Synthesis and electrochemical studies of a new iron tetra-catecholamide complex.

A new tetra-catecholamide compound N5,N6-thiodipropanoyl-bis[N1,N10-bis(2,3-dihydroxybenzoyl-spermidi ne)] (H8L) has been synthesised as an iron chelator of Fe (III). Cyclic voltammogram of the iron complex H2LFe run under an argon atmosphere shows a quasi-reversible redox process with E0 = -430 mV vs. SCE in CH3OH/H20 (60/40). This value approaches the range of biological reductants and consequently the complex may mimic the release of iron from enterobactin to the agents which are directly involved in cell metabolism.

Conjugates of catecholamines. VII. Synthesis and beta-adrenergic activity of peptide catecholamine conjugates.

A series of novel catecholamine derivatives has been prepared in which one of the N-methyl substituents of isoproterenol has been extended by a spacer consisting of a chain of four methylenes which terminates with an amide linkage to a peptide, the point of attachment being via the aromatic amino group of p-aminophenylalanine. In one of the derivatives, two catecholamines are attached to the same peptide in this manner. The peptides, which range in size from three to eight amino acid residues and contain phenylalanine, glycine, and L-alpha-amino-delta-hydroxyvaleric acid, were synthesized via stepwise and fragment condensation techniques. The beta-adrenergic agonist activities of the derivatives were evaluated in vitro by measuring the intracellular accumulation of cyclic AMP in S49 mouse lymphoma cells.

Conjugates of catecholamines. 6. Synthesis and beta-adrenergic activity of N-(hydroxyalkyl)catecholamine derivatives.

A new series of catecholamines has been prepared in which the N-alkyl substituent of dl-epinephrine or dl-isoproterenol has been extended by a methylene chain terminated by a hydroxyl group or derived functionality (e.g., carbamate or ester). These functionalized catecholamines (congeners) and model compounds were prepared with the goal of eventual attachment to polymeric carrier molecules. The beta-adrenergic agonist activity of the derivatives was evaluated in vitro by measuring the intracellular accumulation of cyclic AMP in S49 mouse lymphoma cells and by the displacement of iodocyanopindolol (ICYP). A n-butylcarbamate derivative (compound 15) was the most active compound in this series with a potency 190 times greater than dl-isoproterenol in the S49 assay. The biological results indicate that minor modifications in structure in the N-alkyl substituent of the catecholamine can influence the pharmacologic activity.

Conjugates of catecholamines. 1. N-alkyl-functionalized carboxylic acid congeners and amides related to isoproterenol.

A series of functionalized catecholamines (congeners) has been synthesized in which, formalistically, the N-isopropyl group of isoproterenol has been extended by a linear alkyl chain of varying length, terminated by a carboxy group or a substituted amide. The compounds were prepared generally via the reductive amination of norepinephrine with a keto acid or a preformed keto amide. An alternate synthesis of the model amide derivatives, involving activation of the carboxylic acid congeners and coupling with amines, was complicated in the case of short-chain derivatives by facile cyclization to lactams. In vitro evaluation of these compounds as potential beta-adrenergic agonists has shown that, while the carboxylic acid congeners have relatively low potencies, the model amide derivatives have potencies that are highly dependent on both the length of the alkyl chain and also the nature of the substituent on the amide. In general, aromatic amides are the most potent, although the nature and position of substituents on the aromatic group dramatically influences their potency. The implications of these studies, in terms of general beta-adrenergic drug design and also the attachment of the carboxylic acid congeners to carriers, are discussed.