A New Chemotype of Chemically Tractable Nonsteroidal Estrogens Based on a Thieno[2,3-d]pyrimidine Core.

Despite continued interest in the development of nonsteroidal estrogens and antiestrogens, there are only a few chemotypes of estrogen receptor ligands. Using targeted screening in a ligand sensing assay, we identified a phenolic thieno[2,3-d]pyrimidine with affinity for estrogen receptor α. An efficient three-step synthesis of the heterocyclic core and structure-guided optimization of the substituents resulted in a series of potent nonsteroidal estrogens. The chemical tractability of the thieno[2,3-d]pyrimidine chemotype will support the design of new estrogen receptor ligands as therapeutic hormones and antihormones.

Influence of dityrosine nanotubes on the expression of dopamine and differentiation in neural cells.

In this study, we report the synthesis of self-assembled dityrosine nanotubes as a biologically functional scaffold and their interactions with neural cells. Quantum chemical methods were used to determine the forces involved in the self-assembly process. The physicochemical properties of the nanostructures relevant to their potential as bioactive scaffolds were characterized. The morphology, secondary structure, crystallinity, mechanical properties, and thermal characteristics of YY nanotubes were analyzed. The influence of these nanotubes as scaffolds for neural cells was studied in vitro to understand their effects on cell proliferation, morphology, and gene expression. The scanning electron microscopy and fluorescence confocal microscopy demonstrated the feasibility of nanotube scaffolds for enhanced adhesion to rat and human neural cells (PC12 and SH-SY5Y). Preliminary ELISA and qPCR analyses demonstrate the upregulation of dopamine synthesis and genes involved in dopamine expression and differentiation. The expression levels of DßH, AADC, VMAT2 and MAOA in SH-SY5Y cells cultured on the nanotube scaffolds for 7 days were elevated in comparison to the control cells.

Design and synthesis of C-aryl angular luotonins via a one-pot aza-Nazarov-Friedlander sequence and their Topo-I inhibition studies along with C-aryl vasicinones and luotonins.

A facile one-pot synthesis of C-ring substituted angular luotonins has been realized via a methanesulfonic acid mediated aza-Nazarov-Friedlander condensation sequence on quinazolinonyl enones. Topoisomerase I (topo-I) inhibition studies revealed that the angular luotonin library (7a-7l) and their regioisomeric analogs (linear luotonins, 8a-8l) are weak negative modulators, compared to camptothecin. These results would fare well for the design of topo-I-inert luotonins for non-oncological applications such as anti-fungal and insecticide lead developments. Surprisingly, the tricyclic vasicinones (9h, 9i, and 9j) showed better topo-I inhibition compared to pentacyclic C-aryl luotonins providing a novel pharmacophore for further explorations.