title: Synthesis and cytotoxicity of substituted ethyl 2-phenacyl-3-phenylpyrrole-4-carboxylates.
abstract: The substituted ethyl-2-phenacyl-3-phenylpyrrole-4-carboxylates were synthesized by a condensation of a beta-chloroenal and an alpha-aminoketone under neutral conditions. They proved to be potent cytotoxic agents against the growth of murine L1210 and P388 leukemias and human HL-60 promyelocytic leukemia, HuT-78 lymphoma, and HeLa-S(3) uterine carcinoma. Selective compounds were active against the growth of Tmolt(3) and Tmolt(4) leukemias and THP-1 acute monocytic leukemia, liver Hepe-2, ovary 1-A9, ileum HCT-8 adenocarcinoma, and osteosarcoma HSO. A mode of action study in HL-60 cells demonstrated that DNA and protein syntheses were inhibited after 60 min at 100 microM. DNA and RNA polymerases, PRPP-amido transferase, dihydrofolate reductase, thymidylate synthase, and TMP kinase activities were interfered with by the agent with reduction of d[NTP] pools. Nonspecific interaction with the bases of DNA and cross-linking of the DNA may play a role in the mode of action of these carboxylates.
authors.affiliation: Department of Chemistry and Biochemistry, Rider University, Lawrenceville, NJ 08648, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Evans
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Smith
authors.forename: Justin M
authors.initials: JM
authors.lastname: Holub
authors.forename: Anthony
authors.initials: A
authors.lastname: Argenti
authors.forename: Mafoloe
authors.initials: M
authors.lastname: Hoff
authors.forename: Gerard A
authors.initials: GA
authors.lastname: Dalglish
authors.forename: Donna L
authors.initials: DL
authors.lastname: Wilson
authors.forename: Brett M
authors.initials: BM
authors.lastname: Taylor
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Berkowitz
authors.forename: Bruce S
authors.initials: BS
authors.lastname: Burnham
authors.forename: Keith
authors.initials: K
authors.lastname: Krumpe
authors.forename: John T
authors.initials: JT
authors.lastname: Gupton
authors.forename: Tanya C
authors.initials: TC
authors.lastname: Scarlett
authors.forename: Richard W
authors.initials: RW
authors.lastname: Durham
authors.forename: Iris H
authors.initials: IH
authors.lastname: Hall
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D053938:DNA Fragmentation; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D051379:Mice; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011758:Pyrroles