Mini Reviews in Medicinal Chemistry - Volume 7, Issue 4, 2007

Microwave irradiation has been used to enhance organic reactions since the mid 80's, its use within the field of medicinal chemistry is not so widely evident in the literature. The present review highlights the use of microwave chemistry as an important tool for the fast development of structure activity relationship in several programs related to various therapeutic areas.

Sphingolipids comprise a family of bioactive lipids that exert antagonizing roles in diverse cellular functions such as cell proliferation, growth arrest or apoptosis. Synthesized in the ER/Golgi, sphingolipids are subsequently distributed to different compartments, most predominantly in the plasma membrane, where they integrate signaling platforms. In addition to its precursor role in the synthesis of complex glycosphingolipids, ceramide has been identified as a cell death effector and its generation increases in response to apoptotic stimuli including stress, radiation, chemotherapy, and death ligands. In contrast, sphingosine-1-phosphate (S1P) has been mainly characterized as an antiapoptotic sphingolipid mediating cell proliferation and survival. Thus, the relative balance between ceramide and SIP has important implications in disease pathogenesis, and therefore the pharmacological modulation of enzymes involved in regulation of the ceramide to SIP ratio could constitute a novel therapeutic approach for the treatment of human diseases and cancer.

Fondaparinux is a synthetic, five-saccharide chain, AT-dependent, anti-FXa agent. Studies showed that fondaparinux acts in prevention and treatment of venous thromboembolism and in ischemic heart disease, without significant bleeding risk. The drug inhibits thrombin generation, has long half-life and can be administered once-daily without laboratory monitoring. It may be used in HIT treatment.

The development of resistance by the antibiotics in the Gram-positive pathogenic bacteria over the last twenty years and continuing today has created a need for new antibiotic classes, which may be unaffected by existing bacterial resistance. The oxazolidin-2-ones represent not only a new class with a novel mechanism of action, but also satisfy the requirement for overcoming the resistance mechanisms. Both linezolid and eperozolid, the first chemical candidates, arose from the piperazine subclass, with the first one being chosen further development because of its enhanced pharmacokinetic properties. The main attractive traits of the oxazolidinone series has encouraged further work in the area, and the patent literature reveals that extensive chemical investigation is currently being made. The unexpected early resistance development emphasizes the need for further exploration of features of the oxazolidinone to eliminate these deficiencies. Recently, several changes, involving the C5 side chain as well the N-phenyl heterocyclic ring, give promise for such improvement. Oxazolidinone antibacterial agents comprise also ketolides, derivatives of macrolides, such as erythromycin A, with a newly formed carbamate cycle, with a largely unexplored potential. The oxazolidinone nucleus does not appear only in the structures of antimicrobial drugs, but a number of biological activities are connected with frameworks including the oxazolidinone ring. A partial list of these activities comprises enzyme inhibitors, agonists and antagonists, with a particular citation for a new generation of selective monoamino oxidase inhibitors (befloxatone). The oxazolidinone moiety was found in the structure of few biologically active natural products, such as (-)-cytoxazone and streptazolin. Moreover, in some cases the oxazolidinone ring has been chosen for the preparation of isosteric aza analogues of natural compounds (podophyllotoxin, pilocarpine) that can be more easily synthesised and more hardly inactivated. Finally, the participation of oxazolidinone chiral auxiliaries to several syntheses of natural products must be acknowledged.

Artemisinin and its synthetic derivatives are widely used for antimalarial agents in the world. Moreover, they are discovered to additionally use as anticancer, antiangiogenesis, antiviral, immunosuppressive, and antifungal agents. Recent research results supported that it is a very promising field in drug discovery. In this review, it will discuss the structural and biological features of artemisinin and its derivatives that have published since 2003 except antimalarial, and show that they are useful lead compounds for novel drug discovery.

For almost half a century immunologists have tried to tear down the MHC barrier, which separates two unrelated individuals during transplantation. Latest experimental data suggest that a breakthrough in vitro is imminent. Dendritic cells (DCs),which activate naive allo-reactive T-cells (TCs), play a central role in the establishment of allo-antigenspecific immunity. Allograft solid organ rejection is initiated at the foreign endothelial cell (EC) layer, which forms an immunogenic barrier for migrating DCs. Thus, DC/EC interactions might play a crucial role in antigen-specific allograft rejection. Organ rejection is mediated by host allo-reactive TCs, which are activated by donor DCs (direct activation) or host DCs (indirect activation). Direct allo-antigen presentation by regulatory dendritic cells (DCreg) can play an instructive role towards tolerance induction. Several groups established that, DCregs, if transplanted beforehand, enter host thymus, spleen, or bone marrow where they might eventually establish allo-antigen-specific tolerance. A fundamental aspect of DC function is migration throughout the entire organism. After solid organ transplantation, host DCs bind to ECs, invade allograft tissues, and finally transmigrate into lymphoid vessels and secondary lymphoid organs, where they present allo-antigens to naive host TCs. Recent data suggest that in vitro manipulated DCregs may mediate allo-transplantation tolerance induction. However, the fundamental mechanisms on how such DCregs cause host TCs in the periphery towards tolerance remain unclear. One very promising experimental concept is the simultaneous manipulation of DC direct and indirect TC activation/suppression, towards donor antigen-specific allo-transplantation tolerance. The allo-antigenspecific long-term tolerance induction mediated by DCreg pre-transplantation (with simultaneous short-term immunosuppression) has become reproducible in the laboratory animal setting. Despite the shortcomings of laboratory animal studies, strong promises are deriving from these studies for clinical kidney, heart, and liver transplantation.

New drugs are introduced to the market every year and each individual drug represents a privileged structure for its biological target. In addition, these new chemical entities (NCEs) not only provide insights into molecular recognition, but also serve as drug-like leads for designing future new drugs. To these ends, this review covers the syntheses of 22 NCEs marketed in 2005.