title: Synthesis and cytotoxicity of 2,4-disubstituted and 2,3,4-trisubstituted brominated pyrroles in murine and human cultured tumor cells.
abstract: The 2,4-disubstituted and 2,3,4-trisubstituted brominated pyrroles were successfully prepared and demonstrated potent cytotoxicity against the growth of suspended murine and human tumors, i.e. leukemia and lymphomas, acute monocytic leukemia, and HeLa-S3 uterine carcinoma. The brominated compounds were more selective in inhibiting the growth of tumors derived from human solid tumors. Nevertheless, activity with some of the derivatives occurred in the human KB nasopharynx, SW-480 colon, and HCT ileum adenocarcinoma, and lung A549 carcinoma screens. In Tmolt4 T cell leukemia cells DNA synthesis was reduced over 60 min from 25 to 100 microM followed by RNA synthesis reduction. De novo purine synthesis was retarded with the regulatory enzyme PRPP-amido transferase being markedly inhibited with less effects on the activities of IMP dehydrogenase, dihydrofolate reductase,, and the nucleoside kinases. After 60 min incubations d[TTP] and d[GTP] pools were marginally reduced. In vitro ct-DNA studies suggest that the agents may affect the DNA molecule itself with increased DNA viscosity and the Tmolt4 studies suggest that DNA cross-linking of DNA strands may be present.
authors.affiliation: Division of Medicinal and Natural Products, School of Pharmacy, University of North Carolina, Chapel Hill 27577-7360, USA.
authors.forename: J T
authors.initials: JT
authors.lastname: Gupton
authors.forename: B S
authors.initials: BS
authors.lastname: Burham
authors.forename: K
authors.initials: K
authors.lastname: Krumpe
authors.forename: K
authors.initials: K
authors.lastname: Du
authors.forename: J A
authors.initials: JA
authors.lastname: Sikorski
authors.forename: A E
authors.initials: AE
authors.lastname: Warren
authors.forename: C R
authors.initials: CR
authors.lastname: Barnes
authors.forename: I H
authors.initials: IH
authors.lastname: Hall
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002470:Cell Survival; D004273:DNA, Neoplasm / Q000187:drug effects; D006801:Humans; D006842:Hydrocarbons, Brominated / Q000138:chemical synthesis* / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis* / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D006842:Hydrocarbons, Brominated; D011758:Pyrroles