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[Display omitted] • A series of nucleoside derivatives bearing sulfonamide scaffold as potent and selective PRMT5 inhibitors were designed and synthesized. • The representative compound 23n was identified as a potent, selective and SAM-competitive PRMT5 inhibitor with an IC 50 value of 8 nM. • Prodrug 36 was designed by using the Trimethyl Lock prodrug strategy and exhibited largely improved antiproliferative activity against Z-138 and MOLM-13 cell lines than compound 23n. Protein arginine methyltransferase 5 (PRMT5) is a promising target for the treatment of malignant tumors. The discovery of nucleoside-derived inhibitors against PRMT5 with novel scaffold has been challenging. Herein, we report our effort on the design and synthesis of nucleoside derivatives bearing sulfonamide scaffold as potent PRMT5 inhibitors. The representative compound 23n was identified as a potent and selective PRMT5 inhibitor with an IC 50 value of 8 nM. Molecular docking study demonstrated the binding mode of compound 23n and illustrated its inhibitory activity to PRMT5. The Trimethyl Lock prodrug strategy was used to afford prodrug 36 with lower polarity which could rapidly release the active compound 23n after entering the tumor cells. Cell-based assays revealed that the prodrug 36 restrained the proliferation of Z-138 and MOLM-13 cells and suppressed methylation of PRMT5 substrate more potently than 23n. Additionally, both compound 23n and 36 exerted antiproliferative effects against Z-138 cells mainly by inducing apoptosis effectively rather than arresting cell cycle. Thus, compounds 23n and 36 represent a series of potent PRMT5 inhibitor with novel scaffold. [ABSTRACT FROM AUTHOR]

[Display omitted] • A novel series of p300 bromodomain inhibitors were discovered and more tumor cell lines sensitive to p300/CBP bromodomain inhibition were also identified. • Compound B4 showed potent p300 bromodomain inhibitory activity and improved proliferation inhibition on sensitive tumor cells than CCS1477. • Compound B4 could suppress the expression of c-Myc and reduce H3K27 acetylation significantly. • Compound B4 is metabolic stabilizable in human liver microsomes and has no hERG risk. p300/CBP bromodomain plays an important role in transcriptional regulation, and its overexpression is closely related to various diseases such as cancers. Two inhibitors of this target are currently in clinical trials but only CCS1477 (A1) have been published with the chemical structure. Herein, we modified the structure of CCS1477 based on the principle of bioisosterism and reasonable scaffold hopping, and discovered a series of new p300 bromodomain inhibitors with improved potency. More tumor cell lines sensitive to p300/CBP bromodomain inhibition were also identified. Among our new inhibitors, (R)-5-methylpyrrolidin-2-one derivitive B4 was the most potent one which showed comparable inhibitory activity against p300 (IC 50 = 0.060 μM) as lead A1 (IC 50 = 0.064 μM) at molecular level, and performed more potent proliferation inhibitory activities on various tumor cells than A1. Further we found that compound B4 had the high cell permeability and overcame the defect of the high efflux rate of A1 , which could also explain the possible reason why B4 showed more potent inhibitory activities on sensitive tumor cells than lead A1. Western blotting analysis proved the target effects that B4 could suppress the expression of c-Myc and reduce H3K27 acetylation significantly. Liver microsomal metabolic stability assay and hERG channel inhibition evaluation illustrate compound B4 is metabolic stabilizable in human liver microsomes and has no hERG risk, which further demonstrate the good drug-likeness of B4. Therefore, compound B4 is a promising compound for further optimization and development. [ABSTRACT FROM AUTHOR]