Store-operated calcium (Ca 2+ ) entry is an important homeostatic mechanism in cells, whereby the release of Ca 2+ from intracellular endoplasmic reticulum stores triggers the activation of a Ca 2+ influx pathway. Mediated by Orai1, this Ca 2+ influx has specific and essential roles in biological processes as diverse as lactation to immunity. Although pharmacological inhibitors of this Ca 2+ influx mechanism have helped to define the role of store-operated Ca 2+ entry in many cellular events, the lack of isoform specific modulators and activators of Orai1 has limited our full understanding of these processes.Here we report the identification and synthesis of an Orai1 activity enhancer that concurrently potentiated Orai1 Ca 2+ -dependent inactivation (CDI). This unique enhancer of Orai1 had only a modest effect on Orai3 with weak inhibitory effects at high concentrations in intact MCF-7 breast cancer cells. The Orai1 enhancer heightened vascular smooth muscle cell migration induced by platelet-derived growth factor and the unique store-operated Ca 2+ entry pathway present in skeletal muscle cells. These studies show that IA65 is an exemplar for the translation and development of Orai isoform selective agents. The ability of IA65 to activate CDI demonstrates that agents can be developed that can enhance Orai1-mediated Ca 2+ influx but avoid the cytotoxicity associated with sustained Orai1 activation. IA65 and/or future analogues with similar Orai1-and CDIactivating properties could function to fine-tune physiological processes important in specific disease states, such as cellular migration and immune cell function.

A series of phenstatin/isocombretastatin–chalcones were synthesized and screened for their cytotoxic activity against various human cancer cell lines. Some representative compounds exhibited significant antiproliferative activity against a panel of sixty human cancer cell lines of the NCI, with GI50 values in the range of 0.11 to 19.0 μM. Three compounds (3b, 3c and 3e) showed a broad spectrum of antiproliferative efficacy on most of the cell lines in the sub-micromolar range. In addition, all the synthesized compounds (3a–l and 4a–l) displayed moderate to excellent cytotoxicity against breast cancer cells such as MCF-7 and MDA-MB-231 with IC50 values in the range of 0.5 to 19.9 μM. Moreover, the tubulin polymerization assay and immunofluorescence analysis results suggest that some of these compounds like 3c and 3e exhibited significant inhibitory effect on the tubulin assembly with an IC50 value of 0.8 μM and 0.6 μM respectively. A competitive binding assay suggested that these compounds bind at the colchicine-binding site of tubulin. A cell cycle assay revealed that these compounds arrest at the G2/M phase and lead to apoptotic cell death. Furthermore, this was confirmed by Hoechst 33258 staining, activation of caspase 9, DNA fragmentation, Annexin V-FITC and mitochondrial membrane depolarization. Molecular docking studies indicated that compounds like 3e occupy the colchicine binding site of tubulin.

Fused β-carbolines were synthesized via a visible light photoredox catalyzed oxidation/[3+2] cycloaddition/oxidative aromatization reaction cascade in batch and flow microreactors. Several structurally diverse heterocyclic scaffolds were obtained in good yields by coupling of tetrahydro-β-carbolines with a variety of dipolarophiles under photoredox multiple C-C bond forming events. The photoredox coupling of tetrahydro-β-carboline with 1,4-benzoquinone was significantly faster in continuous flow microreactor and the desired products were obtained in higher yields compared to batch reactor.

An operationally simple, one-pot, two-step cascade method has been developed to afford biologically important fused 1,2,3-triazolo-heterocyclic scaffolds from 2-alkynyl aryl(heteroaryl) aldehydes and phenacyl azides. This unique atom economical transformation engages four reactive centers (aldehyde, alkyne, active methylene, and azide) under metal-free catalysis.

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