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ABCB1-mediated multidrug resistance (MDR) is a principal obstacle for successful cancer chemotherapy. A series of pyrimidine-based hybrid molecules containing 1,2,3-triazole moiety were evaluated for their reversal activities against MDR. The majority of target compounds displayed moderate to great reversal potency. Among these compounds, compound 25 displayed the most potent reversal activity, about 7-fold more potent than Verapamil (VRP). Further mechanism studies revealed that compound 25 could obviously reverse paclitaxel (PTX) resistance in SW620/AD300 cells by increasing accumulation and extending maintenance of PTX. Our findings indicate that the 1,2,3-triazole-pyrimidine-based derivatives may serve as an interesting lead for the development of new potent and efficacious ABCB1-dependent MDR modulators. [ABSTRACT FROM AUTHOR]

Histone lysine specific demethylase 1 (LSD1) plays an important role in epigenetic modifications, and aberrant expression of LSD1 predicts tumor progression and poor prognosis in human esophageal cancers. In this study, a series of LSD1 inhibitors were synthesized and proved to be highly potent against human esophageal squamous cell carcinoma (ESCC). Our data showed that these LSD1 inhibitors selectively suppressed the viability of esophageal cancer cell line (EC-109) bearing overexpressed LSD1. Among these, compound LPE-1 (LSD1 IC 50 = 0.336 ± 0.003 μM) significantly suppressed proliferation, induced apoptosis, arrested cell cycle of EC109 cells at G2/M phase, and caused changes of the associated protein markers correspondingly. We also found that compound LPE-1 potently inhibited the migration and invasion of EC-109 cells. Docking studies showed that the cyano group formed hydrogen bonds with Val811 and Thr810. Additionally, the thiophene moiety formed arene-H interaction with Trp761 residue. In vivo studies showed that compound LPE-1 inhibited tumor growth of xenograft models bearing EC-109 without obvious toxicity. Collectively, our findings indicate that LSD1 may be a potential therapeutic target in ESCC, and compound LPE-1 could serve as a lead compound for further development for anti-ESCC drug discovery. [ABSTRACT FROM AUTHOR]