Investigating structure-charge transport relationships in thiophene substituted naphthyridine crystalline materials by computational model systems.

The development of novel π-conjugated charge transfer mediators is at the forefront of current research efforts and interests. Among the plethora of building blocks, diketopyrrolopyrroles have been widely employed, associated to the ease of tailoring their optoelectronic properties by systematic peripheral substitutions. It is somehow of surprise to us that their six-member ring bis-lactam analogues, naphthyridines have been overlooked and reports are scarce and almost solely limited to their use in polymeric materials. Herein we report a comprehensive theoretical analysis of the charge transfer properties of 1,5-naphthyridine-based materials by means of a number of bespoke model systems, further able to quantitatively predict experimental mobility observations. Our results imply that thiophene substituted naphthyridine crystalline materials represent a promising class of organic π-conjugated systems with an experimentally observed ability to self-assemble in the solid state conforming to one dimensional stacking motifs. These highly sought-after charge propagation channels are characterised by large wavefunction overlap and thermal integrity and have as a result the potential to outperform currently exploited alternatives. We anticipate this work to be of interest to materials scientists and hope it will pave the way towards the realisation of novel charge transfer mediators exploiting naphthyridine chemistries.

Discovery of novel small molecule inhibitors of S100P with in vitro anti-metastatic effects on pancreatic cancer cells.

S100P, a calcium-binding protein, is known to advance tumor progression and metastasis in pancreatic and several other cancers. Herein is described the in silico identification of a putative binding pocket of S100P to identify, synthesize and evaluate novel small molecules with the potential to selectively bind S100P and inhibit its activation of cell survival and metastatic pathways. The virtual screening of a drug-like database against the S100P model led to the identification of over 100 clusters of diverse scaffolds. A representative test set identified a number of structurally unrelated hits that inhibit S100P-RAGE interaction, measured by ELISA, and reduce in vitro cell invasion selectively in S100P-expressing pancreatic cancer cells at 10 µM. This study establishes a proof of concept in the potential for rational design of small molecule S100P inhibitors for drug candidate development.

Resolving Inflammation: Synthesis, Configurational Assignment, and Biological Evaluations of RvD1n-3 DPA.

New drugs that can resolve inflammation without immunosuppressive effects are at the medicinal chemistry frontier. Pro-resolving endogenously formed small molecules, that is, the resolvins, are excellent candidates displaying such bioactions. The first total synthesis of the specialized pro-resolving mediator RvD1n-3 DPA has been achieved using the underutilized sp3 -sp3 Negishi cross coupling reaction and an alkyne hydrosilylation-protodesilylation protocol. Biological evaluations revealed that this novel mediator displays low nanomolar pro-resolving properties and potently activates the human DRV1/GPR32 receptor. As such, this endogenous natural product is a lead compound for the development of novel immunoresolvents.

Total Synthesis of Aetheramide A.

The first total synthesis of the highly potent anti-HIV natural product aetheramide A was accomplished in 18 steps from four equally complex building blocks. The synthesis established the unknown configuration at C26 and used a configurationally labile ß-ketoester moiety for the self-adjustment of the configuration at a methyl branch. The pivotal macrolactamization was achieved by trapping a thermally generated acylketene which was derived from its corresponding dioxinone.