Molecular mechanism of tanshinone IIA and cryptotanshinone in platelet anti-aggregating effects: an integrated study of pharmacology and computational analysis.

Tanshinone IIA and cryptotanshinone are two pharmacologically active diterpenoids extracted from the roots of Salvia milthiorriza Bunge, a plant used in Chinese traditional medicine for the treatment of some cardiovascular and cerebrovascular disease. Until now, the molecular mechanisms of action of these two diterpenoids on platelets are partially known. To clarify this aspect, here we utilized an integrated study of pharmacology and computational analysis. Our results demonstrate that cryptotanshinone is able to inhibit in a concentration dependent manner the rat platelet aggregation and also is endowed of Gi-coupled P2Y12 receptor antagonist as demonstrated by docking studies. This computational method was also performed for tanshinone IIA demonstrating even for this diterpenoid an interaction with the same receptor. The findings from our study enable a better understanding of tanshinone IIA and cryptotanshinone biological properties, which could ultimately lead to the development of novel pharmaceutical strategies for the treatment and/or prevention of some cardiovascular disease

Identification of the key structural elements of a dihydropyrimidinone core driving toward more potent Hsp90 C-terminal inhibitors

Hsp90 C-terminal modulation represents an attractive strategy for the development of potent and safer antitumor compounds. Continuing our investigation on DHPM type inhibitors here we report a new set of potent C-terminal ligands which allowed us to identify the key structural features crucial for the biological activity

A Novel Potent Nicotinamide Phosphoribosyltransferase Inhibitor Synthesized via Click Chemistry

The inhibition of NAD synthesis or salvage pathways has been proposed as a novel target for antitumoral drugs. Two molecules with this mechanism of action are at present undergoing clinical trials. In searching for similar novel molecules, we exploited copper-catalyzed [3 þ 2] cycloaddition between azides and alkynes (click chemistry) to synthesize 185 novel analogues. The most promising compound displays an IC50 for cytotoxicity in vitro of 3.8 ( 0.3 nM and an IC50 for NAD depletion of 3.0 ( 0.4 nM. Herein, we strengthen previous data suggesting that this class of compounds induces autophagic cell death. In addition to characterizing this compound and providing a rationale via molecular docking, we reinforce the excellent potential of click chemistry for rapidly generating structure-activity relationships and for drug screening

3,4-dihydropyrimidin-2(1H)-one as a useful scaffold for Hsp90 C-terminal inhibition

Heat shock protein 90 (Hsp90) is a highly conserved molecular chaperone that plays a crucial role in stabilizing and activating more than 200 “client proteins”, many of which are involved in signal transduction, cell cycle regulation and apoptosis [1]. Therefore a considerable interest in developing chemotherapeutic drugs that specifically disrupt the function of Hsp90 has aroused. Recently several N-terminal Hsp90 inhibitors have been identified and are currently in clinical trials, while only few C-terminal inhibitors have been reported. Here we describe the synthesis of 3,4- dihydropyrimidin-2(1H)-ones performed through a microwave-assisted Biginelli reaction [2]. These compounds have been extensively evaluated for their biological activity using several assays including surface plasmon resonance (SPR), inhibition of cell proliferation and cell cycle arrest, depletion of client proteins. From these studies a new promising molecule has emerged. In order to identify the binding site on the target protein we have performed limited proteolysis experiments which suggested the interaction of the compound with the C-terminal domain of Hsp90 and a binding mode has been proposed by molecular docking