Bromodomain-containing protein 4 ( BRD4 ), an epigenetic reader, has been recognized as a target with therapeutic potential in several types of cancer and cardiovascular diseases. In this study, a series of 1,7-dibenzyl substituted theophylline derivatives were synthesized and their BRD4 inhibitor activities were evaluated. Most of the compounds showed detectable activities with IC 50 values in the range of 2.51–10.50 µM. Therein, compound 6e showed significant selectivity for two bromodomains of BRD4, the inhibition of BD1 ( IC 50 = 2.51 µM ) was 20 times greater than that of BD2 (IC 50 > 50 µM). Similarly, compounds 6b – 6d, 6f, 6j and 8a also displayed favorable BRD4-BD1 selectivity. In addition, molecular docking of compound 6e was performed to predict conceivable binding patterns of it with BRD4, prompting residue Ile146 might be crucial to the observed selectivity of BRD4-BD1. These findings will be of great value and significance for the development of novel BRD4-BD1 inhibitors.

C44H76CaO19S2, monoclinic, C2 (no. 5), a = 25.5446(14) Å, b = 7.38025(19) Å, c = 18.8450(10) Å, β = 136.543(10)°, Z = 2, V = 2443.6(4) Å3, Rgt(F) = 0.0419, wRref(F2) = 0.1161, T = 293(2) K.

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C43H78CaO22S2, monoclinic, P21 (no. 4), a = 18.2539(3) Å, b = 15.3118(3) Å, c = 18.3718(4) Å, β = 91.2637(17)°, Z = 4, V = 5133.65(18) Å3, Rgt(F) = 0.0544, wRref(F2) = 0.1622, T = 293(2) K.