Hooman Shadnia

Stability of carbon-centered radicals: Effect of functional groups on the energetics of addition of molecular oxygen

In this paper we examine a series of hydrocarbons with structural features which cause a weakening of the CH bond. We use theoretical calculations to explore whether the carbon‐centered radicals R• which are created after breaking the bond can be stabilized enough so that they resist the addition of molecular oxygen, i.e. where the reaction R• + O2 → ROO• becomes energetically unfavorable. Calculations using a B3LYP‐based method provide accurate bond dissociation enthalpies (BDEs) for RH and ROO• bonds, as well as Gibbs free energy changes for the addition reaction. The data show strong correlations between ROO• and RH BDEs for a wide variety of structures. They also show an equally strong correlation between the ROO• BDE and the unpaired spin density at the site of addition. Using these data we examine the major functional group categories proposed in several experimental studies, and assess their relative importance. Finally, we combine effects to try to optimize resistance to the addition of molecular oxygen, an important factor in designing carbon‐based antioxidants.

Rational Design, Synthesis, and Optical Properties of Film-Forming, Near- Infrared Absorbing, and Fluorescent Chromophores with Multidonors and Large Heterocyclic Acceptors

A new series of film-forming, low-bandgap chromophores (1 a,b and 2 a,b) were rationally designed with aid of a computational study, and then synthesized and characterized. To realize absorption and emission above the 1000 nm wavelength, the molecular design focuses on lowering the LUMO level by fusing common heterocyclic units into a large conjugated core that acts an electron acceptor and increasing the charge transfer by attaching the multiple electron-donating groups at the appropriate positions of the acceptor core. The chromophores have bandgap levels of 1.27-0.71 eV, and accordingly absorb at 746-1003 nm and emit at 1035-1290 nm in solution. By design, the relatively high molecular weight (up to 2400 g mol(-1)) and non-coplanar structure allow these near-infrared (NIR) chromophores to be readily spin-coated as uniform thin films and doped with other organic semiconductors for potential device applications. Doping with [6,6]-phenyl-C(61) butyric acid methyl ester leads to a red shift in the absorption only for 1 a and 2 a. An interesting NIR electrochromism was found for 2 a, with absorption being turned on at 1034 nm when electrochemically switched (at 1000 mV) from its neutral state to a radical cation state. Furthermore, a large Stokes shift (256-318 nm) is also unique for this multidonor-acceptor type of chromophore, indicating a significant structural difference between the ground state and the excited state. Photoluminescence of the film of 2 a was further probed at variable temperatures and the results strongly suggest that the restriction of bond rotations certainly helps to diminish non-radiative decay and thus enhance the luminescence of these large chromophores.

A-CD estrogens. I. Substituent effects, hormone potency, and receptor subtype selectivity in a new family of flexible estrogenic compounds.

Long-term use of estrogen supplements by women leads to an increased risk of breast and uterine cancers. Possible mechanisms include metabolism of estradiol and compounds related to tumor-initiating quinones, and ligand-induced activation of the estrogen receptors ERα and ERβ which can cause cancer cell proliferation, depending on the ratio of receptors present. One therapeutic goal would be to create a spectrum of compounds of variable potency for ERα and ERβ, which are resistant to quinone formation, and to determine an optimum point in this spectrum. We describe the synthesis, modeling, binding affinities, hormone potency, and a measure of quinone formation for a new family of A-CD estrogens, where the A-C bond is formed by ring coupling. Some substituents on the A-ring increase hormone potency, and one compound is much less quinone-forming than estradiol. These compounds span a wide range of receptor subtype selectivities and may be useful in hormone replacement therapy.

Design and synthesis of 2-phenoxynicotinic acid hydrazides as anti-inflammatory and analgesic agents.

A series of 2‐phenoxynicotinic acid hydrazides were synthesized and evaluated for their analgesic and anti‐inflammatory activities. Several compounds having an unsubstituted phenyl/4‐pyridyl or C‐4 methoxy substituent on the terminal phenyl ring showed moderate to high analgesic or anti‐inflammatory activity in comparison to mefenamic acid as the reference drug. The compounds with highest anti‐inflammatory activity were subjected to in vitro COX‐1/COX‐2 inhibition assays and showed moderate to good COX‐1 and weak COX‐2 inhibition activities.

Interaction force diagrams: new insight into ligand-receptor binding

A method is described to calculate and visualize the interaction forces of ligand-receptor complexes. Starting from an X-ray crystallographic structure, a “thawing” procedure results in a force-field energy-minimized geometry which is close to the crystallographic starting point. By subtracting non-bonded interactions of the ligand with each amino acid residue and using the resulting force vectors to describe the slope of the remaining potential, two types of interaction force diagrams are created; the first shows the direction of the force vectors in 3D and the second shows the magnitude of the force vectors. The latter representation leads to definition of an ‘Interaction Force Fingerprint’ (IFFP) which is characteristic of the ligand-receptor binding. IFFPs are used to discuss ligand binding in the human estrogen receptors ERα and ERβ, and provide new insight into ligand selectivity between receptor isoforms.

Deconstructing estradiol: Removal of B-ring generates compounds which are potent and subtype-selective estrogen receptor agonists

Estradiol and related estrogens have been widely used as supplements to relieve menopausal symptoms, but they lead to an increased risk of breast and endometrial cancer. Here we report the synthesis of a new family of compounds where we have removed the B-ring from the steroid ABCD structure, and functionalized the A-ring. These A-CD compounds show a preferential affinity for the estrogen receptor subtype ERbeta. Some show binding affinities which are greater than estradiol. The presence of electron-withdrawing substituents on the A-ring should reduce the tendency of these compounds to form carcinogenic metabolites, so they might lead to a safer approach to hormone replacement therapy.

Computational modeling of substituent effects on phenol toxicity.

Standard computational models of cytotoxicity of substituted phenols relate the toxicity to a set of quatitative structure-activity relationship (QSAR) descriptors such as log P, p K a, OH bond dissociation enthalpy (BDE), etc. Implicit in this approach is the idea that the phenoxyl radical is disruptive to the cell and factors increasing its production rate will enhance the toxicity. To improve the QSAR correlations, substituents are usually divided into electron-donating groups (EDG) and electron-withdrawing groups (EWG), which are treated separately and thought to follow different mechanisms of toxicity. In this paper, we focus on one important aspect of toxicity, the rate constant for production of phenoxyl radical. Activation energies are obtained for the reaction of X-phenol with peroxyl radical by using the Evans-Polanyi principle, giving rate constants as a function of DeltaBDE values for both EDG and EWG sets. We show that (i) a plot of log k for phenoxyl formation vs DeltaBDE shows a double set of straight lines with different slopes, justifying the usual EDG and EWG separation but without requiring any change in mechanism; (ii) the same method can be effectively used for different target radicals (e.g., tert-butoxyl) or different sets of parent compounds (e.g., substituted catechols), thus giving a useful general approach to analysis of toxicity data; (iii) regions of constant toxicity in all cases are predicted; and (iv) we argue that competing parallel mechanisms of toxicity are likely to be dominant for EWG-substituted phenols.

Using Molecular Strain and Aromaticity To Create Ultraweak C−H Bonds and Stabilized Carbon-Centered Radicals

An approach based on relief of molecular strain in the parent hydrocarbon, extended conjugation in the radical, and the driving force toward aromaticity is used to design molecules with ultraweak C-H bonds. The molecular strain is generated by two fused rings containing (5,5)-, (5,6)-, or (6,6)-membered ring structures. Homodesmotic reactions are used to calculate the molecular strain enthalpy (MSE) of the parent hydrocarbons and the corresponding radicals, and to analyze how it changes through these reactions. B3LYP calculations are used to obtain the bond dissociation enthalpies (BDEs) for breaking one or more C-H bonds as well as the C-O bond formed after oxygen addition to the radical. Loss of a second H-atom can lead to very low R-H BDE values, especially when the ultimate product is aromatic. Molecular structures based on these ideas may be of interest as novel antioxidants based on carbon-centered radicals.