ChemInform Abstract: Synthesis and Biological Activity of Some New Bis(2‐pyrazolin‐3‐yl) benzenes and ‐pyridines.

Reddy, D. Bhaskar; Seshamma, T.; Seenaiah, B.; Reddy, M. V. Ramana

doi:10.1002/chin.199112193

Cited by 1 publication

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“…The synthesis of bis-chalcones 4a–4s is outlined in the following reaction scheme (Figure 1). The bis-chalcones were prepared by a base-catalyzed Claisen–Schmidt condensation between 2,6-diacetylpyridine (1 equivalent) and the appropriate aryl aldehyde (2.1 equivalents) using either method a or b. Bis-chalcones 4a, 4d, 4f [25], 4g [26] 4l [27] and 4p [28] were previously cited in the literature. More detailed description of the synthesis along with the spectral data for each compound can be found in the experimental section of the Supplemental Materials.…”

Section: Resultsmentioning

confidence: 99%

Novel Curcumin Inspired Bis-Chalcone Promotes Endoplasmic Reticulum Stress and Glioblastoma Neurosphere Cell Death

Sansalone

Véliz

Myrthil

et al. 2019

Cancers

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Glioblastoma (GBM) has a dismal prognosis and successful elimination of GBM stem cells (GSCs) is a high-priority as these cells are responsible for tumor regrowth following therapy and ultimately patient relapse. Natural products and their derivatives continue to be a source for the development of effective anticancer drugs and have been shown to effectively target pathways necessary for cancer stem cell self-renewal and proliferation. We generated a series of curcumin inspired bis-chalcones and examined their effect in multiple patient-derived GSC lines. Of the 19 compounds synthesized, four analogs robustly induced GSC death in six separate GSC lines, with a half maximal inhibitory concentration (IC50) ranging from 2.7–5.8 μM and significantly reduced GSC neurosphere formation at sub-cytotoxic levels. Structural analysis indicated that the presence of a methoxy group at position 3 of the lateral phenylic appendages was important for activity. Pathway and drug connectivity analysis of gene expression changes in response to treatment with the most active bis-chalcone 4j (the 3,4,5 trimethoxy substituted analog) suggested that the mechanism of action was the induction of endoplasmic reticulum (ER) stress and unfolded protein response (UPR) mediated cell death. This was confirmed by Western blot analysis in which 4j induced robust increases in CHOP, p-jun and caspase 12. The UPR is believed to play a significant role in GBM pathogenesis and resistance to therapy and as such represents a promising therapeutic target.

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