The first two projects described in this Thesis involve the use of artemisone, or 4-[(3'R,5'aS,6'R,8'aS,9'R,10'R,12'aR),3',6',9'-trimethyldecahydro-3',12'-epoxy-l',2'-dioxepino-4',3'-i-isochromen-10'-yl] thiomorpholine-1,1-dioxide. This is a new artemisinin derivative which differs from previous artemisinin derivatives, first made by the Chinese, in having an alkylamino group attached to C-10. It is representative of a class of artemisinin antimalarial which is more active than any other artemisinin derivative, or synthetic trioxolane type antimalarial reported to date. It has been selected by Bayer AG for development as a new antimalarial drug.

Radiolabelled artemisone bearing ¹⁴C in a metabolically stable position was required by Bayer for the identification of metabolites when arte...[ Read more ]

The first two projects described in this Thesis involve the use of artemisone, or 4-[(3'R,5'aS,6'R,8'aS,9'R,10'R,12'aR),3',6',9'-trimethyldecahydro-3',12'-epoxy-l',2'-dioxepino-4',3'-i-isochromen-10'-yl] thiomorpholine-1,1-dioxide. This is a new artemisinin derivative which differs from previous artemisinin derivatives, first made by the Chinese, in having an alkylamino group attached to C-10. It is representative of a class of artemisinin antimalarial which is more active than any other artemisinin derivative, or synthetic trioxolane type antimalarial reported to date. It has been selected by Bayer AG for development as a new antimalarial drug.

Radiolabelled artemisone bearing ¹⁴C in a metabolically stable position was required by Bayer for the identification of metabolites when artemisone is submitted to preclinical studies with animals, and with isolated enzymes such as recombinant CYP enzymes, and in isolated liver microsomes. The radiolabelled compound is also required to examine how artemisone is taken up by tissues and vital organs in preclinical animal studies as part of preclinical toxicology. The artemisone bearing ²H (D or deuterium) was also required to develop an analytical method for detecting artemisone and metabolites in analysis of plasma in both Phase I and Phase II clinical trials. Therefore at HKUST, methods were examined for incorporating deuterium. After extensive examination of methods using later synthetic precursors of artemisone, a method was finally developed based on artemisitene. The methylene group at C-9 of artemisitene was cleaved by ozonolysis, or by RuC1₃-NaIO₄ to give the 9-desmethyl-9-oxa-artemisinin. Wittig reaction of 9-desmethyl-9-oxa-artemisinin with C²H₂-methylidene triphenylphosphorane gave 9-[C²H₂]-artemisitene, and reduced to dihydroartemisitene. Ionic reduction with Et₃Si²H and boron trifluoride etherate gave 9-[C²H₃]-anhydrodihydroartemisinin, which was converted into 9-[C²H₃]-artemisone. Another method involved ionic reduction of 9-[C²H₂]-artemisitene with Et₃Si²H and boron trifluoride etherate to give 9-[C²H₃]-artemisinin, which was also converted into artemisone. The technology was transferred to Bayer AG for preparation of the ¹⁴C-labelled artemisone. The task was successfully carried out, and all metabolites of artemisone were thereby identified at Bayer.

The second artemisone project is involved with the synthesis of the major metabolite M1 identified at Bayer AG. This has unsaturation at C2-C3 in the thiomorpholine S,S-dioxide ring. It was shown at Bayer to arise by metabolism of artemisone with CYP 3A4 enzyme. The possible chemistry involved in the metabolic formation of this compound was considered. Attempts were made to follow this chemistry in our laboratory. However, it was not successful. Semisynthesis was then attempted by attaching various functionalized amino groups at C10 of dihydroartemisinin and then convert these into the unsaturated thiomorpholine S,S-dioxide ring. However, all attempts to convert these into the M1 metabolite were not successful. This is because the groups mainly tended to undergo elimination to anhydrodihydroartemisinin under the basic conditions required to construct the unsaturated thiomorpholine S,S-dioxide ring. Finally, artemisone was submitted to ozonolysis at low temperature according to a method used to convert tertiary amines into the tertiary enamines. This method was successful, and the M1 was isolated cleanly, although it was formed in relatively low yield, providing that the ozonolysis was stopped after 2h. If the ozonolysis went longer, complex product mixtures were obtained. Also isolated was a small amount of a compound tentatively identified as artemisone bearing a hydroxyl group in the thiomorpholine S,S-dioxide ring α to the nitrogen atom.

The third part of this thesis involves the preparation of artemisinin derivatives with the lactone oxygen of artemisinin replace by a nitrogen atom. The parent compounds was prepared by treatment of artemisinin with ammonia followed by acid treatment. The 11-azaartemiinin was then deprotonated with lithium diisopropylamide in tetrahydrofuran to generate the lithiated azaartemisinin. This was then treated with a series of aromatic and aliphatic sulfonyl chlorides to generate the sulfonylazartemisinin derivatives. The lithiated 11-azaartemisinin also reacted with aryl isothiocyanate to generate the corresponding acyl urea derivative. All compounds have been submitted for screening against malaria parasite, and other infective agents.