(-)-Epigallocatechin gallate derivatives for inhibiting proteasome

The invention provides (-)-EGCG derivatives that overcome the low absorption of the natural product. The compounds of the invention exhibit enhanced cellular uptake, induce apoptosis and exhibit potent activity in tumor xenograft models at concentrations where the natural product (-)-EGCG is inactive. The compounds may have utility as prophylactic, chemopreventive and chemotherapeutic agent.

The invention provides a process of manufacture of the preferred compounds. The process of the invention provides pure crystalline (-)-epigallocatechin-3-gallate, as the major product.

Catechins are natural product extracts. The Catechins (-)-epigallocatechin-3-gallate (EGCG), (-)-epigallocatechin (EGC), epicatechin-3-gallate (ECG) and (-)epicatechin (EC) are the principal polyphenolic constituents of green tea.

(-)-EGCG is the most abundant catechin, which has been reported to be chemopreventive at high doses and exhibit antibacterial, antiviral, and hypocholesterolemic effects. However, (-)-EGCG has low bioavailability. In one study (-)-EGCG showed 0.012% bioavailability following oral administration in rodent. This property renders these natural products attractive neutraceuticals but ineffective therapeutics, except at very high doses.

The preferred compounds of the invention are characterized as pro-drugs. The compounds undergo cellular uptake and metabolize to the natural product intracellularly. The preclinical and clinical safety and tolerability of the natural product (-)-EGCG has been thoroughly investigated. The compounds exhibit potent anti-tumor activity in clinically relevant rodent models.