Synthesis artemisinin analogues

A high level of activity continues in connection with the synthesis of antimalarial artemisinin analogues and congeners, in which the 1,2-dioxepane moiety is embedded. Recent examples include the syntheses of various 10-substituted deoxoartemisinins of type 123 (eg. R1 = Cl COMe) from dihydroartemisinin acetate, and of type 124 (eg. R2 = a-OH, R3 = Me), from Grignard reagent addition to 10-(2-oxoethyl)deoxoartemisinin . 

Posner and coworkers have developed versatile methodology for the synthesis of novel 1,2,4-trioxanes that has allowed detailed investigation of their Structure-Activity Relationships (SAR) , while Jefford and coworkers first synthesized fenozan BO-7, so naturally some of their work has centered on its mechanism of action. Avery and coworkers have also contributed significantly to the area by the syntheses and QSAR (Quantitative SAR) studies of many artemisinin analogues. 

The Avery group has produced a large number of artemisinin analogues by semisyntheses and elegant total synthesis . This has enabled Avery to develop predictive 3-D QSAR (CoMFA) analyses for the artemisinin class of antimalarial. This information coupled with the ADME approach described above should permit highly potent and orally bioavailable semi-synthetic analogues to be designed by a truly rational approach. 

Dihydroqinghaosu (32) (Scheme 1) is a key intermediate in the synthesis of artemisinin analogues / derivatives, which have shown antimalarial activity. Following the Chinese scientists s work, Lin et al. [95] synthesized a series of water soluble derivatives of artemisinin of which artenilic acid (36d) was found to exhibit activity and better stability than artemisinin or artesunate. Brossi et al. [96] reported the synthesis of arteether (36b), which after preclinical studies is now in clinical evaluation in India [96a], Deoxyqinghaosu described in scheme 11 has been reported to have high antimalarial activity. Synthesis of (+)-12-butyldeoxoartemisinin (99) and some tricyclic analogues (100) of artemisinin has recently been achieved [97,98]. 

Initially, we sought a practical total synthesis of the natural enantiomer (+)-artemisinin (1) to support clinical therapeutic studies with artemisinin and derived prodrug congeners, such as artemether and artesunate, and by providing a radiolabeled version of artemisinin for metabolism and mode of action studies (Eq. 1). Associated model studies from our total synthesis resulted in numerous additional analogues for our fledgling SAR study and the conception of other structural... 

To better understand the importance of optical activity towards antimalarial activity and to further improve this CoMFA study, the synthesis of (-)-artemisinin and various other analogues having unnatural configuration are underway. In addition, further analogues needed to complete this study are (3-face substituents in the B and C rings of artemisinin, or primarily the axial positions at C-5, C-7, and C-8. Analogues such as 422 pave the way for the latter of these cases, C-83 substituted analogues. 

It appears that, apart from such specialized methods of synthesis that have been developed as part of an overall effort to prepare analogues of artemisinin (9), the most popular and effective general methods for preparing the ring systems described involve the cyclization of a ring component that contains [6 + 0] ring atoms or the insertion of a one atom unit in a [5 + 1] annulation process. These general methods have found wide use, notably in the preparation of triazine-based compounds. 

With the Chinese claims validated in 1984 by Klayman and coworkers,94 studies in the early 1980s rapidly addressed two key issues with the advancement of artemisinin as an antimalarial drug. One, how could it be made commercially and if so, what is its mode of action Although the former question was addressed,95,96 the lack in understanding its activity was reported by Gu.97 Here, evidence from prior studies indicated that, while active analogues could be prepared, including dihydroartemisinin and artemether (Figure 3.8), the endoperoxide function was key to this activity.98 In their work, Gu and co-workers postulated that the activity arose from modification of protein synthesis within the malaria parasite, Plasmodium falciparum 1 This was followed by a series of studies that indicated that the activity of artemisinin was attenuated by addition... 

Hindley, S. Ward, S. A. Storr, R. C. Searle, N. L. Bray, R G. et al. Mechanism-hased design of parasite-targeted artemisinin derivatives Synthesis and antimalarialactivity of new diamine containing analogues. J. Med. Chem., 2002, 45 1052-1063. 

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