Table of Contents
Metal-Based Drugs
Volume 5 (1998), Issue 3, Pages 147-160
http://dx.doi.org/10.1155/MBD.1998.147

Cytotoxicity of Poly(Phenolic)Sulfonates and Their Sodium Salts in L1210 Lymphoid Leukemia Cells

Division of Medicinal Chemistry and Natural Products, University of North Carolina Chapel Hill, Chapel Hill 27599-7360, N.C., USA

Received 2 April 1998; Accepted 24 April 1998

Copyright © 1998 Hindawi Publishing Corporation. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Poly(phenolic)-sulfonates demonstrated very good cytotoxicity against the growth of tumor cell lines (L1210, Tmolt-3, HeLa-S3) and are comparable in potency with typical clinically used anticancer drugs. Four of the most active compounds, i.e. GL-2021, GL-2029, GL-2041 and GL-2063, were selected for a mode of action study in L1210 lymphoid leukemia cells at concentration of 25μM to 100μM for 60 min. The agents did not alkylate bases of ct-DNA, cause intercalation between base pairs, produce cross linking of ct-DNA strands or generate free radicals although L1210 DNA fragmentation was observed after 24 hr incubation. L1210 DNA synthesis was preferentially inhibited which was achieved by (1) suppressing DNA polymerase α activity which reduced the synthesis of new strands of DNA, (2) reducing of de novo purine synthesis at the regulatory enzyme PRPP amido transferase which reduced d(GMP) levels, and (3) inhibiting of nucleoside kinase activities which further reduced DNA synthesis. DNA template activity was altered by the poly(phenolic)sulfonates since they reduced DNA polymerase α and m-RNA and t-RNA polymerase activities. The kinetic studies at 50 μM over 2 hr demonstrated that the agents’ effect on PRPP-amido transferase activity is probably a major target of the compounds.