Modular, Enantioselective Entry into Polysubstituted Shapeshifting Molecules.

Dynamic, shapeshifting hydrocarbons have emerged as enabling frameworks across drug discovery, materials science, and catalysis. Their employment, however, is often hampered by a lack of efficient synthetic methods for their preparation. Herein, we report a unified, concise, and modular synthesis of enantioenriched shapeshifting hydrocarbons (barbaralones and bullvalones) and multisubstituted bullvalenes, leveraging mild photochemical and base-induced rearrangements.

A Shapeshifting Roadmap for Polycyclic Skeletal Evolution.

Polycyclic ring systems are ubiquitous three-dimensional (3D) structural motifs central to the function of many biologically active small molecules and organic materials. Indeed, subtle changes to the overall molecular shape and connectivity of atoms in a polycyclic framework (i.e., isomerism) can drastically alter its function and properties. Unfortunately, direct evaluation of these structure-function relationships typically requires the development of distinct synthetic strategies toward a specific isomer. Dynamic, "shapeshifting" carbon cages present a promising approach for sampling isomeric chemical space but are often difficult to control and are largely limited to thermodynamic mixtures of positional isomers about a single core scaffold. Here, we describe the development of a new shapeshifting C9-chemotype and a chemical blueprint for its evolution into structurally and energetically diverse isomeric ring systems. By leveraging the unique molecular topology of π-orbitals interacting through-space (homoconjugation), a common skeletal ancestor evolved into a complex network of valence isomers. This unusual system represents an exceedingly rare small molecule capable of undergoing controllable and continuous isomerization processes through the iterative use of just two chemical steps (light and organic base). Computational and photophysical studies of the isomer network provide fundamental insight into the reactivity, mechanism, and role of homoconjugative interactions. Importantly, these insights may inform the rational design and synthesis of new dynamic, shapeshifting systems. We anticipate this process could be a powerful tool for the synthesis of structurally diverse, isomeric polycycles central to many bioactive small molecules and functional organic materials.

Taming Shapeshifting Anions: Total Synthesis of Ocellatusone C.

Guided by a synthetic design aimed at late-stage diversification, we report the preparation of unusual shapeshifting anions and their subsequent application to the total synthesis of the polyketide natural product ocellatusone C. Site-selective core functionalization of a readily accessible bicyclo[3.3.1]nonane architecture sets the stage for shape-selective side chain installation via a nonfluxional π-allyl Pd-complex derived from a barbaralyl-type anion. Several interesting chemical findings, including substituent-dependent bridged bicycloisomerism and the isolation of a stabilized, 3° carbon-bound Pd-ketone enolate complex, are reported.

Acute Putrescine Supplementation with Schwann Cell Implantation Improves Sensory and Serotonergic Axon Growth and Functional Recovery in Spinal Cord Injured Rats.

Schwann cell (SC) transplantation exhibits significant potential for spinal cord injury (SCI) repair and its use as a therapeutic modality has now progressed to clinical trials for subacute and chronic human SCI. Although SC implants provide a receptive environment for axonal regrowth and support functional recovery in a number of experimental SCI models, axonal regeneration is largely limited to local systems and the behavioral improvements are modest without additional combinatory approaches. In the current study we investigated whether the concurrent delivery of the polyamine putrescine, started either 30 min or 1 week after SCI, could enhance the efficacy of SCs when implanted subacutely (1 week after injury) into the contused rat spinal cord. Polyamines are ubiquitous organic cations that play an important role in the regulation of the cell cycle, cell division, cytoskeletal organization, and cell differentiation. We show that the combination of putrescine with SCs provides a significant increase in implant size, an enhancement in axonal (sensory and serotonergic) sparing and/or growth, and improved open field locomotion after SCI, as compared to SC implantation alone. These findings demonstrate that polyamine supplementation can augment the effectiveness of SCs when used as a therapeutic approach for subacute SCI repair.

Immediate and mid-term effects of pyrimethanil toxicity on microalgae by simulating an episodic contamination.

Since pesticides can represent a threat for non-target aquatic communities, including microalgae, we looked at the effects of the fungicide pyrimethanil on the growth of the freshwater green microalgae Selenastrum capricornutum. Additionally, attenuation of the toxicity of pyrimethanil due to its dissipation in the water was assessed. Pyrimethanil-contaminated samples were taken from outdoor mesocosms one (1.4 mg L(-1) of pyrimethanil) and ten (0.78 mg L(-1) of pyrimethanil) days after pyrimethanil application. Different dilutions were prepared using both nutrient-rich culture medium (LC Oligo) and non-contaminated mesocosm samples, and cell growth inhibition was assessed. Reference mesocosm samples were also diluted with LC Oligo in order to verify how the nutrient concentration in the LC Oligo could improve cell growth. Comparing cell growth of population exposed to pyrimethanil-treated sample taken at day 1 with cells growing in reference sample and LC Oligo, the growth inhibition was 80% (± 6.5) and 95% (± 2.0), respectively. The toxicity of samples taken from contaminated mesocosms at day 10 was attenuated to 34% (± 15) (when compared with reference sample) and 88% (± 3.0) (when compared with LC Oligo), as pyrimethanil concentrations in the mesocosms decreased. In conclusion, (i) pyrimethanil can be an environmental disturber for the microalgae; (ii) the toxicity of pyrimethanil in water was reduced almost 2.4 times (when compared with the reference sample) at as short a period as 10d if assuming that pesticide entrance is not continuous; (iii) toxicity of an environmental sample could be underestimated if the sample/medium used in dilution presents different nutrient levels.

Avoidance response of Danio rerio to a fungicide in a linear contamination gradient.

The present study examines the ability of juvenile Danio rerio to avoid pyrimethanil-contaminated water. An avoidance assay system was used with a contamination gradient formed by seven compartments, through which the fish could move and choose the preferred compartment(s). Additionally, the influence of fish movements in promoting the mixing between compartments and thus disruption of the gradient over time was also examined by testing sodium chloride (NaCl) at sublethal concentrations. Samples with pyrimethanil were obtained from the commercial formulation Mythos®, which was applied to mesocosm systems. Samples of the pyrimethanil-contaminated mesocosms water were collected and a series of seven concentrations (0.2 to 1.4mgL(-1) plus a control) diluted with reference (uncontaminated) mesocosm water were added to the system to form the gradient. After 4h exposure, fish avoidance in the three highest pyrimethanil concentrations ranged from 29 to 66%. The 4h-AC50 (concentration at which 50% of the fish avoided pyrimethanil after 4h exposure) was 1.10 (confidence interval: 1.07 to 1.12)mgL(-1). However, the avoidance pattern after 12h was strongly reduced and it was not possible to calculate the AC50. This is explained by the results of the NaCl experiment, which showed that the movement of fish in the system accelerates the mixing of the solutions between compartments. As pyrimethanil can trigger avoidance response in D. rerio, this fungicide, even at non-lethal concentrations, could be considered an environmental disturber.

Transplantation of Schwann cells and/or olfactory ensheathing glia into the contused spinal cord: Survival, migration, axon association, and functional recovery.

Schwann cells (SCs) and olfactory ensheathing glia (OEG) have shown promise for spinal cord injury repair. We sought their in vivo identification following transplantation into the contused adult rat spinal cord at 1 week post-injury by: (i) DNA in situ hybridization (ISH) with a Y-chromosome specific probe to identify male transplants in female rats and (ii) lentiviral vector-mediated expression of EGFP. Survival, migration, and axon-glia association were quantified from 3 days to 9 weeks post-transplantation. At 3 weeks after transplantation into the lesion, a 60-90% loss of grafted cells was observed. OEG-only grafts survived very poorly within the lesion (<5%); injection outside the lesion led to a 60% survival rate, implying that the injury milieu was hostile to transplanted cells and or prevented their proliferation. At later times post-grafting, p75(+)/EGFP(-) cells in the lesion outnumbered EGFP(+) cells in all paradigms, evidence of significant host SC infiltration. SCs and OEG injected into the injury failed to migrate from the lesion. Injection of OEG outside of the injury resulted in their migration into the SC-injected injury site, not via normal-appearing host tissue but along the pia or via the central canal. In all paradigms, host axons were seen in association with or ensheathed by transplanted glia. Numerous myelinated axons were found within regions of grafted SCs but not OEG. The current study details the temporal survival, migration, axon association of SCs and OEG, and functional recovery after grafting into the contused spinal cord, research previously complicated due to a lack of quality, long-term markers for cell tracking in vivo.