Can. J. Chem. 68, 1044 (1990). The structure of Mezzettiaside 3, a highly acylated trisaccharide obtained from the stem bark of Mezzettia leptopoda, was determined by a combination of double-quantum-filtered {'H,'H) correlation spectroscopy, two-dimensional homonuclear Hartmann-Hahn, and 'H-detected {'H,'~c) one-bond and multiple-bond shift correlation nuclear magnetic resonance experiments, in conjunction with fast-atom-bombardment mass spectrometry. Mezzettiaside 3 was found to be the a- 1044 (1990).La structure du Mezzettiaside 3, un trisaccharide trks acylC, obtenu a partir de 1'Ccorce du tronc de Mezzettia leptopoda, a Ct C elucidCe en faisant appel a la spectromCtrie de masse par bombardement avec des atomes rapides (SM-FAB) en combinaison avec les methodes de rCsonance magnitique nuclCaire (RMN) suivantes : spectroscopie de corrClation {'H,'H) doublement filtrC d'un point de vue quantique, spectroscopie Hartmann-Hahn homonuclCaire bidimensionelle et spectroscopie de corrClation des dCplacements {'H,'~c) par liaisons simples et multiples avec dCtection de 'H. On a trouvt? que la Mezzettiaside 3 est l'a-(n-octy1)glycoside du 3,4-di-O-ac~tyl-~-rhamnopyranosyl-a(1+3)-2,4-di-0-ac~tyl-~-rhamnopyranosyl-a(1~3)-4-0-hexanoyl-L-rhamnopyranose. La technique de corrClation hCtCronucltaire des liaisons multiples par RMN s'est avCrCe trks utile pour determiner la position des groupements 0-acylCs de ce carbohydrate complexe.

A significant number of patients with AIDS and AIDS-related complex develop neurological complications. Therefore, it is critical that anti-HIV agents penetrate the blood-brain barrier and suppress viral replication in the brain. In an effort to increase the brain delivery of anti-HIV nucleosides, in vitro and in vivo pharmacokinetics of dihydropyridine derivatives of 3'-azido-2',3'-dideoxyuridine (AzddU, AZDU, or CS-87) and 3'-azido-3'-deoxythymidine (AZT, Zidovudine) have been studied. In vitro studies of the prodrugs (AzddU-DHP and AZT-DHP) in human serum, mouse serum, and mouse brain homogenate indicated that the rates of serum conversion from prodrugs to parent drugs are species dependent: mouse brain homogenate greater than mouse serum greater than human serum. Half-lives in human serum, mouse serum, and mouse brain homogenate are 4.33, 0.56, 0.17 h, respectively, for AzddU and 7.70, 1.40, and 0.18 h, respectively, for AZT. In vivo studies of AzddU-DHP and AZT-DHP showed that the prodrugs have areas under the serum concentration-time curves (AUC) similar to those of the parent drugs. The AUC in serum for AzddU following prodrug administration is 25.79 micrograms h/mL, which is similar to the value of 25.83 micrograms h/mL when AzddU was administered. Analogously, the serum AUCs for AZT when AZT-DHP and AZT were administered are 25.38 and 26.64 micrograms h/mL, respectively. However, the brain AUCs for both AzddU and AZT derived from prodrugs, being 11.43 and 11.28 micrograms h/mL, respectively, are greater than the brain AUCs for AzddU (2.09 micrograms h/mL) and AZT (1.21 micrograms h/mL) when the parent drugs were administered. Thus, the relative brain exposure (re) for AzddU (5.47) and AZT (9.32) indicate a significant increase in exposure to the anti-HIV nucleosides following prodrug administrations. The results of extended half-lives of the synthesized prodrugs in human serum along with the higher re values in vivo warrant studies in larger animals to determine the potential usefulness of the prodrugs in humans.

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