Synthetic trioxanes

In addition to artemisinin, other synthetic trioxanes and endoperoxides (fenozan BO-7 4 and arteflene 5 " ) have enjoyed some success arteflene reached Phase II pre-clinical trials. More recently, Vennerstrom and coworkers have reported on the outstanding antimalarial properties of several 1,2,4-trioxolanes, one of which, OZ 277 (6), has entered clinical trials in man . These exciting, easily prepared drugs will be discussed in detail later in this chapter. In order to determine the parasiticidal action of this class of antimalarial, many research groups have focused their efforts on artemisinin and its semi-synthetic derivatives (artemether, arteether and artesunate Ic, Id and le), and this is the point where our discussion will begin. 

Synthetic trioxanes, simplified analogs of artemisinin, supposed to act in the same way, have also been developed (37). Future studies will provide information on die pharmacokinetics parameters of these artemisinin mimicks and tell us if these molecules have longer half-life times in plasma. 

The mechanism of oxetane formation is similar to the one discussed for cyclobutane formation in chapter 4.3.3. The 1,4-diradicals can be efficiently trapped with molecular oxygen. The resulting 1,2,4-trioxanes are interesting synthetic intermediates (4.81) 495>. 

Artemisinin, a tetracyclic 1,2,4-trioxane isolated from Artemisia annua L., is currently recommended as a first-line agent against Plasmodium falciparum malaria. Artemisinin and its synthetic derivatives have also been shown to be promising prototypes for the development of new antiproliferative agents. This chapter presents the recent advances on the analytic methods for extraction and quantification of artemisinin from A. annua plants as well as the biological properties of this natural product. 

Posner and Oh, and later Jefford and coworkers led the earliest investigations by synthetic chemists into the mechanism of action of 1,2,4-trioxane antimalarials. Both proposed that formation of a C-centred radical was essential for activity but the nature of the radical (primary or secondary) and the mechanistic pathways put forward were not identical. The iron degradation studies of Posner and coworkers implicated a role for the... 

Other synthetic candidates worthy of mention inclnde the C3 aryl trioxanes (75a and 75b) " and the endoperoxide analogue (76) ". These latter compounds have oral activity (ED50) as low as 0.5 mgkg in mice infected with Plasmodium berghei. 

Posner and coworkers have prepared a series of semi-synthetic and synthetic ether and ester-linked dimers that were found to have potent anti-proliferative and antitumour activities in vitro. Some of these trioxane dimers were found to be as antiproliferative as calcitriol, the hormonally active form of vitamin D, which is used to treat psoriasis, a skin disorder characterized by uncontrolled cell prohferation. Of the semi synthetic dimers, a polyethylene glycol-linked dimer 107, with S-stereochemistry at both of the lactol acetal positions, was found to be very anti-proliferative and showed activity against leukaemia and colon cancer cell hues in the National Cancer Institute (NCI), USA 60-cell line assay. 

It also can be produced directly from natural gas, methane, and other aliphatic hydrocarbons, but this process yields mixtures of various oxygenated materials. Because both gaseous and liquid formaldehyde readily polymerize at room temperature, formaldehyde is not available in pure form. It is sold instead as a 37 percent solution in water, or in the polymeric form as paraformaldehyde [HO(CH20)nH], where n is between 8 and 50, or as trioxane (CH20)3. The greatest end use for formaldehyde is in the field of synthetic resins, either as a homopolymer or as a copolymer with phenol, urea, or melamine. It also is reacted with acetaldehyde to produce pentaerythritol [C(CH2OH)4], which finds use in polyester resins. Two smaller-volume uses are in urea-formaldehyde fertilizers and in hexamethylenetetramine, the latter being formed by condensation with ammonia. 

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