Using a simple model of ligand−receptor interactions, the interactions between ligands and receptors of varying complexities are studied and the probabilities of binding calculated. It is observed that as the systems become more complex the chance of observing a useful interaction for a randomly chosen ligand falls dramatically. The implications of this for the design of combinatorial libraries is explored. A large set of drug leads and optimized compounds is profiled using several different properties relevant to molecular recognition. The changes observed for these properties during the drug optimization phase support the hypothesis that less complex molecules are more common starting points for the discovery of drugs. An extreme example of the use of simple molecules for directed screening against thrombin is provided.

Molecular Complexity and Its Impact on the Probability of Finding Leads for Drug Discovery

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Palladium‐Catalyzed Direct Arylation of (Hetero)Arenes with Aryl Boronic Acids

A simple and general copper-catalyzed method has been developed for transformations of various functional groups (-I, -N(3), -SO(2)R, -OH, -NH(2), and -NO(2)) on aromatic rings from arylboronic acids in water under air. The protocol uses cheap and readily available inorganic salts (KI, NaN(3), NaSO(2)R, NaOH, NaNO(2)) and aqueous ammonia as the functional-group sources, simple Cu(2)O/NH(3) as the catalyst system, environmentally friendly water as the solvent, and oxygen in air as the oxidant. Importantly, the copper catalyst system in water was recyclable. This study should provide a useful strategy for interconversions of the functional groups on aromatic rings.

General Copper‐Catalyzed Transformations of Functional Groups from Arylboronic Acids in Water

The coupling of enantiomerically enriched amines with aryl bromides produces the corresponding N-aryl derivatives. The choice of ligand in the palladium-catalyzed coupling is critical to the format...

Palladium-Catalyzed Coupling of Optically Active Amines with Aryl Bromides

Boronic Esters in Stereodirected Synthesis

A process for the preparation of alkyl amines in which the reagents are generated in situ under mild and convenient reaction conditions is described. An organoborane is prepared via hydroboration, aqueous ammonium hydroxide is added, and then aqueous sodium hypochlorite is added to the mixture. Two of the alkyl groups in the trialkylborane are converted to the corresponding amines in good yield. (BLM)

Convenient synthesis of alkyl amines via the reaction of organoboranes with ammonium hydroxide

To determine the myocardial uptake and retention properties of radioiodinated tellurium fatty acids, we prepared two new tellurium fatty acids in which iodine-/sup 125/ has been chemically stabilized by attachment as a trans-vinyl iodide (I-CH . CH-R-Te-R'-COOH) and evaluated them in rats. Fabrication of 18-iodo-13-tellura-17-octadecenoic acid was accomplished by coupling 1,5-diiodo-1-pentene with sodium 12-(methoxycarbonyl)-n-dodecan-1-yl telluride. The (5-/sup 125/I)-1,5-diiodo-1-pentene was prepared by an organoborane technique involving /sup 125/I+ treatment of 5-iodo-1-penten-1-ylboronic acid (I(CH/sub 2/)/sub 3/CH . CHB(OH)/sub 2/). The absolute heart uptake of this agent was moderate (1.47-2.52% dose/g after 60 min), but the heart/blood ratios were low (approximately 2.6:1). Only marginal in vivo deiodination occurred, since the thyroid uptake was low (15-18% dose/g after 60 min). The effect of tellurium in position 13 was unexpected. To determine if the low heart specificity and low heart/blood ratios were dependent upon the position of the tellurium, we prepared an analogue with the same chain length, 18-(/sup 125/I)iodo-7-tellura-17-octadecenoic acid, in the same manner by reaction of (11-/sup 125/I)-1,11-diiodo-1-undecene with sodium 6-(methoxycarbonyl)-n-hexan-1-yl telluride. This agent showed pronounced heart uptake (2.47-3.94% dose/g after 60 min) and prolonged retention (1.76-3.14% dose/g after 4 h) in rats. Furthermore, the heart/blood ratios remained high for several hours (13:1more » after 60 min; 9:1 after 4 h). Iodine-123 labeled 18-iodo-7-tellura-17-octadecenoic acid is an attractive new compound for evaluation as a myocardial imaging agent.« less

New myocardial imaging agents: stabilization of radioiodine as a terminal vinyl iodide moiety on tellurium fatty acids

Radioiodine-labeled pharmaceuticals have been used extensively in diagnostic nuclear medicine. We have developed a rapid and mild method for incorporating radioiodine into functionally substituted molecules. The new process involves the reaction of the radioiodide ion with organoboranes in the presence of gentle oxidizing reagents. The radioiodide is utilized nearly quantitatively in a matter of seconds. The radiochemical yields are excellent, and parallel those obtained when iodine monochloride is reacted with organoboranes.

http://jnm.snmjournals.org/content/22/10/908.full.pdf

Rapid and Mild Syntheses of Radioiodine-Labeled Radiopharmaceuticals

Synthesis of arylboronic acids via the reaction of borane with arylmagnesium halides

The effect of tellurium (Te) position on myocardial specificity and retention of fatty acids in which radioiodide is stabilized as a trans-(E)-vinyl iodide has been evaluated in rats. Five analogues of 18-iodo-17-octadecenoic acid (ICH = CH-R-Te-R'-COOH) with Te at positions 5, 7, 9, 11, and 13 were prepared by coupling of a trans-diiodoalkene (ICH = CH-R-I) with the requisite sodium [(alkoxycarbonyl)alkyl]telluride substrate (NaTe-R'-COOR"; R" = Me or Et), followed by basic hydrolysis. By varying R and R', a series of analogues with a chain length of 18 carbon atoms was prepared. The telluride substrates were generated in situ by NaBH4 reduction of the corresponding ditellurides, and the diiodoalkenes were prepared by sodium iodide-chloramine-T treatment of the corresponding vinylboronic acids [(HO)2BCH = CH-R-I)]. The vinylboronic acids were prepared by treatment of the terminal acetylenes (HC identical to C-R-I), synthesized from commercially available materials, with catecholborane. All new compounds were analyzed by TLC, NMR, MS, and elemental analyses. The 125I analogues [(E)-125ICH = CH-R-Te-R'-COOH] were prepared in the same manner and evaluated in rats (four per group). Heart uptake and retention were dependent upon the Te position. The analogue with Te at position 5 showed the most pronounced (5-min values) heart uptake (3.7-4.1 dose/g), myocardial retention, and heart/blood ratios (37:1) and is a candidate for radiolabeling with 123I and further evaluation as a myocardial imaging agent.

Kunda A. R. Sastry

Papers

Convenient synthesis of alkyl amines via the reaction of organoboranes with ammonium hydroxide

New myocardial imaging agents: stabilization of radioiodine as a terminal vinyl iodide moiety on tellurium fatty acids

Rapid and Mild Syntheses of Radioiodine-Labeled Radiopharmaceuticals

Synthesis of arylboronic acids via the reaction of borane with arylmagnesium halides

Effect of tellurium position on the myocardial uptake of radioiodinated 18-iodotellura-17-octadecenoic acid analogues.