Mini Reviews in Medicinal Chemistry - Volume 11, Issue 9, 2011

Epipolythiodioxopiperazines (ETPs), characterized by a unique bridged disulfide or polysulfide dioxopiperazine six-membered ring, occur in many fungi. Due to its broad spectra of bioactivities, ETPs have drawn wide attention in recent years. This review covers diverse natural sources that produce ETPs, the synthetic chemistry of ETPs and an overview of promising bioactivities exhibited by some well studied ETPs. The plausible biosynthetic hypotheses of ETPs and some new results on antitumor activity of ETPs are also reviewed.

Tyrosine kinase receptors have been shown to play an important role in epithelial thyroid tumor growth and angiogenesis. Thyroid cancers commonly present oncogene mutations involved in MAPK kinase pathway like BRAF and RET; they are also frequently dependent on VEGF stimuli. Preliminary clinical experiences suggest a promising role of sunitinib (a tyrosine kinase inhibitor) for the treatment of advanced thyroid cancers. This review deals with the available data on the effect of sunitinib in the treatment of metastatic, radioiodine refractory thyroid cancers. We also report our experience with the off-label use of sunitinib in such patients.

6-ethyl-chedeoxycholic acid (6E-CDCA) is a farnesoid X receptor (FXR) ligand endowed with agonistic activity under development for treatment of cholestatic liver diseases including primary biliary cirrhosis (PBC) and liverrelated metabolic disorders including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). FXR is a bile sensor that acts in coordination with other nuclear receptors to regulate essential steps of bile acid uptake, metabolism and excretion. 6E-CDCA has been investigated in preclinical models of cholestasis, liver fibrosis and diet-induced atherosclerosis. In a phase II clinical trial in patients with PBC, 6E-CDCA met the primary endpoint of a reduction in alkaline phosphatase levels but safety data indicated that the drug exacerbated pruritus, one of the main symptoms of PBC, suggesting that 6E-CDCA or FXR are mediators of pruritus in humans. Treatment of patients with diabetes and liver steatosis resulted in amelioration of insulin sensitivity despite a slight reduction in HDL and increased levels of LDL were observed. These side effects on bile acids and lipid metabolism were all predicted by pre-clinical studies, suggesting that potent FXR ligands hold promise but potential side effects might limit their development.

Spinal Cord Injury (SCI) is a complex process which leads to destruction of neuronal tissue and also vascular structure. After SCI many potentially toxic substances are activated and released into the injury site causing secondary degeneration. Erythropoietin (EPO) is a possible therapeutic strategy to treat SCI. Over the last decade attention has been focused on the molecular mechanisms underlying its neuroprotective effects. A major concern expressed by clinicians is that besides its protective effects, EPO also demonstrates hematopoietic activity and increases the risk for thrombosis after the systemic administration of multiple doses of this glycoprotein. Recently, tissue protective functions of EPO have been separated from its hematopoietic actions leading to the development of EPO derivatives and mimetics. Neuroscientists are focusing on recombinant human EPO (rhEPO) and its non-erythropoietic derivatives, investigating their anti-apoptotic potential and anti-inflammatory function as well as their role in restoring vascular integrity. Carbamylated erythropoietin (CEPO) and asialo erythropoietin (AsialoEPO) are structural derivatives of EPO that have no effect on erythrocyte mass whereas they retain its neuroprotective effects. In this review article, we provide a short overview of the animal studies on rhEPO and its derivatives in experimental models of SCI. Both the efficacy and the safety profile of EPO-structural and functional variants are still to be demonstrated in patients. Further clinical studies should reveal whether derivatives and variants of erythropoietin provide any benefits over the use of rhEPO in the treatment of spinal cord injury observed in the experimental studies.

Dihydropyrazole, a small bioactive molecule, is a prominent structural motif found in numerous pharmaceutically active compounds. The chiral dihydropyrazole structure has been demonstrated to bear important biological activities such as anticancer, antimicrobial, antimalarial, antinociceptive, antiviral, antitubercular, antiinflammatory, anticonvulsant and steroidal, and can also act as MAO inhibitors, CB1 receptor antagonists and nitric oxide synthase inhibitors. The review describes the latest advances in the synthesis of dihydropyrazole derivatives incorporating physiologically active substances. It is the first attempt at a general and systematic account of the extensive literature data on this subject.