tenulin and Carcinoma-256--Walker

Systematic structural modifications were performed on the natural sesquiterpene lactone tenulin to define those groupings essential to, or significant in, its in vivo antitumor activity. Accordingly, the following tenulin analogs were prepared: dihydrotenulin, 2,3-epoxytenulin, isotenulin, dihydroisotenulin, 2,3-epoxyisotenulin, and tetrahydrodeacetylisotenulin. Both the cyclopentenone and the hemiketal units in tenulin were necessary for high in vivo activity.

Topics: Animals; Antineoplastic Agents, Phytogenic; Carcinoma 256, Walker; Female; Lactones; Leukemia, Experimental; Mice; Rats; Sesquiterpenes; Structure-Activity Relationship

Evidence is presented that sesquiterpene lactones or ketones containing the O=CC=CH2 moiety, e.g., tenulin and helenalin, alkylate the thiol group of reduced glutathione and L-cysteine in vitro. A proposal is offered that this mechanism of action is responsible for the observed potent in vivo antitumor activity of these agents in the Ehrlich ascites and Walker 256 carcinosarcoma and to a lesser extent in the P388 leukemic screen. Inhibition of tumor growth is thought to occur due to the O=CC=CH2 system alkylating by rapid Michael addition the SH biological nucleophiles of key regulatory enzymes of nucleic acid and chromatin metabolism. This proposition is in accord with the ability of these agents to inhibit DNA synthesis and gene activity of Ehrlich ascites cells.

Topics: Animals; Antineoplastic Agents, Phytogenic; Ascitic Fluid; Carcinoma 256, Walker; Carcinoma, Ehrlich Tumor; Chromatin; Cyclopentanes; Cysteine; DNA, Neoplasm; Glutathione; Histidine; Lactones; Leukemia, Experimental; Leukemia, Lymphoid; Male; Mice; Mice, Inbred DBA; Neoplasm Proteins; Rats; Sesquiterpenes; Sesquiterpenes, Guaiane; Spectrophotometry, Ultraviolet; Time Factors