Malaria-infected mice are cured by oral administration of new artemisinin derivatives.

In four or five chemical steps from the 1,2,4-trioxane artemisinin, a new series of 23 trioxane dimers has been prepared. Eleven of these new trioxane dimers cure malaria-infected mice via oral dosing at 3 x 30 mg/kg. The clinically used trioxane drug sodium artesunate prolonged mouse average survival to 7.2 days with this oral dose regimen. In comparison, animals receiving no drug die typically on day 6-7 postinfection. At only 3 x 10 mg/kg oral dosing, seven dimers prolong the lifetime of malaria-infected mice to days 14-17, more than double the chemotherapeutic effect of sodium artesunate. Ten new trioxane dimers at only a single oral dose of 30 mg/kg prolong mouse average survival to days 8.7-13.7, and this effect is comparable to that of the fully synthetic trioxolane drug development candidate OZ277, which is in phase II clinical trials.

Malaria-infected mice are cured by a single dose of novel artemisinin derivatives.

We disclose here for the first time the curative activity of a new generation of trioxane dimers, designed logically and prepared easily from the natural trioxane artemisinin in only four or five chemical steps that would be easily accomplished also on a manufacturing scale. Four of these trioxane dimers cure malaria-infected mice after only a single subcutaneous dose, and two other dimers cure after three oral doses.

Cyclopentanone ring expansion leading to functionalized delta-lactams: short synthesis of simple sedum alkaloids.

Monosubstituted epoxides react with (cyclopentenyloxy)trimethylsilane to afford, after subsequent oxidative fragmentation, a pair of diastereomeric 8-membered iodolactones. When these lactones are separately treated with sodium azide, followed by reduction over Lindlar's catalyst, lactone ring contraction yields 6-membered monosubstituted lactams. When (R)-1,2-epoxypentane is used in this 5 + 3 - 2 overall ring expansion sequence, one final step involving delta-lactam to piperidine reduction yields natural (-)-halosaline and (-)-epihalosaline in five steps and 12% and 23% overall yields, respectively.

Potent, selective and low-calcemic inhibitors of CYP24 hydroxylase: 24-sulfoximine analogues of the hormone 1alpha,25-dihydroxyvitamin D(3).

A dozen 24-sulfoximine analogues of the hormone 1alpha,25-dihydroxyvitamin D(3) were prepared, differing not only at the stereogenic sulfoximine stereocenter but also at the A-ring. Although these sulfoximines were not active transcriptionally and were only very weakly antiproliferative, some of them are powerful hydroxylase enzyme inhibitors. Specifically, 24-(S)-NH phenyl sulfoximine 3a is an extremely potent CYP24 inhibitor (IC(50) = 7.4 nM) having low calcemic activity. In addition, this compound shows high selectivity toward the CYP24 enzyme in comparison to CYP27A1 (IC(50) > 1000 nM) and CYP27B (IC(50) = 554 nM).

Use of bis-(chiral alpha-methylbenzyl)glycine esters for synthesis of enantiopure beta-hydroxyamino esters.

[reaction: see text] Aldol reactions using bis-(chiral alpha-methylbenzyl)glycine esters with aldehydes gave excellent diastereoselectivity. Thus, an enantiopure ribosylglycine was prepared for the synthesis of analogues of the natural antibiotics muraymycin. This method was extended for formation of beta-hydroxyamino esters.

Highly antiproliferative, low-calcemic, side-chain amide and hydroxamate analogs of the hormone 1alpha,25-dihydroxyvitamin D3.

Four new side-chain amide (2 and 3) and hydroxamate (4 and 5) analogs of the hormone calcitriol (1) have been prepared. Even though lacking the 25-OH group characteristic of natural calcitriol (1), analogs 2-4 are as antiproliferative in vitro as calcitriol (1) but are 20-40 times less calciuric in vivo than calcitriol (1).