Recognition of Symmetry as a Powerful Tool in Natural Product Synthesis

The design of concise and efficient synthetic strategies to access naturally occurring, pharmaceutically active complex molecules is of utmost importance in current chemistry. It not only enables rapid access to these molecules and their analogues but also provides sufficient quantities for their biological evaluation. Identification of any symmetric or pseudosymmetric synthetic intermediates upon retrosynthetic bond disconnection of the target molecule holds the promise to significantly streamline the route towards the compound of interest. This review will highlight recent examples of successful natural product syntheses reported within the past five years that benefited from the recognition of symmetry elements during the retrosynthetic design.

The development of three ruthenium-based antimicrobial metallodrugs: Design, synthesis, and activity evaluation against Staphylococcus aureus

The development of new classes of antimicrobial is urgently needed due to the widespread occurrence of multi-resistant pathogens. In this study, three novel ruthenium complexes: [Ru(dmob)2(BTPIP)](PF6)2 (Ru(II)-1), [Ru(dbp)2(BTPIP)](PF6)2 (Ru(II)-2), and [Ru(dpa)2(BTPIP)](PF6)2 (Ru(II)-3) (dpa = 2,2’-dipyridylamine, dmob = 4,4’-dimethoxy-2,2’-bipyridyl, dbp = 4,4’-di- tert-butyl-2,2’-dipyridyl, BTPIP = 4-(benzo[ b]thiophen-2-yl)phenyl-1 H-imidazo[4,5- f][1,10]phenanthroline) are synthesized and investigated as antimicrobial metallodrugs. We demonstrate that all three complexes have significant antimicrobial activity against Staphylococcus aureus by testing their minimal inhibitory concentrations = 0.0015–0.0125 mg/mL. The antibacterial activity of the best active complex Ru(II)-3 is 13 times that of ofloxacin (minimal inhibitory concentration = 19.5 μg/mL). Importantly, Ru(II)-3 not only increases the susceptibility of Staphylococcus aureus to existing common antibiotics but also shows noticeably delayed and decreased resistance in Staphylococcus aureus since the minimal inhibitory concentration values of Ru(II)-3 only increased eightfold times after 20 passages. Furthermore, the biofilms formation and rabbit erythrocyte hemolysis assays verified that Ru(II)-3 also efficiently inhibit the biofilm formation and toxin secretion of Staphylococcus aureus.

Leishmania type II dehydrogenase is essential for parasite viability irrespective of the presence of an active complex I

Type II NADH dehydrogenases (NDH2) are monotopic enzymes present in the external or internal face of the mitochondrial inner membrane that contribute to NADH/NAD+ balance by conveying electrons from NADH to ubiquinone without coupled proton translocation. Herein, we characterize the product of a gene present in all species of the human protozoan parasite Leishmania as a bona fide, matrix-oriented, type II NADH dehydrogenase. Within mitochondria, this respiratory activity concurs with that of type I NADH dehydrogenase (complex I) in some Leishmania species but not others. To query the significance of NDH2 in parasite physiology, we attempted its genetic disruption in two parasite species, exhibiting a silent (Leishmania infantum, Li) and a fully operational (Leishmania major, Lm) complex I. Strikingly, this analysis revealed that NDH2 abrogation is not tolerated by Leishmania, not even by complex I–expressing Lm species. Conversely, complex I is dispensable in both species, provided that NDH2 is sufficiently expressed. That a type II dehydrogenase is essential even in the presence of an active complex I places Leishmania NADH metabolism into an entirely unique perspective and suggests unexplored functions for NDH2 that span beyond its complex I–overlapping activities. Notably, by showing that the essential character of NDH2 extends to the disease-causing stage of Leishmania, we genetically validate NDH2—an enzyme without a counterpart in mammals—as a candidate target for leishmanicidal drugs.

A Photolabile Fe Catalyst for Light-Triggered Alkyd Paint Curing

In search for cobalt replacements for alkyd paint curing we show that the photo-active complex [(Cp)Fe(C₆H₆)]+ (Cp = cyclopentadienyl) acts as a latent catalytic drier that allows for photochemical control over the onset of curing, without the need for anti-skinning agents such as the volatile MEKO normally used to prevent curing during paint storage. The highly soluble neutral complex [(Cp)Fe(Ch)] (Ch = cyclohexadienyl) readily converts to the photo-active complex [(Cp)Fe(C₆H₆)]⁺ upon oxidation in alkyd, allowing the latter to be dosed in a wide range of concentrations. Infrared and Raman studies show similar spectral changes of the alkyd paint matrix as have been observed in alkyd curing mediated by the known commercial cobalt- and manganese-based driers Durham NUODEX® Cobalt 10 Neo and NUODEX® DryCoat. The new [(Cp)Fe(Ch)] / [(Cp)Fe(C₆H₆)]⁺ system performs equally well as both commercial paint driers in terms of drying time, and outperforms NUODEX® DryCoat by showing a hardness development (increase) similar to the cobalt-based drier. Based on an observed light-dark on/off effect and EPR studies we propose that photolysis of [(Cp)Fe(C₆H₆)]+ generates short-lived active Fe^II species, explaining the excellent latency. The novel alkyd curing system [(Cp)Fe(Ch)] / [(Cp)Fe(C₆H₆)]⁺ presented herein is the first example of an intrinsically latent paint curing catalyst that is: (1) based on an abundant and harmless transition metal (Fe), (2) doesn’t require any anti-skinning agents, and (3) shows excellent performance in terms of drying times and hardness development. <br>

A Photolabile Fe Catalyst for Light-Triggered Alkyd Paint Curing

In search for cobalt replacements for alkyd paint curing we show that the photo-active complex [(Cp)Fe(C₆H₆)]+ (Cp = cyclopentadienyl) acts as a latent catalytic drier that allows for photochemical control over the onset of curing, without the need for anti-skinning agents such as the volatile MEKO normally used to prevent curing during paint storage. The highly soluble neutral complex [(Cp)Fe(Ch)] (Ch = cyclohexadienyl) readily converts to the photo-active complex [(Cp)Fe(C₆H₆)]⁺ upon oxidation in alkyd, allowing the latter to be dosed in a wide range of concentrations. Infrared and Raman studies show similar spectral changes of the alkyd paint matrix as have been observed in alkyd curing mediated by the known commercial cobalt- and manganese-based driers Durham NUODEX® Cobalt 10 Neo and NUODEX® DryCoat. The new [(Cp)Fe(Ch)] / [(Cp)Fe(C₆H₆)]⁺ system performs equally well as both commercial paint driers in terms of drying time, and outperforms NUODEX® DryCoat by showing a hardness development (increase) similar to the cobalt-based drier. Based on an observed light-dark on/off effect and EPR studies we propose that photolysis of [(Cp)Fe(C₆H₆)]+ generates short-lived active Fe^II species, explaining the excellent latency. The novel alkyd curing system [(Cp)Fe(Ch)] / [(Cp)Fe(C₆H₆)]⁺ presented herein is the first example of an intrinsically latent paint curing catalyst that is: (1) based on an abundant and harmless transition metal (Fe), (2) doesn’t require any anti-skinning agents, and (3) shows excellent performance in terms of drying times and hardness development. <br>

fNIRS Outcomes for a Pilot Clinical Trial Combining Frontal tDCS With Walking Rehabilitation in Older Adults

This pilot study assessed a novel intervention to enhance both walking and executive function in older adults. The primary hypothesis was that eighteen sessions of frontal lobe tDCS combined with walking rehabilitation would be feasible, safe, and show preliminary efficacy. Eighteen participants were randomized to one of three intervention groups: active tDCS and rehabilitation with complex walking tasks (Active/Complex); sham tDCS and rehabilitation with complex walking tasks (Sham/Complex); or sham tDCS and rehabilitation with typical walking (Sham/Typical). Outcome measures included multiple tests of walking function, executive function, and prefrontal activity during walking as measured by functional near infrared spectroscopy (fNIRS). Of the three groups, the Active/Complex group demonstrated the broadest improvements across outcome measures including for prefrontal activity. The functional range of prefrontal activity in this group was increased considerably, as conceptualized by the Compensation Related Utilization of Neural Circuits Hypothesis. Frontal tDCS is a promising adjuvant to walking rehabilitation.

Combining frontal tDCS with walking rehabilitation to enhance mobility and cognition: a pilot clinical trial

Walking function is compromised with older age, particularly for cognitively demanding complex walking tasks. Frontal lobe brain networks are important to both complex walking and cognitive function. There is a need for interventions that target this brain region. This pilot study assessed a novel intervention to enhance both walking and executive function in older adults. The primary hypothesis was that eighteen sessions of frontal lobe tDCS combined with complex walking rehabilitation would be feasible, safe, and show preliminary efficacy for improvements in walking and cognition. Eighteen participants were randomized to one of three intervention groups: active tDCS and rehabilitation with complex walking tasks (Active/Complex); sham tDCS and rehabilitation with complex walking tasks (Sham/Complex); or sham tDCS and rehabilitation with typical walking (Sham/Typical). Outcome measures included multiple tests of walking function, executive function, and prefrontal activity during walking measured by functional near infrared spectroscopy. For the walking tests, effect sizes for Active/Complex were generally higher than for Sham/Complex. The Sham/Typical group exhibited walking test effect sizes that were often larger than either of the complex walking groups, possibly due to higher intervention step count. For the executive function tests, effect sizes were largest for the Active/Complex group. Improvements in prefrontal activity during walking were observed, as conceptualized by the Compensation Related Utilization of Neural Circuits Hypothesis. These preliminary findings support that tDCS combined with complex walking rehabilitation in older adults is feasible and may enhance both walking function and executive function.