Designing fluorescent molecules requires considering multiple interrelated molecular properties, as opposed to properties that straightforwardly correlated with molecular structure, such as light absorption of molecules. In this study, we have used a de novo molecule generator (DNMG) coupled with quantum chemical computation (QC) to develop fluorescent molecules, which are garnering significant attention in various disciplines. Using massive parallel computation (1024 cores, 5 days), the DNMG has produced 3643 candidate molecules. We have selected an unreported molecule and seven reported molecules and synthesized them. Photoluminescence spectrum measurements demonstrated that the DNMG can successfully design fluorescent molecules with 75% accuracy ( n = 6/8) and create an unreported molecule that emits fluorescence detectable by the naked eye.

Our developed algorithm, BLOX (BoundLess Objective-free eXploration), successfully found “out-of-trend” molecules potentially useful for photofunctional materials from a drug database.

Molecules that can exist in multiple states with the possibility of toggling between those states based on different stimuli have potential for use in molecular switching or sensing applications. Multimodal chemical or photochemical oxidative switching of an antioxidant-substituted resorcinarene macrocycle is reported. Intramolecular charge-transfer states, involving hemiquinhydrones are probed and these interactions are used to construct an oxidation-state-coupled molecular switching manifold that reports its switch-state conformation via striking variation in its electronic absorption spectra. The coupling of two different oxidation states with two different charge-transfer states within one macrocyclic scaffold delivers up to five different optical outputs. This molecular switching manifold exploits intramolecular coupling of multiple redox active substituents within a single molecule.

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© F e r r a t a S t o r t i F o u n d a t i o n(ROS) production or reduced antioxidant capacity. A principle antioxidant pathway is regulated by the redox sensitive transcription factor, NF-E2 p45-related factor-2 (NRF2/NFE2L2). In unstressed cells, low levels of NRF2 are maintained through interaction with Kelch-like ECHassociated protein 1 (KEAP1), an adapter for the E3 ubiquitin ligase Cullin 3 (CUL3) that directs NRF2 for proteasomal degradation. 13 Modification of redox and electrophile sensitive cysteine residues inhibits the substrate adaptor activity of KEAP1 allowing NRF2 accumulation. The interaction of KEAP1 with NRF2 is further modulated by phosphorylation of NRF2 at serine 40 by protein kinase C (PKC).14 Within the nucleus, NRF2 forms heterodimers with v-maf musculoaponeurotic fibrosarcoma oncogene homolog (MAF) proteins (MAF-F, G and K) and binds to antioxidant response elements (AREs) in the promoters of target genes such as those required for glutathione synthesis and its own promoter. 15 This activity is regulated by the transcriptional repressor BTB and CNC homology 1 transcription factor (BACH1) which competes for the MAF binding partners and for binding to gene promoters. 16 In addition, genetic models suggest that binding of Nrf-2 and its activity are regulated by the ATM substrate, Brca1. 17The most compelling evidence for the role of ATM in redox homeostasis comes from studies of the human radiosensitivity syndrome, Ataxia Telangiectasia (A-T), where both ATM alleles are inactivated. Cells from these patients display increased oxidative stress as a consequence of elevated levels of ROS, increased oxidized/reduced glutathione (GSSG/GSH) ratio, diminished capacity to scavenge ROS and mitochondrial dysfunction. 12,18 Furthermore, ATM is directly activated by oxidative stress 19 and can exert antioxidant activity through regulation of the pentose-phosphate pathway. 20 Recent evidence suggests that ATM might regulate oxidative stress through NRF2. Namely, Nrf2 target gene expression was decreased in Atm-/-murine osteoblasts and this was rescued by the ectopic expression of PKC delta (PKCδ). 21 In this study, we tested the hypothesis that ATM-null CLLs have an intrinsic defect in their antioxidant defenses that might be exploited to induce synthetic lethality of tumor cells by escalating oxidative stress. We show that compared to ATM-wild type (wt) CLL, ATM-null CLL tumors exhibited defective NRF2-dependent antioxidant transcriptional responses, decreased antioxidant capacity, elevated mitochondrial ROS, and increased sensitivity to pro-oxidants both in vitro and in vivo. Furthermore, we demonstrate that pro-oxidant treatment bypassed the need for a functional DRR and induced cell death via a p53-and caspase-independent mechanism involving apoptosis inducing factor (AIF). Methods Patients' samples and cell linesChronic lymphocytic leukemia samples were obtained from Birmingham and Bournemouth Hospitals (Online Supplementary Table S1). These were comprised of 3 CLLs with monoallelic ATM...

A new class of bifunctional hydrogen-bond donor organocatalyst using oxoporphyrinogens having increased intramolecular hydrogen-bond donor distances is reported. Oxoporphyrinogens are highly non-planar rigid macrocycles containing a multiple hydrogen bond-forming binding site. In this work, we describe the first example of non-planar OxPs as hydrogenbond donor catalysts prepared using a molecular engineering approach of the binding site for dual activation of substrates.[a]

Chromophores that generate singlet oxygen ( 1 O 2 ) in water are essential to developing noninvasive disease treatments using photodynamic therapy (PDT). A facile approach for formation of stable colloidal nanoparticles of 1 O 2 photosensitizers, which exhibit aggregation enhanced 1 O 2 generation in water toward applications as PDT agents, is reported. Chromophore encryption within a fuchsonarene macrocyclic scaffold insulates the photosensitizer from aggregation induced deactivation pathways, enabling a higher chromophore density than typical 1 O 2 generating nanoparticles. Aggregation enhanced 1 O 2 generation in water is observed, and variation in molecular structure allows for regulation of the physical properties of the nanoparticles which ultimately affects the 1 O 2 generation. In vitro activity and the ability of the particles to pass through the cell membrane into the cytoplasm is demonstrated using confocal fluorescence microscopy with HeLa cells. Photosensitizer encryption in rigid macrocycles, such as fuchsonarenes, offers new prospects for the production of biocompatible nanoarchitectures for applications involving 1 O 2 generation.

Singlet oxygen sensitization involving a class of hemiquinonoid-substituted resorcinarenes prepared from the corresponding 3,5-di-t-butyl-4-hydroxyphenyl-substituted resorcinarenes is reported.