Polyphosphorous acid catalyzed cyclization in the synthesis of cryptolepine derivatives

11-Oxo-10,11-dihydroxy-SH-indolo[3,2,b]quinoline7-carboxylic acid was obtained specifically by polyphosphorous acid catalyzed cyclization with optimal reaction conditions. Biological assays showed that it potentially inhibits the proteasomal chymotrypsin-like activity in vitro and suppresses breast cancer cell growth.

Physiological levels of ATP negatively regulate proteasome function

Intracellular protein degradation by the ubiquitin-proteasome system is ATP dependent, and the optimal ATP concentration to activate proteasome function in vitro is -100 μM. IntraceUular ATP levels are generally in the low millimolar range, but ATP at a level within this range was shown to inhibit proteasome peptidase activities in vitro. Here, we report new evidence that supports a hypothesis that intracellular ATP at the physiological levels bidirectionally regulates 26S proteasome proteolytic function in the cell. First, we confirmed that ATP exerted bidirectional regulation on the 26S proteasome in vitro, with the optimal ATP concentration （between 50 and 100μM） stimulating proteasome chymotrypsin-like activities. Second, we found that manipulating intracellular ATP levels also led to bidirectional changes in the levels of proteasome-specific protein substrates in cultured cells. Finally, measures to increase intracellular ATP enhanced, while decreasing intraceHular ATP attenuated the ability of proteasome inhibition to induce cell death. These data strongly suggest that endogenous ATP within the physiological concentration range can exert a negative impact on proteasome activities, allowing the cell to rapidly upregulate proteasome activity on ATP reduction under stress conditions.

Molecular modeling for the interaction between proteasome beta 5 subunit and organotin compounds

It has been reported that organotins can inhibit the proteasomal chymotrypsin-like activity and induce cell death,but the interaction mode of organotins with proteasome has not been well defined.In this study,the IC50 of butyltins and phenyltins against the proteasomal activity and the nature of their inhibition were investigated.It was found that both mono-and di-organotins were weak,reversible inhibitors against the proteasome,while tributyltin and triphenyltin were potent,irreversible proteasome inhibitors.In silico studies using the reversible organotin proteasome inhibitors demonstrated a tight correlation of the estimated proteasomal inhibition constants(Ki) with the experimental IC50 values for proteasome inhibition.Furthermore,the Sn atom in TBT and TPT was found susceptible to form a coordinate bond with Thr 1 OY of the β5 subunit,which may account for the irreversible proteasome inhibition.The computational docking approach well predicted the inhibition nature of organotins toward the proteasomal chymotrypsin-like activity.This predictive model might aid in understanding the cytotoxic behavior of similar organometallic compounds.