title: Synthetic prodigiosenes and the influence of C-ring substitution on DNA cleavage, transmembrane chloride transport and basicity.
abstract: Analogues of the tripyrrolic natural product prodigiosin bearing an additional methyl and a carbonyl group at the C-ring were synthesised and evaluated. In vitro anticancer activity screening (NCI) and the study of modes of action (copper-mediated cleavage of double-stranded DNA and transmembrane transport of chloride anions) showed that the presence of the methyl group is not detrimental to activity. Furthermore, although the presence of an ester conjugated to the prodigiosene C-ring seems to decrease both pK(a) and chloride transport efficiency compared to the natural product, these analogues still exhibit a high rate of chloride transport. All analogues exhibit good in vitro anticancer activity and reduced toxicity compared to the natural product: compare an acute systemic toxicity of 100 mg kg(-1) in mice vs. 4 mg kg(-1) for prodigiosin, pointing towards a larger therapeutic window than for the natural product.
authors: Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA.
authors: Soumya
authors: S
authors: Rastogi
authors: Estelle
authors: E
authors: Marchal
authors: Imam
authors: I
authors: Uddin
authors: Brandon
authors: B
authors: Groves
authors: Julie
authors: J
authors: Colpitts
authors: Sherri A
authors: SA
authors: McFarland
authors: Jeffery T
authors: JT
authors: Davis
authors: Alison
authors: A
authors: Thompson
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D002244:Carbon / Q000737:chemistry*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism*; D060326:Chemistry Techniques, Synthetic; D002712:Chlorides / Q000378:metabolism*; D053837:DNA Cleavage / Q000187:drug effects*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051379:Mice; D011353:Prodigiosin / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D002712:Chlorides; D002244:Carbon; D011353:Prodigiosin