A non-cytotoxic N-dehydroabietylamine derivative with potent antimalarial activity.

Malaria caused by the Plasmodium parasites continues to be an enormous global health problem owing to wide spread drug resistance of parasites to many of the available antimalarial drugs. Therefore, development of new classes of antimalarial agents is essential to effectively treat malaria. In this study, the efficacy of naturally occurring diterpenoids, dehydroabietylamine and abietic acid, and their synthetic derivatives was assessed for antimalarial activity. Dehydroabietylamine and its N-trifluoroacetyl, N-tribromoacetyl, N-benzoyl, and N-benzyl derivatives showed excellent activity against P. falciparum parasites with IC50 values of 0.36 to 2.6 µM. Interestingly, N-dehydroabietylbenzamide showed potent antimalarial activity (IC50 0.36), and negligible cytotoxicity (IC50 >100 µM) to mammalian cells; thus, this compound can be an important antimalarial drug. In contrast, abietic acid was only marginally effective, exhibiting an IC50 value of ~82 µM. Several carboxylic group-derivatives of abietic acid were moderately active with IC50 values of ~8.2 to ~13.3 µM. These results suggest that a detailed understanding of the structure-activity relationship of abietane diterpenoids might provide strategies to exploit this class of compounds for malaria treatment.

2-Amino-5-benzoyl-4-phenylthiazoles: Development of potent and selective adenosine A1 receptor antagonists.

A series of 2-amino-5-benzoyl-4-phenylthiazole derivatives was investigated in radioligand binding studies at adenosine receptor (AdoR) subtypes with the goal to obtain potent and A(1)-selective antagonists. Acylation of the 2-amino group was found to be crucial for high A(1) affinity. The best compound of the present series was 2-benzoylamino-5-p-methylbenzoyl-4-phenylthiazole (16 m) showing a K(i) value of 4.83 nM at rat and 57.4 nM at human A(1) receptors combined with high selectivity versus the other AdoR subtypes. The compound behaved as an antagonist in GTP shift assays at A(1) receptors. Compound 16 m may serve as a new lead structure for the development of second-generation non-xanthine-derived A(1) antagonists which have potential as novel drugs.

Identifying the structure-activity relationship of leelamine necessary for inhibiting intracellular cholesterol transport.

Leelamine is an anticancer chemotherapeutic agent inhibiting intracellular cholesterol transport. Cell death mediated by leelamine occurs due to the lysosomotropic property of the compound, its accumulation in the lysosome, and inhibition of cholesterol transport leading to lack of availability for key processes required for functioning of cancer cells. The present study dissects the structure-activity-relationship of leelamine using synthesized derivatives of leelamine and abietic acid, a structurally similar compound, to identify the moiety responsible for anti-cancer activity. Similar to leelamine, all active derivatives had an amino group or a similar moiety that confers a lysosomotropic property to the compound enabling its accumulation in the lysosome. Active derivatives inhibited intracellular cholesterol transport and hindered xenografted melanoma tumor development without obvious systemic toxicity. In silico studies suggested that active derivatives accumulating in lysosomes bound to NPC1, a protein responsible for cholesterol export from the lysosome, to inhibit its activity that then caused accumulation, and lack of cholesterol availability for other key cellular activities. Thus, active derivatives of leelamine or abietic acid maintained lysosomotropic properties, bound to NPC1, and disrupted cellular cholesterol transport as well as availability to retard tumor development.

New insight into adenosine receptors selectivity derived from a novel series of [5-substituted-4-phenyl-1,3-thiazol-2-yl] benzamides and furamides.

A series of [5-substituted-4-phenyl-1,3-thiazol-2-yl] benzamide and furamide analogues were investigated in radioligand binding studies at adenosine receptor subtypes with an aim to obtain potent and selective adenosine receptor ligands. Benzamide and furamide linked to thiazole was found to be crucial for high adenosine receptor affinity. The most potent compound indentified in this study was 5d with low nanomolar affinity for all four adenosine receptor subtypes. Compounds 5a and 5g showed moderate selectivity for A2A adenosine receptors. Molecular docking versus all four human adenosine receptors combined with membrane molecular dynamics studies were performed to rationalise the peculiar selectivity profile of 5d antagonist.

Targeting the MAPK pathway in melanoma: why some approaches succeed and other fail.

The Mitogen Activated Protein Kinase (MAPK) pathway plays a key role in melanoma development making it an important therapeutic target. In normal cells, the tightly regulated pathway relays extracellular signals from cell membrane to nucleus via a cascade of phosphorylation events. In melanomas, dysregulation of the MAPK pathway occurs frequently due to activating mutations in the B-RAF and RAS genes or other genetic or epigenetic modifications, leading to increased signaling activity promoting cell proliferation, invasion, metastasis, migration, survival and angiogenesis. However, identification of ideal pathway member to therapeutically target for maximal clinical benefit to melanoma patients remains a challenge. This review provides an overview of the obstacles faced targeting the MAPK pathway and why certain therapeutic approaches succeed while others fail. The review summarizes the roles played by the proteins, therapeutic potential and the drugs available to target each member of the pathway as well as concerns related to each. Potential for targeting multiple points and inhibiting other pathways along with MAPK inhibition for optimal efficacy are discussed along with explanations for development of drug resistance, which includes discussions related to cross-talk between pathways, RAF kinase isoform switching and phosphatase deregulation. Finally, the use of nanotechnology is reviewed as an approach to target the MAPK pathway using both genetic and pharmacological agents simultaneously targeting multiple points in the pathway or in combination with other cascades.