Synthesis of (-)-epibatidine.

The synthesis of (-)-epibatidine has been accomplished utilizing a highly exo-selective asymmetric hetero Diels-Alder reaction. The key steps employed to transform the resulting bicycle into the natural product include a fluoride-promoted fragmentation and a Hofmann rearrangement. Reaction: see text.

Enantioselective and diastereoselective Mukaiyama-Michael reactions catalyzed by bis(oxazoline) copper(II) complexes.

The scope of highly enantioselective and diastereoselective Michael additions of enolsilanes to unsaturated imide derivatives has been developed with use of [Cu((S,S)-t-Bu-box)](SbF6)2 (1a) as a Lewis acid catalyst. The products of these additions are useful synthons that contain termini capable of differentiation under mild conditions. Michael acceptor pi-facial selectivity is consistent with two-point binding of the imide substrate and can be viewed as an extension of substrate enantioselection in the corresponding Diels-Alder reactions. A model analogous to the one employed to describe the hetero Diels-Alder reaction is proposed to account for the observed relation between enolsilane geometry and product absolute diastereocontrol. Insights into modes of catalyst inactivation are given, including spectroscopic evidence for inhibition of the catalyst by a dihydropyran intermediate that evolves during the course of the reaction. A procedure is disclosed in which an alcohol additive is used to hydrolyze the inhibiting dihydropyran and afford the desilylated Michael adduct in significantly shortened reaction time.

Structure-based design, synthesis and evaluation of conformationally constrained cysteine protease inhibitors.

The inhibition of cysteine proteases is being studied as a strategy to combat parasitic diseases such as Chagas' disease, leishmaniasis, and malaria. Cruzain is the major cysteine protease of Trypanosoma cruzi, the etiologic agent of Chagas' disease. A crystal structure of cruzain, covalently inactivated by fluoromethyl ketone inhibitor 1 (Cbz-Phe-Ala-FMK), was used as a template to design potential inhibitors. Conformationally constrained gamma-lactams containing electrophilic aldehyde (12, 17, 18, 25, 26, and 29) or vinyl sulfone (43, 44, and 46) units were synthesized. Constrained lactam 26 had IC50 values of ca. 20 nM against the Leishmania major protease and ca. 50 nM versus falcipain, an important cysteine protease isolated from Plasmodium falciparum. However, all of the conformationally constrained inhibitors were weak inhibitors of cruzain, compared to unconstrained peptide aldehyde (e.g. 5 ) and vinyl sulfone inhibitors (e.g. 48, which proved to be an excellent inhibitor of cruzain with an apparent second order inhibition rate constant (k(inact)/Ki) of 634,000s(-1)M(-1). A significant reduction in activity was also observed with acyclic inhibitors 30 and 51 containing alpha-methyl phenylalanine residues at the P2 position. These data indicate that the pyrrolidinone ring, especially the quarternary center at P2, interferes with the normal substrate binding mode with cruzain, but not with falcipain or the leishmania protease.

Diffuse abdominal uptake of technetium-99m-HDP after colectomy in Gardner's syndrome.

A 37-yr-old man presented with increasing abdominal girth and multiple palpable intra-abdominal masses 3 yr after colectomy for polyposis coli. Whole-body skeletal scintigraphy performed prior to laparotomy demonstrated diffuse abdominal uptake of 99mTc-HDP consistent with mesenteric fibromatosis confirmed at surgery. When diffuse abdominal uptake of skeletal imaging agents occurs in patients with prior colectomy for polyposis coli, mesenteric fibromatosis as a manifestation of Gardner's syndrome should be suspected. This case illustrates another cause of diffuse abdominal uptake of skeletal imaging agents.

Triple-phase bone scan findings in aggressive fibromatosis. Before and after radiation therapy.

The authors present comparative triple-phase bone scan findings in three cases of histologically proven aggressive fibromatosis both before (initial evaluation) and after radiation therapy. The purpose of the study was to compare triple-phase bone scan findings in aggressive fibromatosis both before and after radiation therapy and to determine whether any additional physiological information could be obtained. Before radiation therapy, the triple-phase bone scintigraphy demonstrated increased flow and radiotracer pooling in the areas of tumors on dynamic flow and immediate blood pool images, respectively. However, the delayed static images demonstrated variable radiotracer uptake. When compared to preradiation therapy triple-phase bone scan, decreased vascularity was well demonstrated in all three patients after radiation therapy. In addition, it also provided information regarding the changes in the size and extent of tumor, noninvaded underlying bone, and remainder of the skeleton. This additional information can be particularly useful in patients with equivocal or questionable histologic diagnosis especially from small, unrepresentative biopsies.

Assessing the activity of sarcoidosis: quantitative 67Ga-citrate imaging.

Three different methods of quantitating 67Ga-citrate lung images--a visual index, a computer-assisted index, and the total-lung-to-background ratio--were compared in 71 studies of patients with biopsy-proven sarcoidosis. Fifty consecutive cases were analyzed independently by two different observers using all three methods. In 45 patients, both gallium lung scans and bronchoalveolar lavage were performed within 2 weeks. In these studies, each index was correlated with the cell differential in the bronchoalveolar lavage fluid. The total-lung-to-background ratio proved to be the simplest to perform; correlated best with the original visual index (r = 0.81, p less than 0.00001) and the percentage of lymphocytes obtained in bronchoalveolar lavage fluid (r = 0.39, p less than 0.004); and showed the lowest interobserver variation. Sensitivity for detecting active disease was 84% compared with 64% and 58% for the visual and computer-assisted indices, respectively, with no sacrifice in specificity.