(-)-epigallocatechin gallate derivatives for inhibiting proteasome

Abstract

(-)-EGCG, the most abundant catechin, was found to be chemopreventive and anticancer agent. However, (-)-EGCG has at least one limitation: it gives poor bioavailability. This invention provides compounds of generally formulae below, wherein R₁₁, R₁₂, R₁₃, R₂₁, R₂₂, R₂, R₃, and R₄ are each independently selected from the group consisting of -H, and C₁ to C₁₀ acyloxyl group; and R₅ is selected from the group consisting of -H, C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkynyl, C₃-C₇-cycloalkyl, phenyl, benzyl and C₃-C₇-cycloalkenyl, whereas each of the last mentioned 7 groups can be substituted with any combination of one to six halogen atoms; at least one of R₁₁, R₁₂, R₁₃, R₂₁, R₂₂, R₂, R₃ and R₄ is -H, which were found to be more potent than their non-protected counterparts, which can be used as proteasome inhibitors to reduce tumor cell growth. (-)-EGCG是最丰富的儿茶素，其被认为是化学预防及抗癌剂。然而，(-)-EGCG具有至少一个局限性：其生物利用度差。本发明提供了具有下列通式的化合物，其中R₁₁, R₁₂, R₁₃, R₂₁, R₂₂, R₂, R₃,和R₄ 均各自独立地选自-H和C₁ to C₁₀酰氧基；以及R₅选自-H、C₁-C₁₀烷基、 C₂-C₁₀烯基、C₂-C₁₀炔基、C₃-C₇环烷基、苯基、苯甲基和C₃-C₇环烯基， 同时，最后提到的7个基团中的每一个都可用1到6个卤素原子的任 意组合取代；R₁₁, R₁₂, R₁₃, R₂₁, R₂₂, R₂, R₃和R₄中至少有一个是 -H，这些化合物被证实比其用作蛋白酶体抑制剂以减少肿瘤细胞生长的未被保护对应物更有效。