Synthesis and Anticancer Activity of Epipolythiodiketopiperazine Alkaloids.

Synthesis and Anticancer Activity of Epipolythiodiketopiperazine Alkaloids.

Chem Sci. 2013 Apr 1; 4(4): 1646-1657
Boyer N, Morrison KC, Kim J, Hergenrother PJ, Movassaghi M

The epipolythiodiketopiperazine (ETP) alkaloids are a highly complex class of natural products with potent anticancer activity. Herein, we report the application of a flexible and scalable synthesis, allowing the construction of dozens of ETP derivatives. The evaluation of these compounds against cancer cell lines in culture allows for the first expansive structure-activity relationship (SAR) to be defined for monomeric and dimeric ETP-containing natural products and their synthetic cognates. Many ETP derivatives demonstrate potent anticancer activity across a broad range of cancer cell lines, and kill cancer cellsviainduction of apoptosis. Several traits thatbode well for the translational potential of the ETP class of natural products includeconcise and efficient synthetic access, potent induction of apoptotic cell death, activity against a wide range of cancer types, and a broad tolerance for modifications at multiple sitesthat should facilitate small-molecule drug development, mechanistic studies, and evaluation in vivo. HubMed – drug

Effect of antimalarial drug primaquine and its derivatives on the ionization potential of hemoglobin: A QM/MM study.

Medchemcomm. 2013 Aug 1; 4(8): 1145-1147
Liu H, Ding Y, Walker LA, Doerksen RJ

We used quantum mechanics/molecular mechanics calculations to test if antimalarial primaquine (PQ) and its derivatives aid the conversion of hemoglobin to methemoglobin by binding to hemoglobin and merely lowering hemoglobin’s ionization potential (IP). Our results showed that PQ and its derivatives do not significantly lower the hemoglobin IP, disproving the hypothesis. HubMed – drug

Discovery of Protein-Protein Interaction Inhibitors of Replication Protein A.

ACS Med Chem Lett. 2013 Jul 11; 4(7): 601-605
Patrone JD, Kennedy JP, Frank AO, Feldkamp MD, Vangamudi B, Pelz NF, Rossanese OW, Waterson AG, Chazin WJ, Fesik SW

Replication Protein A (RPA) is a ssDNA binding protein that is essential for DNA replication and repair. The initiation of the DNA damage response by RPA is mediated by protein-protein interactions involving the N-terminal domain of the 70 kDa subunit with partner proteins. Inhibition of these interactions increases sensitivity towards DNA damage and replication stress and may therefore be a potential strategy for cancer drug discovery. Towards this end, we have discovered two lead series of compounds, derived from hits obtained from a fragment-based screen, that bind to RPA70N with low micromolar affinity and inhibit the binding of an ATRIP-derived peptide to RPA. These compounds may offer a promising starting point for the discovery of clinically useful RPA inhibitors. HubMed – drug

Evaluating the resistance of eimeria spp. Field isolates to anticoccidial drugs using three different indices.

Iran J Parasitol. 2013 Apr; 8(2): 234-41
Arabkhazaeli F, Modrisanei M, Nabian S, Mansoori B, Madani A

In this study, the presence of resistance to diclazuril, amprolium+ethopabate and salinomycin, representing some of the commonest anticoccidials in Iran’s poultry industry, against three mixed Eimeria field isolates were investigated.Three Eimeria field isolates, collected from typical broiler farms in Iran, were propagated once, inoculated to 480 broilers, comprising 30 chicks in each treatment. The non-medicated or medicated diets containing one of the above mentioned anticoccidials were provided ad-lib. Drug efficacy was determined using the Global index (GI), Anticoccidial Sensitivity Test (AST) and Optimum Anticoccidial Activity (OAA).None of the field isolates were fully sensitive to the selected anticoccidials. All isolates showed reduced sensitivity/partial resistance to salinomycin. Resistance to amprolium+ethopabate was evident and partial to complete resistance was recorded for diclazuril.Limited efficacy of the selected anticoccidials is obvious. Considering the cost of continuous use of anticoccidials in the field, altering the prevention strategy and rotation of the anticoccidials with better efficacy, would prevent further economic losses induced by coccidiosis. HubMed – drug