D/TZV(2d,2p) level of theory. Predicted free energy barrier height differences are in agreement with experimental ee's for the propargylation of benzaldehyde and substituted analogues. The origin of enantioselectivity was pinpointed through distortion-interaction analyses. The stereoselectivity arises in part from through-space electrostatic interactions of the carbonyl carbon with the Cl ligands bound to Si, rather than noncovalent aryl-aryl interactions between the aromatic aldehyde and the helix as previously proposed. Moreover, aryl-aryl interactions between the aldehyde and helix are predicted to favor transition states leading to the R enantiomer, and ultimately reduce the enantioselectivity of this reaction. (S)-2,2'-bipyridine N-oxide was studied as a model catalyst in order to quantify the inherent enantioselectivity arising from different chiral arrangements of ligands around the hexacoordinate silicon in the stereocontrolling transition state for these reactions. The predicted selectivities arising from different chiral octahedral silicon complexes provide guidelines for the development of transition state models for N-oxide-based alkylation catalysts.

Complexes of 9-methyladenine with 46 heterocycles commonly found in drugs were located using dispersion-corrected density functional theory, providing a representative set of 408 unique stacked dimers. The predicted binding enthalpies for each heterocycle span a broad range, highlighting the strong dependence of heterocycle stacking interactions on the relative orientation of the interacting rings. Overall, the presence of NH and carbonyl groups lead to the strongest stacking interactions with 9-methyadenine, and the strength of π-stacking interactions is sensitive to the distribution of heteroatoms within the ring as well as the specific tautomer considered. Although molecular dipole moments provide a sound predictor of the strengths and orientations of the 28 monocyclic heterocycles considered, dipole moments for the larger fused heterocycles show very little correlation with the predicted binding enthalpies.

It is well known that many patients continue to smoke cigarettes after being diagnosed with cancer. Although smoking cessation has typically been presumed to possess little therapeutic value for cancer, a growing body of evidence suggests that continued smoking is associated with reduced efficacy of treatment and a higher incidence of recurrence. We therefore investigated the effect of cigarette smoke condensate (CSC) on drug resistance in the lung cancer and head and neck cancer cell lines A549 and UMSCC-10B, respectively. Our results showed that CSC significantly increased the cellular efflux of doxorubicin and mitoxantrone. This was accompanied by membrane localization and increased expression of the multi-drug transporter ABCG2. The induced efflux of doxorubicin was reversed upon addition of the specific ABCG2 inhibitor Fumitremorgin C, confirming the role of ABCG2. Treatment with CSC increased the concentration of phosphorylated Akt, while addition of the PI3K inhibitor LY294002 blocked doxorubicin extrusion, suggesting that Akt activation is required for CSC-induced drug efflux. In addition, CSC was found to promote resistance to doxorubicin as determined by MTS assays. This CSC-induced doxurbicin-resistance was mitigated by mecamylamine, a nicotinic acetylcholine receptor inhibitor, suggesting that nicotine is at least partially responsible for the effect of CSC. Lastly, CSC increased the size of the side population (SP), which has been linked to a cancer stem cell-like phenotype. In summary, CSC promotes chemoresistance via Akt-mediated regulation of ABCG2 activity, and may also increase the proportion of cancer stem-like cells, contributing to tumor resilience. These findings underscore the importance of smoking cessation following a diagnosis of cancer, and elucidate the mechanisms of continued smoking that may be detrimental to treatment.