Richard K. Olsen

Retrohydroxamate ferrichrome, a biomimetic analogue of ferrichrome

A new synthetic analogue of ferrichrome, retrohydroxamate ferrichrome, has been examined for biological activity. Although spectroscopic evidence indicates that the analogue is a weaker Fe(III) chelator than ferrichrome, retrohydroxamate ferrichrome is indistinguishable from ferrichrome in its growth factor activity for Arthrobacter flavescens, and in its potency in antagonizing the antibiotic activity of albomyhcin against Bacillus subtilis. It is as active as ferrichrome as a siderophore for the fungus, Ustaligo sphaerogena. In contrast, desmethylretrohydroxamate ferrichrome shows no significant biological activity.

Equilibrium and kinetic studies on the binding of des-N-tetramethyltriostin A to DNA.

The interaction between TANDEM (a des-methyl analogue of triostin A) and poly(dA-dT) results in extension of the helix by 6.8 A for each ligand molecule bound, exactly as predicted for a bis-intercalation reaction. Cooperativity is evident in Scatchard plots for the interaction at ionic strengths of 0.2 and 1.0, where the binding constant is diminished compared to that which pertains at low salt concentrations. Binding to a natural DNA (calf thymus), already considerably weaker than binding to poly(dA-dT), is also sensitive to increased ionic strength. With a self-complementary octanucleotide d(G-G-T-A-T-A-C-C) the binding curve indicates the presence of a single des-N-tetramethyltriostin A binding site per helical fragment with a non-cooperative association constant about 6 . 10(6) M-1. Detergent-induced dissociation of des-N-tetramethyltriostin A-poly(dA-dT) complexes results in a simple exponential decay at all levels of binding, but the time constant of decay is dependent upon the initial binding ratio. This behavior cannot directly explain the cooperativity of equilibrium binding isotherms but suggests the occurrence of relatively long-lived perturbations of the helical structure by binding of the ligand. [Ala3, Ala7]des-N-tetramethyltriostin A, which has a more flexible octapeptide ring lacking the disulphide cross-bridge, dissociates from poly(dA-dT) much faster than des-N-tetramethyltriostin A. Dissociation of des-N-tetramethyltriostin A from calf thymus DNA is more rapid than dissociation of triostin A or other quinoxaline antibiotics, which may account for its low antimicrobial activity.

Synthesis of oxazolidine derivatives of β-[3-(aryloxy)aryl]-α-amino acids by application of the diels-alder reaction

Abstract The Diels-Alder reaction has been used to construct the diaryl ether unit in oxazolidine derivatives of β-[3-(aryloxy)aryl]-α-amino acids. Cycloaddition of acetylenic ketone 6 with substituted aryloxy dienes, and subsequent aromatization, provided the title compounds in good yields. Reaction of 6 with Danishefskys diene furnished optically pure derivatives of L-tyrosine.

Synthesis of des-n-tetramethyltriostin a from C-terminal Z-d-serine tetra-and octadepsipeptide intermediates

Abstract Des-N-tetramethyltriostin A (1), a known DNA-intercalation agent, has been synthesized from tetra- and octapeptide intermediates that have Z- d -serine at the C-terminal position. The procedure thus allows the fragment coupling and cyclization reactions leading to the synthesis of the title compound to occur without racemization at the C-terminal amino acid. Esterification of Boc-Val-OH with the p-bromophenacyl ester of Z- d -serine provided didepsipeptide Z- d -Ser(Boc-Val)-OBpa (4). Stepwise addition of the requisite amino acids provided tetradepsipeptide Z- d -Ser[Boc-Ala-Cys(Acm)-Val]-OBpa (6). Fragment coupling of the respective C- and N-deprotected tetradepsipeptides 7 and 8, derived from 6, furnished linear octadepsipeptide 9, which upon cyclization and disulfide formation gave the bicyclic octadepsipeptide 11, a known synthetic precursor to 1. The degree of racemization incurred in the alanine and valine residues of selected depsipeptides was measured and the results compared with those obtained in previous studies. It was concluded that alanine, perhaps because of sequence effects, undergoes a degree of racemization (4–10%) during hydrolysis of tetradepsipeptide 6 and octadepsipeptide 9.