Joel R. Huff

A peptide–doxorubicin 'prodrug' activated by prostate-specific antigen selectively kills prostate tumor cells positive for prostate-specific antigen in vivo

We covalently linked doxorubicin with a peptide that is hydrolyzable by prostate-specific antigen. In the presence of prostate tumor cells secreting prostate-specific antigen, the peptide moiety of this conjugate, L-377,202, was hydrolyzed, resulting in the release of leucine-doxorubicin and doxorubicin, which are both very cytotoxic to cancer cells. However, L-377,202 was much less cytotoxic than conventional doxorubicin to cells in culture that do not secrete prostate-specific antigen. L-377,202 was approximately 15 times more effective than was conventional doxorubicin at inhibiting the growth of human prostate cancer tumors in nude mice when both drugs were used at their maximally tolerated doses. Nude mice inoculated with human prostate tumor cells secreting prostate-specific antigen showed considerable reductions in tumor burden with minimal total body weight loss when treated with L-377,202. This improvement in therapeutic index correlated with the selective localization of leucine–doxorubicin and free doxorubicin in tissues secreting prostate-specific antigen after exposure to L-377,202.

The total synthesis of myo-inositol polyphosphates

Abstract Total synthesis of the individual enantiomers of myo-inositol 4-phosphate ( 15 ), myo-inositol 1,4-bisphosphate ( 2 ) and myo-inositol 1,4,5-trisphosphate ( 1 ), together with syntheses of racemic myo-inositol 1,3,4-trisphosphate ( 4 ) and myo-inositol 2,4,5-trisphosphate ( 5 ) are reported. The syntheses feature the use of camphanic acid esters for resolution of protected inositols, and the use of tetrabenzylpyrophosphate as an efficient phosphorylating agent for polyhydroxy alcohols.

The total synthesis of (±)-myo-inositol-1,3,4-trisphosphate, (±)-myo-inositol-2,4,5-trisphosphate and (±)-myo-inositol-1,3,4,5-tetrakisphosphate

Abstract A total synthesis of (±)-myo-Inositol-1,3,4-Trisphosphate, (±)-myo-Inositol-2,4,5-Trisphosphate and (±)-myo-Inositol-1,3,4,5-Tetrakisphosphate is described.

Design and synthesis of N-alkylated saccharins as selective α-1a adrenergic receptor antagonists☆

Abstract Benign prostatic hyperplasia can be managed pharmacologically with α-1 adrenergic receptor antagonists. Agents that demonstrate selectivity for the α-1 a receptor subtype may offer advantages in clinical applications with respect to hypotensive side effects. The N-alkylated saccharins reported here represent a new class of subtype selective α-1 a adrenergic receptor antagonists which demonstrate potent effects on prostate function in vivo and are devoid of blood pressure side effects.

The total synthesis of myo-inositol phosphates via myo-inositol orthoformate

Novel selective alkylations of myo-inositol orthoformate (4) have been used to prepare a series of protected myo-inositol derivatives, (5a–e), (7), (10), (12), and (16). These intermediates have been used in efficient total syntheses of myo-inositol 2-phosphate, (9); myo-inositol 4-phosphate, (6); myo-inositol 1,3-bisphosphate, (18); and myo-inositol 1,3,4,5-tetrakisphosphate (14). This report represents the first total synthesis of the important natural metabolites (14) and (18) and significantly improved methods of preparation of (6) and (9).

[3H]L-654,284 as a probe of the central alpha2 adrenoceptor

SummaryL-654,284 ((2R, 12bS)-N-(1,3,4,6,7,12b-hexahydro-2H-benzo[b]-furo[2,3-a]quinolizin-2-yl)-N-methyl-2-hydroxyethanesulfonamide), a potent and selective antagonist of the alpha2 adrenoceptor, was tritiated to high specific activity. Saturation binding to cell membrane suspensions obtained from calf cerebral cortex revealed a high affinity binding site (0.63 nM). Kinetics of association and dissociation were well represented by single exponential processes, and the equilibrium dissociation constant obtained from the ratio of rate constants agreed well with that found by saturation binding. A direct comparison of saturation binding revealed that the antagonist [3H]L-654,284 had roughly the same affinity for the alpha2 adrenoceptor as the agonist [3H]clonidine and eight times the affinity of the antagonist [3H]rauwolseine. The maximum receptor densities of these radioligands were not significantly different. Competition assays with a series of compounds of known receptor affinity revealed that [3H]L-654,284 selectively binds to a site with all of the characteristics expected of the alpha2 adrenoceptor.

Chapter 1. Adenosine as a Neuromodulator in the Mammalian Central Nervous System

Publisher Summary Recently, the neuromodulatory potential of adenosine has received attention. Previously there has been skepticism about a discrete modulatory role for so ubiquitous a compound that is, with its nucleotides, involved in all aspects of cellular metabolism. Despite this, studies on non-cholinergic, non-adrenergic neurotransmission in peripheral tissues, adenosine-elicited increases in brain tissue cyclic AMP level, and other biochemical and electrophysiological studies, have indicated that adenosine, by interacting with extra cellular recognition sites, can modulate cell function in a physiologically relevant manner. Adenosine and its N-substituted cyclohexyl and l -phenyl-isopropyl analogs are potent central depressants. Conversely, the central stimulatory properties of the alkylxanthines, caffeine and theophylline have been ascribed to antagonism of endogenous adenosine. Adenosine and its analogs also have profound effects on the peripheral cardiovascular function, and it is important to distinguish between the direct effects of the compound on nerve tissue excitability and secondary effects resulting from the changes in blood flow. Both cyclic AMP (cAMP) and cyclic GMP (cGMP) have been described as intracellular second messengers. Thus, changes in the levels of these nucleotides by various effectors can be related to nerve cell activity. Adenosine can either stimulate or inhibit cyclic AMP formation in the mammalian tissues depending on the type of receptor activated.