Synthesis and cytotoxicity of substituted ethyl 2-phenacyl-3-phenylpyrrole-4-carboxylates.
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.
Evans
Michael A
MA
Department of Chemistry and Biochemistry, Rider University, Lawrenceville, NJ 08648, USA.
Smith
Daniel C
DC
Holub
Justin M
JM
Argenti
Anthony
A
Hoff
Mafoloe
M
Dalglish
Gerard A
GA
Wilson
Donna L
DL
Taylor
Brett M
BM
Berkowitz
Joshua D
JD
Burnham
Bruce S
BS
Krumpe
Keith
K
Gupton
John T
JT
Scarlett
Tanya C
TC
Durham
Richard W
RW
Hall
Iris H
IH
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
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011758:Pyrroles