Discovery of IACS-52825, a Potent and Selective DLK Inhibitor for Treatment of Chemotherapy-Induced Peripheral Neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a major unmet medical need with limited treatment options. Despite different mechanisms of action, diverse chemotherapeutics can cause CIPN through a converged pathway─an active axon degeneration program that engages the dual leucine zipper kinase (DLK). DLK is a neuronally enriched kinase upstream in the MAPK-JNK cascade, and while it is dormant under physiological conditions, DLK mediates a core mechanism for neuronal injury response under stress conditions, making it an attractive target for treatment of neuronal injury and neurodegenerative diseases. We have developed potent, selective, brain penetrant DLK inhibitors with excellent PK and activity in mouse models of CIPN. Lead compound IACS-52825 (22) showed strongly effective reversal of mechanical allodynia in a mouse model of CIPN and was advanced into preclinical development.

Gracilin A Derivatives Target Early Events in Alzheimer's Disease: in Vitro Effects on Neuroinflammation and Oxidative Stress.

The search for compounds capable of targeting early pathological changes of Alzheimer̀s disease (AD), such as oxidative stress and neuroinflammation, is an important challenge. Gracilin A derivatives were recently synthesized, using a pharmacophore-directed retrosynthesis (PDR) strategy, and found to possess potent neuroprotective effects. In this work, the previously described derivatives 1-7 which demonstrated mitochondrial-mediated, antioxidant effects were chosen for further study. The ability of compounds to modulate the expression of antioxidant genes (CAT, GPx, SODs, and Nrf2) was determined in SH-SY5Y cells, and the simplified derivatives 2 and 3 were found to be the most effective. The anti-neuroinflammatory properties of all derivatives were assessed in BV2 microglial cells activated with lipopolysaccharide (LPS). Several derivatives decreased the release of cytokines (Il-1ß, IL-6, GM-CSF, and TNF-α) and other damaging molecules (ROS, NO) and also regulated the translocation of Nrf2 and NFκB, and reduced p38 activation. These protective effects were confirmed in a trans-well coculture with BV2 and SH-SY5Y cells and several derivatives increased SH-SY5Y survival. This present work demonstrates the neuroprotective properties of gracilin A derivatives, making them promising candidate drugs for AD. Particularly, derivatives 2 and 3 showed the greatest potential as lead compounds for further development.

Simplified immunosuppressive and neuroprotective agents based on gracilin A.

The architecture and bioactivity of natural products frequently serve as embarkation points for the exploration of biologically relevant chemical space. Total synthesis followed by derivative synthesis has historically enabled a deeper understanding of structure-activity relationships. However, synthetic strategies towards a natural product are not always guided by hypotheses regarding the structural features required for bioactivity. Here, we report an approach to natural product total synthesis that we term 'pharmacophore-directed retrosynthesis'. A hypothesized, pharmacophore of a natural product is selected as an early synthetic target and this dictates the retrosynthetic analysis. In an ideal application, sequential increases in the structural complexity of this minimal structure enable development of a structure-activity relationship profile throughout the course of the total synthesis effort. This approach enables the identification of simpler congeners retaining bioactivity at a much earlier stage of a synthetic effort, as demonstrated here for the spongiane diterpenoid, gracilin A, leading to simplified derivatives with potent neuroprotective and immunosuppressive activity.

Thioallenoates in Catalytic Enantioselective [2+2]-Cycloadditions with Unactivated Alkenes.

The application of thioallenoates to catalytic enantioselective [2+2]-cycloadditions with unactivated alkenes is reported.In many cases, the thioallenoates examined exhibit superior reactivity and selectivity compared to the alkoxy analogs generally used in these cycloadditions.

Allenoates in Enantioselective [2+2] Cycloadditions: From a Mechanistic Curiosity to a Stereospecific Transformation.

Identification of a novel catalyst-allenoate pair allows enantioselective [2+2] cycloaddition of α-methylstyrene. To understand the origin of selectivity, a detailed mechanistic investigation was conducted. Herein, two competing reaction pathways are proposed, which operate simultaneously and funnel the alkenes to the same axially chiral cyclobutanes. In agreement with the Woodward-Hoffmann rules, this mechanistic curiosity can be rationalized through a unique symmetry operation that was elucidated by deuteration experiments. In the case of 1,1-diarylalkenes, distal communication between the catalyst and alkene is achieved through subtle alteration of electronic properties and conformation. In this context, a Hammett study lends further credibility to a concerted mechanism. Thus, extended scope exploration, including ß-substitution on the alkene to generate two adjacent stereocenters within the cyclobutane ring, is achieved in a highly stereospecific and enantioselective fashion (33 examples, up to >99:1 er).

Synthesis of (-)-Hebelophyllene†E: An Entry to Geminal Dimethyl-Cyclobutanes by [2+2] Cycloaddition of Alkenes and Allenoates.

The first synthesis of hebelophyllene E is presented, along with assignment of its previously unknown relative configuration through synthesis of epi-ent-hebelophyllene E. Development of a catalytic enantioselective [2+2] cycloaddition of alkenes and allenoates provides access to the required chiral geminal dimethylcyclobutanes. Key to its success is the identification of a novel oxazaborolidine catalyst which promotes the cycloaddition in high enantioselectivities with good functional-group tolerance (9 examples, up to 97:3 e.r.). Thus, a late-stage cycloaddition using a fully functionalized alkene, followed by a diastereoselective reduction allows a concise entry to this class of natural products.

An unexpected Lewis acid catalyzed Diels-Alder cycloaddition of aryl allenes and acrylates.

An unexpected [4+2] cycloaddition of aryl allenes and simple acrylate derivatives is reported. This process functions well with a variety of allenes and acrylates to generate bi- and tricyclic dihydronaphthalene derivatives through a nonconventional bond disconnection.

Synthesis of 1,3-Substituted Cyclobutanes by Allenoate-Alkene [2 + 2] Cycloaddition.

A method for the [2 + 2] cycloaddition of terminal alkenes with allenoates is presented. This process allows for the rapid synthesis of 1,3-substituted cyclobutanes in high yield under simple and robust reaction conditions.

Cyclobutane and cyclobutene synthesis: catalytic enantioselective [2+2] cycloadditions.

Cyclobutanes and cyclobutenes are important structural motifs found in numerous biologically significant molecules, and they are useful intermediates for chemical synthesis. Consequently, [2+2] cycloadditions to access cyclobutanes and cyclobutenes have been established to be particularly useful transformations. Within the last 10 years, an increase in the frequency of publications for catalytic enantioselective [2+2] cycloadditions has occurred. These reactions provide access to a wide array of enantiomerically enriched chemical diversity that was not previously attainable. Described in this review are the advances made in catalytic enantioselective [2+2] cycloadditions to access cyclobutanes and cyclobutenes.

Catalytic enantioselective allenoate-alkene [2 + 2] cycloadditions.

Catalytic enantioselective [2 + 2] cycloadditions between allenoates and alkenes is disclosed. The method functions well for a variety of alkenes, and the products are generated with excellent levels of enantioselectivity. One of the most significant aspects of the present method is that unactivated alkenes are suitable substrates for this method, which is distinctly different from nearly all other catalytic enantioselective [2 + 2] cycloaddition methods.