Triptolide

For a long time, there have been no studies on the structure-activity relationship of the D-ring of triptolide except for two patents, describing some butenolide-modified triptolide analogues without any biological activity data, and our previous paper, reporting that an analogue (compound 6) with a five-membered unsaturated lactam ring has the same activity as the natural triptolide. So the structure-activity relationship of the D-ring is still obscure. To explore whether the five-membered unsaturated lactone ring of triptolide is completely critical to its anticancer activity, compound 3,havinga transposition butenolide, compound 4,which has a furan ring replacing the five-membered unsaturated lactone ring, and compound 5 without the planar D-ring were synthesized for SAR studies of the D-ring. The SAR studies of these tripolide analogues were performed by using ovary (SK-OV-3) and prostate (PC-3) tumor cells.

This study was designed to investigate the potential interactions between NRs and triptolide, triptonide and triptriolide. 12 NRs were first screened through docking calculations to identify the putative molecular targets of triptolide. Then themost likely target ERa-LBD was expressed and purified in vitro. The binding capacities between ERa-LBD and three compounds were determined by Surface Plasmon Resonance (SPR) and Isothermal Titration Calorimetry (ITC) analyses. The results were further validated using reporter gene assays. These data revealed ERa act as a previously unknown binding protein of triptolide and triptonide which may provide valuable information for studying the mechanisms and structure–function relationships of these chemicals in vivo.

Preclinical studies have revealed that triptolide has strong effects against cancer, collagen-induced arthritis, skin allograft rejection and bone marrow transplantation. Several derivatives of triptolide have entered human clinical trials for cancer and other diseases. However, the clinical uses of triptolide and its derivatives have been limited by their toxicity. Triptolide induced cumulative testis toxicity in some experimental and clinical research studies. The mechanisms of testicular injury induced by triptolide are not characterized well.