Reinvestigating the Photoprotection Properties of a Mycosporine Amino Acid Motif

With the growing concern regarding commercially available ultraviolet (UV) filters damaging the environment, there is an urgent need to discover new UV filters. A family of molecules called mycosporines and mycosporine-like amino acids (referred to as MAAs collectively) are synthesized by cyanobacteria, fungi and algae and act as the natural UV filters for these organisms. Mycosporines are formed of a cyclohexenone core structure while mycosporine-like amino acids are formed of a cyclohexenimine core structure. To better understand the photoprotection properties of MAAs, we implement a bottom-up approach by first studying a simple analog of an MAA, 3-aminocyclohex-2-en-1-one (ACyO). Previous experimental studies on ACyO using transient electronic absorption spectroscopy (TEAS) suggest that upon photoexcitation, ACyO becomes trapped in the minimum of an S1 state, which persists for extended time delays (>2.5 ns). However, these studies were unable to establish the extent of electronic ground state recovery of ACyO within 2.5 ns due to experimental constraints. In the present studies, we have implemented transient vibrational absorption spectroscopy (as well as complementary TEAS) with Fourier transform infrared spectroscopy and density functional theory to establish the extent of electronic ground state recovery of ACyO within this time window. We show that by 1.8 ns, there is >75% electronic ground state recovery of ACyO, with the remaining percentage likely persisting in the electronic excited state. Long-term irradiation studies on ACyO have shown that a small percentage degrades after 2 h of irradiation, plausibly due to some of the aforementioned trapped ACyO going on to form a photoproduct. Collectively, these studies imply that a base building block of MAAs already displays characteristics of an effective UV filter

Ultrafast photodissociation dynamics of pyrazole, imidazole and their deuterated derivatives using ab initio multiple cloning

We present results obtained using the ab initio multiple cloning (AIMC) method to simulate fully quantum dynamics for imidazole and its structural isomer pyrazole along with their selectively deuterated species. We simulate the ultrafast dissociation of the N-H/D bond for these molecules along the repulsive 1πσ* state which agrees well with previous experimental results. Our results give evidence for a two-stage dissociation of the N-H/D bond on the sub-50 fs regime for imidazole, pyrazole and their selectively deuterated species, and give evidence for the importance of the repulsive 1πσ* state along the N-H/D bond coordinate for the relaxation of both imidazole and pyrazole. The ability of these calculations to reproduce experimental results lends confidence that larger complex systems could be explored with predictive capabilities with the AIMC method. These results also confirm the ability of the AIMC method to add detailed insights into which experiments are blind

Ultrafast photodissociation dynamics of 2-ethylpyrrole: adding insight to experiment with ab initio multiple cloning

The ultrafast photodissociation dynamics of 2-ethylpyrrole (2-EP) is simulated in a fully quantum manner on the S1 and S2 πσ* states by the ab initio multiple cloning (AIMC) method. AIMC treats electrons with accurate electronic structure methods “on the fly”, and nuclear dynamics with wavefunction propagation via a basis set of Ehrenfest trajectory guided Gaussian wavepackets. Total kinetic energy release (TKER) spectra are produced, as well as velocity map images and N–H dissociation times. These are compared to results from time-resolved velocity map imaging studies, and the AIMC method is able to provide quantitative reproduction of experimental data, including dissociation times of 50–80 fs. Novel insight into the dissociation mechanism is then obtained, with the experimentally obtained time constant shown to be composed of two components. Firstly, there is a contribution in <50 fs from 2-EP molecules that have sufficient energy in the N–H stretch coordinate to dissociate almost immediately over the barrier, and this is followed by a second slower contribution from 2-EP molecules that must sample the potential energy surface before finding a way around the barrier to dissociate. This two component mechanism is not observed experimentally due to the temporal widths of the laser pulses obscuring the dynamics in the <50 fs window, and is shown for the first time via theory. Calculations are also performed on selectively deuterated 2-EP, demonstrating that AIMC is able to produce a kinetic isotope effect for the dissociation time constant, and correctly predict a shift to lower energy in the TKER spectrum. The S2 πσ* state is also shown to be unstable with respect to the S1 πσ* state, with the N–H dissociation proceeding along S1 when initially excited to S2. This work demonstrates that the combination of state of the art theory and experiments can provide unprecedented novel insight into the N–H dissociation mechanism, with the tantalising prospect of providing insight into more general heteroatom hydride bond dissociation

Towards symmetry driven and nature inspired UV filter design

In plants, sinapate esters offer crucial protection from the deleterious effects of ultraviolet radiation exposure. These esters are a promising foundation for designing UV filters, particularly for the UVA region (400 – 315 nm), where adequate photoprotection is currently lacking. Whilst sinapate esters are highly photostable due to a cis-trans (and vice versa) photoisomerization, the cis-isomer can display increased genotoxicity; an alarming concern for current cinnamate ester-based human sunscreens. To eliminate this potentiality, here we synthesize a sinapate ester with equivalent cis- and trans-isomers. We investigate its photostability through innovative ultrafast spectroscopy on a skin mimic, thus modelling the as close to true environment of sunscreen formulas. These studies are complemented by assessing endocrine disruption activity and antioxidant potential. We contest, from our results, that symmetrically functionalized sinapate esters may show exceptional promise as nature-inspired UV filters in next generation sunscreen formulations

Data for Exploring the photochemistry of an ethyl sinapate dimer : An attempt towards a better ultraviolet filter

The photochemistry and photostability of a potential ultraviolet (UV) radiation filter, dehydrodiethylsinapate, with a broad absorption in the UVA region, is explored utilizing a combination of femtosecond time-resolved spectroscopy and steady-state irradiation studies. The time-resolved measurements show that this UV filter candidate undergoes excited state relaxation after UV absorption on a timescale of ~10 picoseconds, suggesting efficient relaxation. However, steady-state irradiation measurements show degradation under prolonged UV exposure. From a photochemical standpoint, this highlights the importance of considering both the ultrafast and “ultraslow” timescales when designing new potential UV filters

A Multipronged Comparative Study of the Ultraviolet Photochemistry of 2-, 3-, and 4-Chlorophenol in the Gas Phase

The S1((1)ππ*) state of the (dominant) syn-conformer of 2-chlorophenol (2-ClPhOH) in the gas phase has a subpicosecond lifetime, whereas the corresponding S1 states of 3- and 4-ClPhOH have lifetimes that are, respectively, ∼2 and ∼3-orders of magnitude longer. A range of experimental techniques-electronic spectroscopy, ultrafast time-resolved photoion and photoelectron spectroscopies, H Rydberg atom photofragment translational spectroscopy, velocity map imaging, and time-resolved Fourier transform infrared emission spectroscopy-as well as electronic structure calculations (of key regions of the multidimensional ground (S0) state potential energy surface (PES) and selected cuts through the first few excited singlet PESs) have been used in the quest to explain these striking differences in excited state lifetime. The intramolecular O-H···Cl hydrogen bond specific to syn-2-ClPhOH is key. It encourages partial charge transfer and preferential stabilization of the diabatic (1)πσ* potential (relative to that of the (1)ππ* state) upon stretching the C-Cl bond, with the result that initial C-Cl bond extension on the adiabatic S1 PES offers an essentially barrierless internal conversion pathway via regions of conical intersection with the S0 PES. Intramolecular hydrogen bonding is thus seen to facilitate the type of heterolytic dissociation more typically encountered in solution studies.status: publishe

Low levels of p27 in association with deregulated p53-pRb protein status enhance tumor proliferation and chromosomal instability in non-small cell lung carcinomas.

BACKGROUND: Down-regulation or overexpression of the cyclin-dependent kinase inhibitor p27 have been observed in a range of malignancies, including lung cancer. To further elucidate the role of the molecule in tumor growth regulation, we evaluated p27 expression in a series of non-small cell lung carcinomas (NSCLCs), and examined its relation with histology, kinetic parameters, ploidy, and overall survival. We extended our investigation into the association of p27 levels with the presence of Ki-ras mutations, as well as with the expression status of p53 and pRb in tumor cells. MATERIAL AND METHODS: p27, p53, and pRb status were immunohistochemically evaluated in a total of 69 NSCLCs. In situ assays were employed to assess the kinetic parameters (Ki-67 immunohistochemistry for proliferation index, Tdt-mediated dUTP nick end labeling assay for apoptotic index). The ploidy status of the tumors was assessed after staining nuclei with the Feulgen procedure, and the presence of Ki-ras mutations was examined by restriction fragment length polymorphisms. All possible associations were assessed with a series of statistical methods. RESULTS: Immunoreactivity for p27 was observed in the entire series of specimens, with the mean percentage of positive cells being 33%. Adenocarcinomas (AdCs) exhibited higher p27 levels compared to squamous cell carcinomas (SqCCs) (p < 0.01). An inverse correlation was established between p27 expression and proliferation index (PI) (r = -0.834, p < 0.01) but not with apoptotic index (AI), whereas aneuploid tumors were characterized by lower p27 levels than diploid ones (p < 0.01). No difference in p27 immunostaining was observed with regard to the presence of Ki-ras mutations, whereas aberrant p53 and/or pRb expression patterns were associated with p27 underexpression (p < 0.01 for p53 status, p < 0.05 regarding pRb levels, and p < 0.01 for a combined deregulation of both proteins). Two or more alterations in the p27/p53/pRb protein network (i.e., p27 levels lower than the estimated mean value, overexpressed p53, and/or aberrant pRb) were associated with increased PI and aneuploidy (p < 0.001 and p < 0.01, respectively). A powerful trend was found between p27 expression and overall survival (p = 0.066). CONCLUSIONS: Our findings confirm the heterogeneity between AdCs and SqCCs, and are suggestive of an increased proliferative activity in NSCLCs underexpressing p27. Furthermore, our analysis supports the concept of p27 forming a functionally compact network with p53 and pRb, which is actively involved in the regulation of cellular proliferation and chromosomal stability