Synthesis of side chain-modified iodothyronines. Synthesis and structure-activity relationships (SARS) of galanthamine derivatives. Total synthesis of (+)-valyldetoxinine. Synthesis and mechanism of cyclic acetal and ketal formation in pentono-1,4-lactone

New side chain-modified iodothyronines have been synthesized. They include: 1- (4-(4-hydroxyphenoxy)-3,5-diiodo-phenyl) -1,2-ethanediol(T{dollar}sb2 {dollar}EG); {dollar}alpha{dollar}-hydroxy-4-(4-hydroxyphenoxy)-3,5-diiodobenzeneacetic acid (T{dollar}sb2{dollar}HAA) and their 4-methylether derivatives (MT{dollar}sb2{dollar}EG, MT{dollar}sb2{dollar}HAA); 1- (4-(hydroxyphenoxy)-3,5-diiodo-phenyl) -2-aminoethanol (T{dollar}sb2{dollar}EA); 1- (4-(4-hydroxy-3-iodophenoxy)-3,5-diiodophenyl) -1,2-ethanediol (T{dollar}sb3{dollar}EG); 1- (4-(4-hydroxy-3-iodophenoxy)-3,5-diiodophenyl) -2-aminoethanol (T{dollar}sb3{dollar}EA); and {dollar}alpha{dollar}-hydroxy-4-(3-iodo-4-hydroxyphenoxy)-3,5-diiodobenzeneacetic acid (T{dollar}sb3{dollar}HAA).; The synthesis and structure-activity relationships (SARs) of galanthamine derivatives are examined. Structural studies of the alkaloid galanthamine, a cortical acetylcholinesterase (AChE) inhibitor, and its salt, galanthamine methiodide, were carried out both in solution and in the solid state, using spectroscopic methods. Structural and pharmacological studies of nineteen analogs of galanthamine were conducted. Systematic derivatization of galanthamine at the cyclohexene ring, tertiary amino, hydroxyl and methoxyl functions indicated that these structural features are essential for biological activity. One derivative, galanthamine n-butyl carbamate, had an LD{dollar}sb{lcub}50{rcub}{dollar} of over 100 mg/kg (i.p.) in mice. In a passive avoidance paradigm, this analog improved performance in a dose-dependent fashion with a peak effect at 0.1 mg/kg in control and 0.5 mg/kg in basal forebrain lesioned mice. With the surprisingly high therapeutic ratio, this compound may be of interest in treating cholinergic deficits of the central nervous system such as Alzheimer's disease.; The total synthesis is described of (+)-valyldetoxinine, a member of the detoxin complex, metabolites produced by Streptomyces caespitosus var. detoxicus 7072 GC{dollar}sb1.{dollar} The detoxin complex is a selective antagonist of the antibiotic blasticidin S. The total syntheses of (+)-valyldetoxinine and (2R,3S,4R)-2-hydroxymethyl-3,4-dihydroxypyrrolidine hydrochloride, a very potent competitive inhibitor of an {dollar}alpha{dollar}-galactosidase and a moderate inhibitor of an {dollar}alpha{dollar}-mannosidase, were both completed. (Abstract shortened with permission of author.)...