Endoperoxides synthetic

Hargreaves has suggested that the insolubilization of some closely related polymers is due to photolytic homolysis of the endoperoxide 0-0 bond and subsequent generation of carbon-centered radicals from the O radicals (19). There are several facts that make this an extremely unlikely explanation for the data described here these include the quantitative insufficiency of the maximum amount of endoperoxide reaction obtainable with a few hundred mJ/cm2 dose (homolysis quantum yield <0.5 (46), and extinction coefficient 1 (M cm)-1 (47)), and the synthetic utility of such homolysis reactions in related molecules in the presence of good hydrogen atom donors (implying facile epoxide formation) (48). Clearly the crosslinking observed under N2 is not accounted for by this mechanism. 

Erratic availability and high costs of the natural compound make further investigations for cheaper natural or synthetic endoperoxide-based antimalarials necessary. Meanwhile, a Belgian company, Dafra Pharma, Turnhout, is bringing the natural product and its derivatives onto the market [44]. 

Biomimetic Fe(ll) chemistry and synthetic studies on antimaiarial and antitumour endoperoxides... 

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. 

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. 

Table 1 summarizes the synthetic and antimalarial profiles of selected endoperoxides. Clearly, synthetic organic chemistry has enabled several excellent potential drng candidates to be prepared, some of which have outstanding antimalarial properties. At the forefront of these efforts are the trioxolanes prepared by Vennerstrom and colleagnes. The challenge in this field in future years will be to construct additional endoperoxide templates that can be prepared in a few steps using scalable synthesis and have similar pharmacological profiles to lead semi-synthetic artemisinins and trioxolanes (e.g. 6). 

TABLE 1. Lead synthetic endoperoxide antimalarials (The table compares the antimalarial activities, the method of synthesis and the number of synthetic steps required for dmg synthesis)... 

As described in this chapter, significant progress has been made in the elucidation of the chemical mechanisms of bioactivation and identification of potential biological targets of the antimalarial endoperoxide class of drug. Equally, medicinal chemists have had success in the preparation of both semi-synthetic artemisinin analogues and simplified... 

J.P. Begue, D. Bonnet-Delpon, The future of antimalarials Artemisinins and synthetic endoperoxides, Drugs Fut. 30 (2005) 509-518. 

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