An expeditive and green chemo-enzymatic route to diester sinapoyl-l-malate analogues: sustainable bioinspired and biosourced UV filters and molecular heaters.

Sinapoyl malate, naturally present in plants, has proved to be an exceptional UV filter and molecular heater for plants. Although there are nowadays industrially relevant sustainable synthetic routes to sinapoyl malate, its incorporation into certain cosmetic formulations, as well as its adsorption on plant leaves, is limited by its hydrophilicity. To overcome these obstacles, it is important to find a way to effectively control the hydrophilic-lipophilic balance of sinapoyl malate to make it readily compatible with the cosmetic formulations and stick on the waxy cuticle of leaves. To this end, herein, we describe a highly regioselective chemo-enzymatic synthesis of sinapoyl malate analogues possessing fatty aliphatic chains of variable length, enabling the lipophilicity of the compounds to be modulated. The potential toxicity (i.e., mutagenicity, carcinogenicity, endocrine disruption, acute and repeated-dose toxicity), bioaccumulation, persistence and biodegradability potential of these new analogues were evaluated in silico, along with the study of their transient absorption spectroscopy, their photostability as well as their photodegradation products.

Understanding the Impact of Symmetrical Substitution on the Photodynamics of Sinapate Esters Using Gas-Phase Ultrafast Spectroscopy.

Two model biomimetic systems, ethyl sinapate (ES) and its symmetrical analogue, diethyl 2-(4-hydroxy-3,5-dimethoxybenzylidene)malonate (or diethyl sinapate, DES), are stripped to their core fundamentals through gas-phase spectroscopy to understand the underlying photophysics of photothermal materials. Following photoexcitation to the optically bright S1(ππ*) state, DES is found to repopulate the electronic ground state over 3 orders of magnitude quicker than its nonsymmetrical counterpart, ES. Our XMS-CASPT2 calculations shed light on the experimental results, revealing crucial differences in the potential energy surfaces and conical intersection topography between ES and DES. From this work, a peaked conical intersection, seen for DES, shows vital importance for the nonradiative ground-state recovery of photothermal materials. This fundamental comparative study highlights the potential impact that symmetrical substitution can have on the photodynamics of sinapate esters, providing a blueprint for future advancement in photothermal technology.

A Concerted Redox- and Light-Activated Agent for Controlled Multimodal Therapy against Hypoxic Cancer Cells.

Hypoxia represents a remarkably exploitable target for cancer therapy, is encountered only in solid human tumors, and is highly associated with cancer resistance and recurrence. Here, a hypoxia-activated mitochondria-accumulated Ru(II) polypyridyl prodrug functionalized with conjugated azo (Az) and nitrogen mustard (NM) functionalities, RuAzNM, is reported. This prodrug has multimodal theranostic properties toward hypoxic cancer cells. Reduction of the azo group in hypoxic cell microenvironments gives rise to the generation of two primary amine products, a free aniline mustard, and the polypyridyl RuNH2 complex. Thus, the aniline mustard triggers generation of reactive oxygen species (ROS) and mtDNA crosslinking. Meanwhile, the resultant biologically benign phosphorescent RuNH2 gives rise to a diagnostic signal and signals activation of the phototherapy. This multimodal therapeutic effect eventually elevates ROS levels, depletes reduced nicotinamide adenine dinucleotide (NADH) and adenosine triphosphate (ATP), and induces mitochondrial membrane damage, mtDNA damage, and ultimately cell apoptosis. This unique strategy allows controlled multimodal theranostics to be realized in hypoxic cells and multicellular spheroids, making RuAzNM a highly selective and effective cancer-cell-selective theranostic agent (IC50  = 2.3 µm for hypoxic HepG2 cancer cells vs 58.2 µm for normoxic THL-3 normal cells). This is the first report of a metal-based compound developed as a multimodal theranostic agent for hypoxia.

Targeted photoredox catalysis in cancer cells.

Hypoxic tumours are a major problem for cancer photodynamic therapy. Here, we show that photoredox catalysis can provide an oxygen-independent mechanism of action to combat this problem. We have designed a highly oxidative Ir(III) photocatalyst, [Ir(ttpy)(pq)Cl]PF6 ([1]PF6, where 'ttpy' represents 4'-(p-tolyl)-2,2':6',2''-terpyridine and 'pq' represents 3-phenylisoquinoline), which is phototoxic towards both normoxic and hypoxic cancer cells. Complex 1 photocatalytically oxidizes 1,4-dihydronicotinamide adenine dinucleotide (NADH)-an important coenzyme in living cells-generating NAD• radicals with a high turnover frequency in biological media. Moreover, complex 1 and NADH synergistically photoreduce cytochrome c under hypoxia. Density functional theory calculations reveal π stacking in adducts of complex 1 and NADH, facilitating photoinduced single-electron transfer. In cancer cells, complex 1 localizes in mitochondria and disrupts electron transport via NADH photocatalysis. On light irradiation, complex 1 induces NADH depletion, intracellular redox imbalance and immunogenic apoptotic cancer cell death. This photocatalytic redox imbalance strategy offers a new approach for efficient cancer phototherapy.

From fundamental science to product: a bottom-up approach to sunscreen development.

Despite the pivotal role of ultraviolet (UV) radiation in sustaining life on Earth, overexposure to this type of radiation can have catastrophic effects, such as skin cancer. Sunscreens, the most common form of artificial protection against such harmful effects, absorb UV radiation before it reaches vulnerable skin cells. Absorption of UV radiation prompts ultrafast molecular events in sunscreen molecules which, ideally, would allow for fast and safe dissipation of the excess energy. However, our knowledge of these mechanisms remains limited. In this article, we will review recent advances in the field of ultrafast photodynamics (light induced molecular processes occurring within femtoseconds, fs, 10-15 s to picoseconds, ps, 10-12 s) of sunscreens. We follow a bottom-up approach to common sunscreen active ingredients, analysing any emerging trends from the current literature on the subject. Moreover, we will identify the main questions that remain unanswered, pinpoint some of the main challenges and finally comment on the outlook of this exciting field of research.

Spectroscopic Studies on Photoinduced Reactions of the Anticancer Prodrug, trans,trans,trans-[Pt(N3 )2 (OH)2 (py)2 ].

The photodecomposition mechanism of trans,trans,trans-[Pt(N3 )2 (OH)2 (py)2 ] (1, py=pyridine), an anticancer prodrug candidate, was probed using complementary Attenuated Total Reflection Fourier Transform Infrared (ATR-FTIR), transient electronic absorption, and UV/Vis spectroscopy. Data fitting using Principal Component Analysis (PCA) and Multi-Curve Resolution Alternating Least Squares, suggests the formation of a trans-[Pt(N3 )(py)2 (OH/H2 O)] intermediate and trans-[Pt(py)2 (OH/H2 O)2 ] as the final product upon 420 nm irradiation of 1 in water. Rapid disappearance of the hydroxido ligand stretching vibration upon irradiation is correlated with a -10 cm-1 shift to the antisymmetric azido vibration, suggesting a possible second intermediate. Experimental proof of subsequent dissociation of azido ligands from platinum is presented, in which at least one hydroxyl radical is formed in the reduction of PtIV to PtII . Additionally, the photoinduced reaction of 1 with the nucleotide 5'-guanosine monophosphate (5'-GMP) was comprehensively studied, and the identity of key photoproducts was assigned with the help of ATR-FTIR spectroscopy, mass spectrometry, and density functional theory calculations. The identification of marker bands for some of these photoproducts (e.g., trans-[Pt(N3 )(py)2 (5'-GMP)] and trans-[Pt(py)2 (5'-GMP)2 ]) will aid elucidation of the chemical and biological mechanism of anticancer action of 1. In general, these studies demonstrate the potential of vibrational spectroscopic techniques as promising tools for studying such metal complexes.

Photophysics of sunscreen molecules in the gas phase: a stepwise approach towards understanding and developing next-generation sunscreens.

The relationship between exposure to ultraviolet (UV) radiation and skin cancer urges the need for extra photoprotection, which is presently provided by widespread commercially available sunscreen lotions. Apart from having a large absorption cross section in the UVA and UVB regions of the electromagnetic spectrum, the chemical absorbers in these photoprotective products should also be able to dissipate the excess energy in a safe way, i.e. without releasing photoproducts or inducing any further, harmful, photochemistry. While sunscreens are tested for both their photoprotective capability and dermatological compatibility, phenomena occurring at the molecular level upon absorption of UV radiation are largely overlooked. To date, there is only a limited amount of information regarding the photochemistry and photophysics of these sunscreen molecules. However, a thorough understanding of the intrinsic mechanisms by which popular sunscreen molecular constituents dissipate excess energy has the potential to aid in the design of more efficient, safer sunscreens. In this review, we explore the potential of using gas-phase frequency- and time-resolved spectroscopies in an effort to better understand the photoinduced excited-state dynamics, or photodynamics, of sunscreen molecules. Complementary computational studies are also briefly discussed. Finally, the future outlook of expanding these gas-phase studies into the solution phase is considered.

Gas-Phase Femtosecond Particle Spectroscopy: A Bottom-Up Approach to Nucleotide Dynamics.

We summarize how gas-phase ultrafast charged-particle spectroscopy has been used to provide an understanding of the photophysics of DNA building blocks. We focus on adenine and discuss how, following UV excitation, specific interactions determine the fates of its excited states. The dynamics can be probed using a systematic bottom-up approach that provides control over these interactions and that allows ever-larger complexes to be studied. Starting from a chromophore in adenine, the excited state decay mechanisms of adenine and chemically substituted or clustered adenine are considered and then extended to adenosine mono-, di-, and trinucleotides. We show that the gas-phase approach can offer exquisite insight into the dynamics observed in aqueous solution, but we also highlight stark differences. An outlook is provided that discusses some of the most promising developments in this bottom-up approach.

Excited-State Dynamics of a Two-Photon-Activatable Ruthenium Prodrug.

We present a new approach to investigate how the photodynamics of an octahedral ruthenium(II) complex activated through two-photon absorption (TPA) differ from the equivalent complex activated through one-photon absorption (OPA). We photoactivated a Ru(II) polypyridyl complex containing bioactive monodentate ligands in the photodynamic therapy window (620-1000 nm) by using TPA and used transient UV/Vis absorption spectroscopy to elucidate its reaction pathways. Density functional calculations allowed us to identify the nature of the initially populated states and kinetic analysis recovers a photoactivation lifetime of approximately 100 ps. The dynamics displayed following TPA or OPA are identical, showing that TPA prodrug design may use knowledge gathered from the more numerous and easily conducted OPA studies.

Bridging the Gap between the Gas Phase and Solution Phase: Solvent Specific Photochemistry in 4-tert-Butylcatechol.

Eumelanin is a naturally synthesized ultraviolet light absorbing biomolecule, possessing both photoprotective and phototoxic properties. We infer insight into these properties of eumelanin using a bottom-up approach, by investigating an ultraviolet absorbing motif of eumelanin, 4-tert-butylcatechol. Utilizing a combination of femtosecond transient electronic absorption spectroscopy and time-resolved velocity map ion imaging, our results suggest an environmental-dependent relaxation pathway, following irradiation at 267 nm to populate the S1 ((1)ππ*) state. Gas-phase and nonpolar solution-phase measurements reveal that the S1 state decays primarily through coupling onto the S2 ((1)πσ*) state which is dissociative along the nonintramolecular hydrogen bonded "free" O-H bond. This process occurs in 4.9 ± 0.6 ps in the gas-phase and 18 ± 1 ps in the nonpolar cyclohexane solution. Comparative studies on the deuterated isotopologue of 4-tert-butylcatechol in both the gas- and solution-phase (cyclohexane) reveal kinetic isotope effects of ∼19 and ∼4, respectively, supportive of O-H dissociation along a barriered pathway, and potentially mediated by quantum tunneling. In contrast, in the polar solvent acetonitrile, the S1 state decays on a much longer time scale of 1.7 ± 0.1 ns. We propose that the S1 decay is now multicomponent, driven by internal conversion, intersystem crossing, and fluorescence, as well as O-H dissociation. The attribution of conformer-driven excited state dynamics to explain how the S1 state decays in the gas- and nonpolar solution-phase versus the polar solution-phase, demonstrates the influence the environment can have on the ensuing excited state dynamics.

Mapping the Ultrafast Dynamics of Adenine onto Its Nucleotide and Oligonucleotides by Time-Resolved Photoelectron Imaging.

The intrinsic photophysics of nucleobases and nucleotides following UV absorption presents a key reductionist step toward understanding the complex photodamage mechanisms occurring in DNA. The decay mechanism of adenine in particular has been the focus of intense investigation, as has how these correlate to those of its more biologically relevant nucleotide and oligonucleotides in aqueous solution. Here, we report on time-resolved photoelectron imaging of the deprotonated 3'-deoxy-adenosine-5'-monophosphate nucleotide and the adenosine di- and trinucleotides. Through a comparison of gas- and solution-phase experiments and available theoretical studies, the dynamics of the base are shown to be relatively insensitive to the surrounding environment. The decay mechanism primarily involves internal conversion from the initially populated (1)ππ* states to the ground state. The relaxation dynamics of the adenosine oligonucleotides are similar to those of the nucleobase, in contrast to the aqueous oligonucleotides, where a fraction of the ensemble forms long-lived excimer states.

Recent advances in experimental techniques to probe fast excited-state dynamics in biological molecules in the gas phase: dynamics in nucleotides, amino acids and beyond.

In many chemical reactions, an activation barrier must be overcome before a chemical transformation can occur. As such, understanding the behaviour of molecules in energetically excited states is critical to understanding the chemical changes that these molecules undergo. Among the most prominent reactions for mankind to understand are chemical changes that occur in our own biological molecules. A notable example is the focus towards understanding the interaction of DNA with ultraviolet radiation and the subsequent chemical changes. However, the interaction of radiation with large biological structures is highly complex, and thus the photochemistry of these systems as a whole is poorly understood. Studying the gas-phase spectroscopy and ultrafast dynamics of the building blocks of these more complex biomolecules offers the tantalizing prospect of providing a scientifically intuitive bottom-up approach, beginning with the study of the subunits of large polymeric biomolecules and monitoring the evolution in photochemistry as the complexity of the molecules is increased. While highly attractive, one of the main challenges of this approach is in transferring large, and in many cases, thermally labile molecules into vacuum. This review discusses the recent advances in cutting-edge experimental methodologies, emerging as excellent candidates for progressing this bottom-up approach.

Competing 1πσ* mediated dynamics in mequinol: O-H versus O-CH3 photodissociation pathways.

Deactivation of excited electronic states through coupling to dissociative (1)πσ* states in heteroaromatic systems has received considerable attention in recent years, particularly as a mechanism that contributes to the ultraviolet (UV) photostability of numerous aromatic biomolecules and their chromophores. Recent studies have expanded upon this work to look at more complex species, which involves understanding competing dynamics on two different (1)πσ* potential energy surfaces (PESs) localized on different heteroatom hydride coordinates (O-H and N-H bonds) within the same molecule. In a similar spirit, the work presented here utilizes ultrafast time-resolved velocity map ion imaging to study competing dissociation pathways along (1)πσ* PESs in mequinol (p-methoxyphenol), localized at O-H and O-CH(3) bonds yielding H atoms or CH(3) radicals, respectively, over an excitation wavelength range of 298-238 nm and at 200 nm. H atom elimination is found to be operative via either tunneling under a conical intersection (CI) (298 ≥ λ ≥ 280 nm) or ultrafast internal conversion through appropriate CIs (λ ≤ 245 nm), both of which provide mechanisms for coupling onto the dissociative state associated with the O-H bond. In the intermediate wavelength range of 280 ≥ λ ≥ 245 nm, mediated H atom elimination is not observed. In contrast, we find that state driven CH(3) radical elimination is only observed in the excitation range 264 ≥ λ ≥ 238 nm. Interpretation of these experimental results is guided by: (i) high level complete active space with second order perturbation theory (CASPT2) calculations, which provide 1-D potential energy cuts of the ground and low lying singlet excited electronic states along the O-H and O-CH(3) bond coordinates; and (ii) calculated excitation energies using CASPT2 and the equation-of-motion coupled cluster with singles and doubles excitations (EOM-CCSD) formalism. From these comprehensive studies, we find that the dynamics along the O-H coordinate generally mimic H atom elimination previously observed in phenol, whereas O-CH(3) bond fission in mequinol appears to present notably different behavior to the CH(3) elimination dynamics previously observed in anisole (methoxybenzene).

Investigation of multiple electronic excited state relaxation pathways following 200 nm photolysis of gas-phase imidazole.

Imidazole acts as a subunit in the DNA base adenine and the amino acid histidine-both important biomolecules which display low fluorescence quantum yields following UV excitation. The low fluorescence quantum yields are attributed to competing non-radiative excited state relaxation pathways that operate on ultrafast timescales. Imidazole is investigated here as a model compound due to its accessibility to high level ab initio calculations and time-resolved gas-phase spectroscopic techniques. Recent non-adiabatic dynamics simulations have identified three non-radiative relaxation mechanisms which are active following 6.0-6.2 eV excitation. Presented herein is a comprehensive investigation of each mechanism using a combination of femtosecond time-resolved ion yield and total kinetic energy release spectroscopies to monitor the formation of associated photoproducts. Relaxation along the (1)πσ state constitutes the predominant deactivation pathway. Timescales for NH-dissociation are extracted and distinguished from alternative H-atom sources based on their kinetic energy distributions. Larger photoproducts are observed to a lesser extent and attributed to ring fragmentation following NH-puckering and CN-stretching relaxation paths.