Multitarget, Selective Compound Design Yields Picomolar Inhibitors of a Kinetoplastid Pteridine Reductase 1

The optimization of compounds with multiple targets is a difficult multidimensional problem in the drug discovery cycle. Here, we present a systematic, multidisciplinary approach to the development of selective anti-parasitic compounds. Computational fragment-based design of novel pteridine derivatives along with iterations of crystallographic structure determination allowed for the derivation of a structure-activity relationship for multitarget inhibition. The approach yielded compounds showing picomolar inhibition of T. brucei pteridine reductase 1 (PTR1), nanomolar inhibition of L. major PTR1, and selective submicromolar inhibition of parasite dihydrofolate reductase (DHFR) versus human DHFR. Moreover, by combining design for polypharmacology with a property-based on-parasite optimization, we found three compounds that exhibited micromolar EC50 values against T. brucei brucei, whilst retaining their target inhibition. Our results provide a basis for the further development of pteridine-based compounds, and we expect our multitarget approach to be generally applicable to the design and optimization of anti-infective agents.

Efficient Synthesis and Biological Evaluation of 6-Trifluoroethoxy Functionalized Pteridine Derivatives as EGFR Inhibitors

Background: Pteridine-based scaffolds have been widely prevalent in pharmaceuticals, such as kinase inhibitors targeting EGFR, FLT3 and PI3K/mTOR, which are attractive targets for anticancer therapy. Objective: This work aimed to design and synthesize 6-2,2,2-trifluoroethoxy functionalized pteridine-based derivatives for investigation of their anti-cancer activities as EGFR inhibitor. Method: Pteridine-based derivatives were synthesized in 6 steps involving amination, bromination, cyclization, alkoxylation, chlorination and coupling reactions. Cellular anti-proliferative activities and inhibition activities on EGFR signaling of these pteridine derivatives in vitro were determined by the MTT assay and western blot analysis, respectively. Molecular docking simulation studies were carried out by the crystallographic structure of the erlotinib/EGFR kinase domain [Protein Data Bank (PDB) code: 1M17]. Results: The compound 7m, with IC50 values of 27.40 μM on A549 cell line, exhibited comparable anti-proliferative activity relative to the positive control. Besides western blots showed its obvious down-regulation of p-EGFR and p-ERK expression at 0.8 μM. Molecular docking model displayed a hydrogen bond between Met-769 amide nitrogen and N-1 in pteridine motif of 7m which lay at the ATP binding site of EGFR kinase domain. Conclusion: The inhibition of 7m on cellular growth was comparable to that of the positive control. The inhibitory activities of 7m on EGFR phosphorylation and ERK phosphorylation in A549 cell line were relatively superior to that of the positive control. Both results suggested that the anti-proliferative activity of 7m against A549 cell line was caused by inhibition of EGFR signaling pathway, providing a new perspective for modification on pteridine-based derivatives as EGFR inhibitor.

Exploring the scope of DBU-promoted amidations of 7-methoxycarbonylpterin

The synthetic utility of pterins is often hampered by the notorious insolubility of this heterocycle, slowing the development of medicinally relevant pteridine derivatives. Reactions which expedite the development of new pterins are thus of great importance. Through a dual role of diazabicycloundecene (DBU), 7-carboxymethylpterin is converted to the soluble DBU salt, with additional DBU promoting an ester-to-amide transformation. We have explored this reaction to assess its scope and identify structural features in the amines which significantly affect success, monitored the reaction kinetics using a pseudo-first order kinetics model, and further adapted the reaction conditions to allow for product formation in as little as 5 min, with yields often >80%.

Pteridine derivatives: novel low-molecular-weight organogelators and their piezofluorochromism

Here, π-conjugated compounds based on pteridine derivatives were synthesized and their self-assembling behaviors in a variety of organic solvents and piezofluorochromism were studied.

Body coloration and mechanisms of colour production in Archelosauria: The case of deirocheline turtles

Animal body coloration is a complex trait resulting from the interplay of multiple colour-producing mechanisms. Increasing knowledge of the functional role of animal coloration stresses the need to study the proximate causes of colour production. Here we present a description of colour and colour producing mechanisms in two non-avian archelosaurs, the freshwater turtles Trachemys scripta and Pseudemys concinna. We compare reflectance spectra; cellular, ultra-, and nano-structure of colour-producing elements; and carotenoid/pteridine derivatives contents in the two species. In addition to xanthophores and melanocytes, we found abundant iridophores which may play a role in integumental colour production. We also found abundant dermal collagen fibres that may serve as thermoprotection but possibly also play role in colour production. The colour of yellow-red skin patches results from an interplay between carotenoids and pteridine derivatives. The two species differ in the distribution of pigment cell types along the dorsoventral head axis, as well as in the diversity of pigments involved in colour production, which may be related to visual signalling. Our results indicate that archelosaurs share some colour production mechanisms with amphibians and lepidosaurs, but also employ novel mechanisms based on the nano-organization of the extracellular protein matrix that they share with mammals.