Photoredox-based late-stage functionalization in SAR study for in vivo potent glucosylceramide synthase inhibitor.

Glucosylceramide synthase (GCS) has drawn much attention as an attractive protein target in the disease pathways of Parkinson's Disease (PD) and lysosomal storage disorders, such as Gaucher's Disease (GD). In previous our study, T-036 and its analogue, 2a, were discovered as novel GCS inhibitors. To further improve activity of this chemical series, SAR was investigated on the fused pyridyl ring core of 2a by employing a photoredox reaction that significantly reduced synthetic demand. Herein, we successfully applied the decarboxylation C-H alkylation photoredox reaction to introduce a wide variety of substituents at the 6-position of the fused pyridine core scaffold. This quick SAR acquisition facilitated the swift identification of the potent GCS inhibitors 2b (IC50 = 5.9 nM) and 2g (IC50 = 3.6 nM). Moreover, 2b exhibited superior in vivo potency to that of our previously reported lead compound, T-036.

Discovery of Brain-Penetrant Glucosylceramide Synthase Inhibitors with a Novel Pharmacophore.

Inhibition of glucosylceramide synthase (GCS) is a major therapeutic strategy for Gaucher's disease and has been suggested as a potential target for treating Parkinson's disease. Herein, we report the discovery of novel brain-penetrant GCS inhibitors. Assessment of the structure-activity relationship revealed a unique pharmacophore in this series. The lipophilic ortho-substituent of aromatic ring A and the appropriate directionality of aromatic ring B were key for potency. Optimization of the absorption, distribution, metabolism, elimination, toxicity (ADMETox) profile resulted in the discovery of T-036, a potent GCS inhibitor in vivo. Pharmacophore-based scaffold hopping was performed to mitigate safety concerns associated with T-036. The ring opening of T-036 resulted in another potent GCS inhibitor with a lower toxicological risk, T-690, which reduced glucosylceramide in a dose-dependent manner in the plasma and cortex of mice. Finally, we discuss the structural aspects of the compounds that impart a unique inhibition mode and lower the cardiovascular risk.

Decarboxylative N-Alkylation of Azoles through Visible-Light-Mediated Organophotoredox Catalysis.

An organophotoredox-catalyzed decarboxylative cross-coupling between azole nucleophiles and aliphatic carboxylic acid-derived redox-active esters is demonstrated. This protocol efficiently installs various tertiary or secondary alkyl fragments onto the nitrogen atom of azole nucleophiles under mild and transition-metal-free conditions. The pyridinium additive successfully inhibits the formation of elimination byproducts from the carbocation intermediate. This reaction is applicable to the synthesis of a protein-degrader-like molecule containing an azole and a thalidomide.

Multinuclear Ru(ii) and Ir(iii) decorated tetraphenylporphyrins as efficient PDT agents.

Two novel porphyrin-core systems were prepared by Sonogashira cross-coupling of the terminal alkyne groups of meso-tetra(4-ethynylphenyl)porphyrin-Zn(ii) (P-1) with halogenated Ru(ii)- or Ir(iii)-phenanthroline complexes. The resulting compounds (P-Ru and P-Ir) were spectroscopically characterised and their photophysical properties were investigated (λem 625, 665 nm; τT 339.6 µs (P-Ru) and λem 530, 612, 664 nm; τT 396.6 µs (P-Ir)). Nanosecond time-resolved transient absorption studies were used to explore the 3MLCT nature of the triplet excited states, and the singlet oxygen quantum yields were determined (ΦΔ 44.8 (P-Ru), 33.2 (P-Ir)%). The subcellular uptake of P-Ru and P-Ir and their application as photosensitisers (PS) in photodynamic therapy (PDT) were explored due to their solution photophysics and absence of dark toxicity. Upon irradiation (λexc = 620-630 nm; 10 min; 33 J cm-2), both P-Ru and P-Ir killed 90% of SKBR-3 cells at 1 µM. Notably P-Ru induced a 77% decrease in cell viability at only 0.25 µM.

Novel ruthenium and iridium complexes of N-substituted carbazole as triplet photosensitisers.

Novel mono- and di-nuclear Ru(ii) and Ir(iii) complexes, bearing a modified carbazole moiety are synthesised. In comparison to their mononuclear analogues, the homonuclear diatomic complexes (RuCRu and IrCIr), in which the carbazole containing-ligand functions as a bridge, display increased absorbance in the visible region, and give rise to higher singlet oxygen quantum yields.

Iridium(III) Complexes Bearing Pyrene-Functionalized 1,10-Phenanthroline Ligands as Highly Efficient Sensitizers for Triplet-Triplet Annihilation Upconversion.

"Chemistry-on-the-complex" synthetic methods have allowed the selective addition of 1-ethynylpyrene appendages to the 3-, 5-, 3,8- and 5,6-positions of IrIII -coordinated 1,10-phenanthroline via Sonogashira cross-coupling. The resulting suite of complexes has given rise to the first rationalization of their absorption and emission properties as a function of the number and position of the pyrene moieties. Strong absorption in the visible region (e.g. 3,8-substituted Ir-3: λabs =481 nm, ϵ=52 400 m-1 cm-1 ) and long-lived triplet excited states (e.g. 5-substituted Ir-2: τT =367.7 µs) were observed for the complexes in deaerated CH2 Cl2 . On testing the series as triplet sensitizers for triplet-triplet annihilation upconversion, those IrIII complexes bearing pyrenyl appendages at the 3- and 3,8-positions (Ir-1, Ir-3) were found to give optimal upconversion quantum yields (30.2 % and 31.6 % respectively).

Highly Efficient Triplet Photosensitizers: A Systematic Approach to the Application of Ir(III) Complexes containing Extended Phenanthrolines.

A series of Ir(III) complexes, based on 1,10-phenanthroline featuring aryl acetylene chromophores, were prepared and investigated as triplet photosensitizers. The complexes were synthesized by Sonogashira cross-coupling reactions using a "chemistry-on-the-complex" method. The absorption properties and luminescence lifetimes were successfully tuned by controlling the number and type of light-harvesting group. Intense UV/Vis absorption was observed for the Ir(III) complexes with two light-harvesting groups at the 3- and 8-positions of the phenanthroline. The asymmetric Ir(III) complex (with a triphenylamine (TPA) and a pyrene moiety attached) exhibited the longest lifetime. Red emission was observed for all the complexes in deaerated solutions at room temperature. Their emission at low temperature (77 K) and nanosecond time-resolved transient difference absorption spectra revealed the origin of their triplet excited states. The singlet-oxygen ((1) O2 ) sensitization and triplet-triplet annihilation (TTA)-based upconversion were explored. Highly efficient TTA upconversion (ΦUC =28.1 %) and (1) O2 sensitization (ΦΔ =97.0 %) were achieved for the asymmetric Ir(III) complex, which showed intense absorption in the visible region (λabs =482 nm, ϵ=50900 m(-1) cm(-1) ) and had a long-lived triplet excited state (53.3 µs at RT).

Perylene-derived triplet acceptors with optimized excited state energy levels for triplet-triplet annihilation assisted upconversion.

A series of perylene derivatives are prepared as triplet energy acceptors for triplet-triplet annihilation (TTA) assisted upconversion. The aim is to optimize the energy levels of the T1 and S1 states of the triplet acceptors, so that the prerequisite for TTA (2E(T1) > E(S1)) can be better satisfied, and eventually to increase the upconversion efficiency. Tuning of the energy levels of the excited states of the triplet acceptors is realized either by attaching aryl groups to perylene (via single or triple carbon-carbon bonds), or by assembling a perylene-BODIPY dyad, in which the components present complementary S1 and T1 state energy levels. The S1 state energy levels of the perylene derivatives are generally decreased compared to perylene. The anti-Stokes shift, TTA, and upconversion efficiencies of the new triplet acceptors are improved with respect to the perylene hallmark. For the perylene-BODIPY dyads, the fluorescence emission was substantially quenched in polar solvents. Moreover, we found that extension of the π-conjugation of BODIPY energy donor significantly reduces the energy level of the S1 state. Low S1 state energy level and high T1 state energy level are beneficial for triplet photosensitizers.