title: Influence of the a-ring on the redox and nuclease properties of the prodigiosins: importance of the bipyrrole moiety in oxidative DNA cleavage.
abstract: Prodigiosin (Prod, 1) is the parent member of a class of polypyrrole natural products that exhibit promising immunosuppressive and cytotoxic activity. They can facilitate copper-promoted oxidative double-strand (ds) DNA cleavage through reductive activation of Cu(II). This is triggered by oxidation of the electron-rich Prod molecule and may provide a basis for the cytotoxicity of the prodigiosins. To gain an understanding of this activity, we prepared several Prod analogues with various A-ring systems to examine their electrochemical properties in acetonitrile (MeCN) as a means to establish a basis for structure-reactivity relationships in copper-promoted nuclease activity. The intact bipyrrole (BP) chromophore is critical for the copper-mediated nuclease properties of the Prods. In fact, simple BP systems are shown to facilitate oxidative single-strand (ss) DNA cleavage. Replacement of the Prod A-pyrrole ring with alternative arenes (phenyl, furan-2-yl, or thiophen-2-yl) inhibits DNA strand scission and raises the half-peak oxidation potential (E(p/2)) of the Prod free base [E(p/2) = 0.44 V vs saturated calomel electrode (SCE) in MeCN] by ca. 200 mV. The same effect was achieved through attachment of an electron-withdrawing group (acetyl) at the 5'-position of the A-pyrrole ring. The structural modifications that inhibit DNA cleavage correlate with known structure-reactivity relationships of Prods against leukemia and melanoma cancer cells. The implications of our findings with regard to the cytotoxicity of the Prods are discussed.
authors.affiliation: Department of Chemistry, Wake Forest University, Winston-Salem, North Carolina 27109-7486, USA.
authors.forename: Matt S
authors.initials: MS
authors.lastname: Melvin
authors.forename: M Wade
authors.initials: MW
authors.lastname: Calcutt
authors.forename: Ronald E
authors.initials: RE
authors.lastname: Noftle
authors.forename: Richard A
authors.initials: RA
authors.lastname: Manderville
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry; D003300:Copper / Q000494:pharmacology; D004563:Electrochemistry; D004706:Endodeoxyribonucleases / Q000737:chemistry / Q000187:drug effects; D010084:Oxidation-Reduction; D011353:Prodigiosin / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D011758:Pyrroles; D003300:Copper; D004706:Endodeoxyribonucleases; C118972:cleavase; D011353:Prodigiosin