Synthesis and antitumor activity of a series of sulfone analogs of 1,4-naphthoquinone

Abstract

A series of novel substituted thiochromones and thiochroman-4-ones was synthesized. Compounds were designed as analogues of naphthoquinone and as potential "bioreductive alkylating agents" and were tested for antitumor activity. The lead compound, 3-(chloromethyl)thiochromone 1,1-dioxide (4), inhibited Ehrlich ascites tumor growth by 100% in CF1 male mice at 10 (mg/kg)/day ip. Similarly, 18 of the 29 related compounds demonstrated good activity in this tumor screen. Few definitive structure-activity correlations were evident regarding the nature of the 3-substituent. However, the 2,3 double bond and a sulfone or sulfoxide were required for activity. Four of the compounds synthesized showed marginal but significant activity against P-388 lymphocytic leukemia.

Effects of 3-Chloromethylthiochromone-1, 1-dioxide on Nucleic Acid, Protein, and Aerobic and Anaerobic Metabolism of Ehrlich Ascites Tumor Cells

“…However, the relative therapeutic effectiveness of intermittent and continuous dosage regimens for these compounds is uncertain (4, 5 ) . Attempted correlations of therapeutic effectiveness with various pharmacokinetic parameters, such as maximum plasma concentration (6), the time period during which drug levels exceed the minimum inhibitory concentration (7), area under the plasma level curve (8), intensity factor (9), and the degree of serum protein binding (lo), have been difficult due to the many interactions between the drug, bacteria, infection site, and host. Information ob-…”

“…The synthesis and physical characteristics were reported previously (9). Certain of these agents were found to be active against the growth of Ehrlich ascites carcinoma and moderately active against P-388 lymphocytic leukemia growth in mice (9). The most potent compound, 3-chloromethylthiochromone-1,l-dioxide (I), afforded 100% 0 A0 I Scheme 1 inhibition of Ehrlich ascites growth at 10-mg/kg/day dose ip (9).…”

“…For example, dichloroallylawsone is currently in clinical trials in the United States (1)(2)(3)(4)(5)(6)(7)(8). An investigation of sulfone analogs of naphthoquinones was undertaken recently (9), resulting in a series of substituted thiochromones and thiochroman-4-ones and their 1,l-dioxides. The synthesis and physical characteristics were reported previously (9).…”

“…An investigation of sulfone analogs of naphthoquinones was undertaken recently (9), resulting in a series of substituted thiochromones and thiochroman-4-ones and their 1,l-dioxides. The synthesis and physical characteristics were reported previously (9). Certain of these agents were found to be active against the growth of Ehrlich ascites carcinoma and moderately active against P-388 lymphocytic leukemia growth in mice (9).…”

“…Certain of these agents were found to be active against the growth of Ehrlich ascites carcinoma and moderately active against P-388 lymphocytic leukemia growth in mice (9). The most potent compound, 3-chloromethylthiochromone-1,l-dioxide (I), afforded 100% 0 A0 I Scheme 1 inhibition of Ehrlich ascites growth at 10-mg/kg/day dose ip (9). Previously, it has been postulated that certain 1,4-naphthoquinones require bioactivation by reduction of the quinone and subsequent displacement of a leaving group to form the potential alkylating agent (10).…”