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Biomedical subjects

D J Abraham

Publications and source records attributed to D J Abraham.

At least 109 records · Page 6Linked to original sources
PubMed1984

Structural correlations of choline acetyltransferase inhibitors: trans-N-(carboxymethyl)-4-(beta-1-naphthylvinyl)pyridinium bromide and cis-N-(2-aminoethyl)-4-(beta-1-naphthylvinyl)-3-methylpyridinium bromide hydrobromide.

This paper correlates the X-ray structures of two 4-(beta-1-naphthylvinyl)pyridine analogues (one cis and one trans) with chemical and biological activity data for this class of cholineacetylase inhibitors. Our results suggest that one of the two proposed mechanisms for inhibition by this class of compounds better describes their efficacy. Previous arguments about coplanarity of the aromatic rings and nucleophilicty across the vinyl linkage need to be modified. Quantum calculations are also included and substantiate previous suggestions about the charge distribution across the vinyl linkages. An alternate new mechanism of inhibition is proposed to encompass the published data and more recent results discussed in this paper.

Chemical Phenomena↗
PubMed1984

Design, synthesis, and testing of potential antisickling agents. 4. Structure-activity relationships of benzyloxy and phenoxy acids.

In this paper we further establish the activity of two classes of small molecules, benzyloxy and phenoxy acids, as potent inhibitors of hemoglobin S (HbS) gelation. Structural modifications with a large number of each class confirm our earlier work that the highest activity is observed with compounds that contain dihalogenated aromatic rings with attached polar side chains. We have also found a halogenated aromatic malonic acid derivative to be quite active. Compounds reported in this paper are compared with other antigelling agents studied in our laboratory. Comments are made concerning the antigelling activity and binding sites of four derivatives and their effect on the allosteric mechanism of hemoglobin (Hb) function.

Acetates↗
PubMed1984

Design, synthesis, and testing of potential antisickling agents. 5. Disubstituted benzoic acids designed for the donor site and proline salicylates designed for the acceptor site.

This paper reports the discovery of a new class of potent antigelling agents. The new compounds, disubstituted benzoic acid derivatives, were designed by using molecular modeling experiments. These molecules contain functional groups positioned to interact with several polar amino acid residues near the Val-6 beta mutation site (donor site) in HbS. The compounds also contain a hydrophobic group designed to occupy a nonpolar ara on the surface of the protein created by several hydrophobic amino acids. The synthesis and testing of these new molecules using a standard solubility assay is reported. A structural comparison is made between one of the most active antigelling agents, compound 13, which has little effect on the oxygen affinity of Hb in solution, and bezafibrate, a known antilipidemic drug that is progelling and has a very potent effect on decreasing Hb oxygen affinity (Perutz, M. F.; Poyart, C. Lancet 1983, 2, 881-882). We also report the synthesis and testing of a series of proline-salicylate molecules designed to react covalently at the mutation acceptor area. This class of molecules did not show significant activity.

Antisickling Agents↗
PubMed1983

Swainsonine affects the processing of glycoproteins in vivo.

Rats, sheep and guinea pigs treated with swainsonine excrete 'high mannose' oligosaccharides in urine. The major rat and guinea pig oligosaccharide is (Man)5GlcNAc, whereas sheep excrete a mixture of oligosaccharides of composition (Man)2-5GlcNAc2 and (Man)3-5GlcNAc. The presence of these oligosaccharides suggests that Golgi alpha-D-mannosidase II as well as lysosomal alpha-D-mannosidase is inhibited by swainsonine resulting in storage of abnormally processed asparagine-linked glycans from glycoproteins. Altered glycoprotein processing appears to have little effect on the health of the intoxicated animal, but the accompanying lysosomal storage produces a disease state.

Alkaloids↗
PubMed1983

Design, synthesis, and testing of antisickling agents. 2. Proline derivatives designed for the donor site.

We have used a three-dimensional model of deoxyhemoglobin to design potential antisickling agents with an intended binding site in the vicinity of the beta-6 mutation (donor site). Two proline derivatives, (4S)-1-butyryl-4-[(carboxymethyl)amino]-L-proline (9a) and its 1-benzoyl analogue (9b), were designed to interact, via ionic or hydrogen bonds, with polar residues beta His-2, beta Thr-4, and beta Lys-132 of hemoglobin S (HbS). Two other proline derivatives containing a salicylate leaving group, (4S)-1-butyryl-4-[(carboxymethyl)methylamino]-L-proline, 2-ester with salicyclic acid (14a), and its 1-benzoyl analogue (14b), were designed to bind covalently to beta Lys-132, as well as to interact with beta His-2 and beta Thr-4 via ionic and hydrogen bonds. This paper describes the synthesis of these agents, beginning with natural L-hydroxyproline methyl ester, and the testing of their ability to increase or decrease the solubility of dHbS by using a standard solubility assay. The covalent derivatives 14a,b were found to be inactive, while the noncovalent compounds 9a,b showed weak antigelling activity, below that observed for phenylalanine. The presence of only weak activity does not invalidate this approach, since only one structural parameter has been investigated.

Antisickling Agents↗
PubMed1983

Physiological and x-ray studies of potential antisickling agents.

Several aromatic compounds have been found to inhibit the gelling of sickle cell hemoglobin. We have tried to correlate the antigelling activity of such compounds with the stereo-chemistry of their binding sites in the hemoglobin molecule. This approach led to the discovery that two known antilipoproteinemia drugs, clofibrate and gemfibrozil, have antigelling activity. X-ray analysis showed that three pairs of molecules of clofibric acid, the active metabolite of clofibrate, bound to the walls of the internal cavity of deoxyhemoglobin A; only one pair bound to a quite different site, between helices A, E, and H of the alpha chains of carbon monoxide hemoglobin A. Unlike other antigelling agents, clofibric acid and related compounds decrease rather than increase the oxygen affinity of hemoglobin.

Antisickling Agents↗
PubMed1982

Long-term central cholinergic hypofunction induced in mice by ethylcholine aziridinium ion (AF64A) in vivo.

Ethylcholine mustard aziridinium ion (AF64A), a neurotoxic choline analog, was evaluated for its interactions with the cholinergic system in mice. Parenterally administered AF64A was lethal (LD50 = 32.6 mumol/kg i.v.) and the lethality could be antagonized even at 8 LD50 doses by pretreatment with choline (714 mumol/kg i.p.) 2 min earlier. Mice that were protected by choline slowly developed neurological motor disturbances such as ataxia and hypokinesia, and lost weight. Intracerebroventricular administration of 65 nmol of AF64A was not acutely lethal, but produced similar delayed behavioral effects similar to those found after parenteral administration of AF64A. Seven days after a single injection of 65 nmol of AF64A i.c.v., there was a significant decrease in acetylcholine content in the cortex, striatum and hippocampus, but no change in choline levels. Acetylcholine content was still significantly reduced in the hippocampus at 3 weeks after this treatment. The reduction in activity of choline acetyltransferase and high-affinity choline transport paralleled the reduction in acetylcholine measured at 7 days post AF64A treatment, whereas muscarinic receptors in all three brain areas were unchanged. These combined data indicate that AF64A is a presynaptic chemical neurotoxin, capable of inducing a persistent deficiency in central cholinergic transmission.

Acetylcholine↗
PubMed1982

Correlation of partition coefficients with antisickling activity of simple alcohols, amides and ureas.

The resultant increase of the solubility of hemoglobin S in the presence of various alcohols, amides, and ureas has been found to correlate with the individual partition coefficients of each agent. Comparisons have been made using the log of the slope of the curves obtained from standard ultracentrifugation gelation assays with the antisickling agents and is expressed in terms of log (slope Cs/[A]) = k log P + k' where Cs is the solubility of HbS in gm/dL, [A] is the concentration of the agent in moles/liter, P is the partition coefficient of A, and k (slope) and k' (y intercept) constants. These results are similar to other structure activity relationships developed by Corwin Hansch and co-workers [5-8, 10]. Such comparisons illustrate in part the quantitative binding capabilities of organic molecules to proteins based upon their inherent hydrophobic character which can be calculated and predicted a priori after a few initial observations. This paper demonstrates that the solubility increase of hemoglobin S by various simple alcohols, amides and ureas results directly from the hydrophobic qualities of each additive in a given series. It is further reasoned that these small molecules interact with hydrophobic areas on hemoglobin S and that this conjugal hydrophobic interaction explains in part their mechanism of action and polymer destabilization. The role of the polar group is also shown to be important for activity.

Alcohols↗