The synthetic approach to the concerted antitumor mechanism of bleomycin is studied by introducing a dynamic change into the O2*activation moiety and DNA-binding site. A model PYML(6)-bleomycin previously reported, possessing an oxygen-activating methoxypyridine moiety and a DNA-binding bithiazole moiety, exhibits a nucleotide cleavage mode virtually identical with that of bleomycin. Herein reported is a newly designed bleomycin analogue, PYML( 6)-(4/?-APA)-distamycin, wherein the 4-methoxypyridine moiety and a DNA-binding distamycin component are connected through an (/?)-4-aminopentanoic acid linker moiety. Synthesis of PYML( 6)-(4/?-APA)-distamycin is carried out by condensation of the hydroxyhistidine-pentanoic acid fragment with the methoxypyridine moiety, followed by introduction of the distamycin moiety. PYML( 6)-(4R-APA)-distamycin cleaves a G4 phage DNA fragment (100 base pairs) at 1 mM concentration in the presence of Fe(II), oxygen, and dithiothreitol and induces dramatically altered adenine/thymine specificity. It is indicated that the specific recognition of base sequences for the cleavage is mainly controlled by the DNA affinity site and that the (/?)-4-aminopentanoic acid linker seems to determine the proper arrangement of the iron-oxygen site and the distamycin moiety on DNA. Bleomycins (BLMs) are chemotherapeutic agents used for the clinical treatment of Hodgkin's lymphoma, carcinomas of the skin, head, and neck, and tumors of the testis.1 The drug was isolated from Streptomyces verticillus as a copper chelate by Umezawa f Synthetic Studies on Antitumor Antibiotic, Bleomycin. 27.

The highly cytostatic didemnins contain a 23-membered cyclopeptolide with a side chain attached to the backbone through the amine group of threonine. Thirty-six derivatives varying the side chain were prepared, but only compounds with D-MeLeu attached to threonine show remarkable biological activities. To protect the macrocycle from degradation by lipases the two ester bonds were replaced successively by amide bonds. Although these variations have a major effect on the conformation and rigidity of the ring, the compound which contains exclusively amide bonds is highly active, equivalent to acetyl-didemnin A.

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After some period of little or no development activities, the field of 5-HT6 receptor antagonists attracted a lot of attention with three companies (GSK, Pfizer and Lundbeck) confirming aggressive development plans and initiating pivotal Phase II and III studies. These studies will be critical to prove that 5-HT6 receptor antagonists have a symptomatic efficacy profile that can be differentiated from that of currently used agents (cholinesterase inhibitors and the NMDA-antagonist memantine). Furthermore, there are several sets of data that point at a disease-modifying potential of this class of agents and these effects are likely to receive critical exploration if the ongoing symptomatic trials bring 5-HT6 antagonists closer to clinical use.

Cyclic hexapeptide analogues representing the modified retro sequence of the amino acid residues 7‐11 of natural somatostatin are known to protect liver cells from phalloidin poisoning. To determine the influence of steric, lipophilic, and charge effects on (a) the conformation of the backbone and the aromatic side chains and (b) the biological response, the side chains of Phe2, Lys4, and Phe6 of cyclo(‐d‐Pro1‐Phe2‐Thr3‐Lys(Z)4‐Trp5‐Phe6‐), 1a, one of the most active peptides found so far, were modified by various residues. The discussion of conformationally relevant parameters proves that neither backbone conformations nor populations of aromatic side chain rotamers were altered by these substitutions. The potency of these derivatives in a cytoprotection assay varies by at most one order of magnitude (more or less active than the parent peptide 1a). A qualitative evaluation of lipophilic, steric, and charge effects reveals the dominance of lipophilic effects of aromatic residues; the most potent compounds contain aromatic substructures in the side chain of Lys4.