Total Synthesis of Bleomycin A2 and Related Agents. 1. Synthesis and DNA Binding Properties of the Extended C-Terminus: Tripeptide S, Tetrapeptide S, Pentapeptide S, and Related Agents

A Bifunctional Platinum(II) Complex Capable of Intercalation and Hydrogen‐Bonding Interactions with DNA: Binding Studies and Cytotoxicity

“…[44] ), which is known to bind to DNA by both intercalation and groove binding. [45] Binding of both 1 and 2 to DNA led to enhancement of the 3 MLCT emission originating from the triplet [Pt!p*(CNN)] excited state. Here, the environmental effects imposed by the 4-dpt or py ligand on the emissive excited state, which primarily involves the CNN ligand, should be minimal.…”

Sequence-specific Changes in the Metal Site of Ferric Bleomycin Induced by the Binding of DNA

“…In contrast, the structural features of Fe-BLM responsible for the sequence and chemical specificity of the DNA degradation reaction remain largely obscure. Indeed, there have been reports implicating almost every region of the Fe-BLM molecule, including the C-terminal bithiazole and dimethylsulfonium groups (15)(16)(17), the N-terminal metal binding site (18 -20), the primary amine of the ␤-aminoalanine residue (21), and the "linker region" that connects the metal binding site with the bithiazole group (22,23), as being responsible, at least in part, for the sequence selectivity of Fe-BLM-mediated DNA degradation. While many of these reports appear to provide conflicting results, the one requirement from all but one (24) of these studies is that for sequencespecific cleavage of DNA to occur, both the metal binding site and bithiazole moiety must be intact.…”

Bleomycin Biosynthesis inStreptomyces verticillusATCC15003: A Model of Hybrid Peptide and Polyketide Biosynthesis

“…There have been continuing attempts to develop new BLM congeners to define the fundamental functional roles of the individual subunits and to search for drugs with better clinical efficacy and lower toxicity (11)(12)(13). Although total chemical synthesis of BLM has been accomplished (4,5,(13)(14)(15)(16)(17) and semisynthesis and directed biosynthesis have produced a large number of BLM congeners (6), the former has very limited practical value and the latter has been problematic due to the heterogeneity and structural complexity of the naturally available BLMs and can only access a few functional groups.…”

“…1). Fujii (18), Umezawa (18,25), Takita (20,21), and coworkers studied the biosynthesis of BLM by feeding experiments with 14 C-and 13 C-labeled compounds. These studies showed that the BLM aglycone, 5, was derived from a serine (Ser), two asparagines (Asn), a histidine (His), an alanine (Ala), an acetate, a threonine (Thr), a ␤-alanine (␤-Ala), and two cysteines (Cys), indicative of a hybrid peptide and polyketide biogenesis, with the two methyl groups from methionine (Met) and the ␤-hydroxy group of His from molecular oxygen (Fig.…”

“…The first evidence supporting the hypothesis that BLM biosynthesis involves a nonribosomal PTS mechanism came from the observation that addition of an amine to the fermentation medium suppressed the production of BLM congeners with other C-terminal amines and that 14 C-labeled amines were incorporated specifically at the C-terminal amine moiety of BLM (26). The assembly of 5 must have initiated at the ␤-aminoalaninamide moiety and concluded with the introduction of the terminal amine, consistent with the multiple carrier thiotemplate model of PTS effecting N to C stepwise assembly of the peptide product (24).…”