Wesley K. M. Chong

The Total synthesis of (+)-artemisinin and (+)-9-desmethyltemesinin

Abstract (+)-Artemisinin has been synthesized from the 3R -methylcyclohexanone 4 in 12 steps.

Synthesis, conformational analysis, and antimalarial activity of tricyclic analogs of artemisinin

Abstract Aspects of synthesis, conformational analysis, and antimalarial activity of artemisinin analogs (±)-5-nor-6-desmethyl-4,5-secoartemisinin (2), (−)-5-nor-4,5-secoartemisinin (3), (+)-4,5-secoartemisinin (4), and (+)-4,5-desethano-artemisinin (5)22 are described. The conformations of these multicyclic structures were determined through a combination of X-ray crystallography, NMR, and computational analysis, with an emphasis on the 1,2,4-trioxane geometry. Two major solution conformations for both 2 and 3 were found: all chair forms 2a and 3a, and twist-boat/twist-boat/chair forms 2b and 3b, respectively. The major solution conformer 2a matched the solid state structure found via X-ray crystallography. Computations suggest that (+)-4,5-Secoartemisinin (4) has three conformations of equal energy: chair/twist-boat, 4a, twist-boat/twist-boat/chair, 4b, corresponding to the X-ray crystal structure, and twist boat/chair/chair, 4c. The 1,2,4-trioxane and lactone rings adopt the twist-boat conformations in 2b, 3b, 4a, and 4c. When compared to artemisinin, these tricyclic, flexible analogs have different geometry yet retain some in vitro antimalarial activity against resistant strains of Plasmodium falciparum. Possible structure/activity correlations are discussed.

Proton spectroscopy in HIV infection: Relaxation times of cerebral metabolites

In vivo proton spectroscopy has demonstrated abnormalities in the cerebral metabolite ratios from subjects with acquired immunodeficiency syndrome (AIDS). Some of the sequences employed are subject to T1 or T2 weighting, which may affect spectroscopic interpretation. The relaxation times of choline (Cho), creatine (Cr), and N-acetyl (NA) resonances have been estimated at 1.5 T in 21 patients infected with the human immunodeficiency virus (HIV) and 8 controls using gradient localised, spin-echo spectroscopic sequences of varying echo and repetition times. A statistically significant increase in the T2 of NA was found in the HIV seropositive patients who had diffuse abnormalities on MR imaging consistent with HIV encephalopathy (493 +/- 199 ms) when compared to controls (292 +/- 118 ms; p < .05). No other statistically significant differences were found in the relaxation times between patients and control subjects. These results demonstrate that signals from the NA resonance obtained using long echo time sequences in subjects who are HIV seropositive are not solely indicative of metabolite concentration.

Synthesis of (+)-8a,9-secoartemisinin and related analogs

Abstract An efficient synthesis of (+)-8a,9-secoartemisinin 2 , ring-D cleaved, tricyclic analog of (+)-artemisinin 1 , has been accomplished. Dioxetane 7 , produced upon ozonolysis of vinyl-silane 5 in methanol, was intercepted with acid to provide the stable bicyclic peroxy-aldehyde 9 , which was readily converted to the title compound(s).

Tricyclic analogues of artemisinin: synthesis and antimalarial activity of (+)-4,5-secoartemisinin and (–)-5-nor-4,5-secoartemisinin

Two ring-A cleaved analogues of the natural product artemisinin have been synthesized and examined for in vitro antimalarial activity.

Synthesis and testing of 17aβ-hydroxy-7α-methyl-d-homoestra-4, 16-dien-3-one: a highly potent orally active androgen

Abstract The title compound, 17aβ-hydroxy-7α-methyl- d -homoestra-4, 16-dien-3-one (3), was synthesized in five steps (17% overall yield) from 7α-methylestrone methyl ether (5) and was found to possess oral androgenic activity, in excess of other known androgens, without using 17α-alkyl substitution. (Steroids 55 :59–64, 1990)

The prevalence of paranasal sinus disease in HIV infection and AIDS on cranial MR imaging.

Sinusitis poses a difficult clinical challenge in the management of patients with AIDS because of high rates of relapse and the association with unusual pathogens. To determine the prevalence and severity of sinus disease in this group we prospectively analysed the condition of the paranasal sinuses shown on cranial MR scans of 156 patients referred for the investigation of suspected intracranial pathologies. These included 104 HIV seropositive patients, including 93 with an AIDS-defining diagnosis (CDC IV). Forty-two scans were performed on age-matched controls. The scans were timed to control for seasonal variations in sinus disease and were interpreted by two radiologists who were blinded to the clinical and serological status of the patients. Severe mucosal disease (more than one sinus showing > 75% obliteration) or moderate mucosal disease (only one sinus showing > 75% obliteration) was seen in 15.1% (14/93) patients with AIDS and none of the 42 controls (chi 2 = 6.73, P < 0.01). The mean maximum mucosal thickness in patients with AIDS was significantly greater than the control group (P < 0.001) and also significantly greater than in seropositive patients who had not had an AIDS-defining diagnosis (CDC II/III) (P = 0.006). Paranasal sinus mucosal abnormalities seen on MRI are greater in prevalence and severity in patients with AIDS and about one in seven would be expected to have at least one sinus largely obliterated.

Cerebral magnetic resonance relaxometry in HIV infection

A prospective, cross-sectional study was designed to determine the magnetic resonance relaxation times of cerebral white matter in human immunodeficiency virus (HIV) infected individuals. T1 and T2 were estimated at 1.5 T using four-point methods. Seventy-five HIV-1 seropositive subjects, 48 seronegative blood donors, and 17 seronegative homosexual men were studied. Associations between relaxometry and clinical classification, neurological status, immunological status, and qualitative MRI were investigated. Statistically significant differences in white matter T1 relaxation time were found comparing low-risk control and AIDS groups (p < .005), seropositive subjects with neurological signs and those without (p < .005), and subjects with low (CD4 < or = 200 x 10(6)/l) and high (CD4 > 200 x 10(6)/1) CD4 cell counts (p < .05). These findings add to the body of information that reveals no HIV-related change in the brain before the onset of symptomatic immunosuppression and go someway to validating the previous visually rated, qualitative findings. Statistically significant difference in white matter T2 relaxation time were also found comparing the two control groups (p < .005) highlighting the need for appropriate controls.

Spatial data analysis in the quantitative assessment of cerebral white matter pathology on MRI in HIV infection

This study was carried out using MRI (proton density-and T2-weighted) on 16 HIV-negative controls, 9 symptom-free HIV-positive patients and 25 with CDC IV HIV disease. The studies from this last group had previously been allocated by a radiologist to the following categories: 8 with focal mass lesions and normal-appearing white matter; 9 with diffuse encephalopathy (high signal on T2-weighted images, affecting most or all of the white matter) and 8 with patchy encephalopathy (high signal affecting only one or two areas within the white matter). MoransI, a statistic of spatial autocorrelation, was calculated for the grey-scale values of a sampled pixel array from a central white matter region of each of the images. All values of MoransI calculated in this study showed a large positive excess over the expected value under randomisation, indicating highly significant positive autocorrelation in the spatial arrangement of the grey-scale values. On T2-weighted images a statistically significant increase in the mean value of MoransI, compared with controls, was found in the diffuse encephalopathy group, indicating that quantifiable changes in the spatial autocorrelation of pixel data can be related to recognised qualitative changes in the appearance of white matter in subjects with HIV disease. A lesser, but significant, rise in the mean value of MoransI was also found in the focal mass lesion group, suggesting that changes in spatial autocorrelation may indicate pathological change in advance of qualitative MRI changes.