Biomedical subjects
Publications and source records attributed to W R Roush.
The dipeptidyl epoxy ketone 4 is a potent, irreversible inhibitor of cruzain, a cysteine protease isolated from Trypanosoma cruzi, with an apparent second order inhibition rate constant of 330,000 sec-1M-1.
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.
BACKGROUND: The trophozoite stage of the malaria parasite infects red blood cells. During this phase of their life-cycle, the parasites use hemoglobin as their principal source of amino acids, using a cysteine protease to degrade it. We have previously reported a three-dimensional model of this cysteine protease, based on the structures of homologous proteases, and the use of the program DOCK to identify a ligand for the malaria protease. RESULTS: Here we describe the design of improved ligands starting from this lead. Ligand design was based on the predicted configuration of the lead compound docked to the model three-dimensional structure of the protease. The lead compound has an IC50 of 6 microM, and our design/synthesis strategy has resulted in increasingly potent derivatives that block the ability of the parasites to infect and/or mature in red blood cells. The two best derivatives to date have IC50(s) of 450 nM and 150 nM. CONCLUSIONS: A new class of anti-malarial chemotherapeutics has resulted from a computational search that was based on a model of the target protease. Despite the lack of a detailed experimental structure of the target enzyme or the enzyme-inhibitor complex, we have been able to identify compounds with increased potency. These compounds approach the activity of chloroquine (IC50 = 20 nM), but have a distinct mechanism of action. This series of compounds could thus lead to new therapies for chloroquine-resistant malaria.
The potential impact of COBRA is staggering and must be confronted. The ultimate scope and effects will take shape quickly. Federal regulations will provide some of the rules, but the most important definitions under the law will develop in court. Because of a lack of understanding hospitals may not have been in compliance with COBRA's strict terms since August 1986 and may only become educated on COBRA through the legal process. Currently, one COBRA lawsuit has been filed in the Chicago court system, and at least one physician group in California has paid a $25,000 fine for COBRA violations. Litigation in the initial phase of COBRA is likely as most hospitals continue to be unaware of the implications of COBRA legislation. EDs, emergency medical services programs, and interhospital transport programs must begin an immediate effort to examine and develop policies to comply with COBRA. Without an effective educational, compliance, and risk management effort, any emergency medical services program or hospital may become a defendant under COBRA legislation. Delays in understanding and implementing the requirements of COBRA may adversely affect the health care system rather than improve it.
Acute urinary retention is a common emergency genitourinary symptom. The etiology of acute retention includes obstructive, neurogenic, pharmacologic, and psychogenic causes. The emergency management of acute urinary retention is bladder decompression, which is usually accomplished with a Foley catheter.
A six-step synthesis of racemic mycarose from allylacetylene is described. Key transformations include the threo-selective epoxidation of (E)-4-methyl-1,4-heptadien-6-ol and the alpha-opening of xylo-4,5-epoxy-4-methylhept-1-en-6-ol (7), which was accomplished via a neighboring group-assisted reaction of xylo-4,5-epoxy-4-methyl-6-(N-phenylcarbamoyloxy)hept-1-ene (12). The latter conversion proceeded wih lower selectivity (3:1) than observed with disubstituted epoxyurethanes because of the greater tendency of trisubstituted epoxides to undergo substitutions with SN1 character at the tertiary center. Methanolysis of ribo-4-methylhept-1-ene-4,5,6-triol 5,6-carbonate, obtained from 12 in up to 61% yield, afforded ribo-4-methylhept-1-ene-4,5,6-triol, which was converted into mycarose by ozonolysis. Similarly, ozonolysis of lyxo-4-methylhept-1-ene-4,5,6-triol, which was prepared (64%) by hydrolysis of 7, afforded racemic 3-epi-axenose.
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