No abstract

2-(4-[(7-Chloro-2-quinoxalinyl)oxy]phenoxy)propionic acid (XK469) is among the most highly and broadly active antitumor agents to have been evaluated in our laboratories and is currently scheduled to enter clinical trials in 2001. The mechanism or mechanisms of action of XK469 remain to be elaborated. Accordingly, an effort was initiated to establish a pharmacophore hypothesis to delineate the requirements of the active site, via a comprehensive program of synthesis of analogues of XK469 and evaluation of the effects of structural modification(s) on solid tumor activity. The strategy formulated chose to dissect the two-dimensional parent structure into three regions-I, ring A of quinoxaline; II, the hydroquinone connector linkage; and III, the lactic acid moiety-to determine the resultant in vitro and in vivo effects of chemical alterations in each region. Neither the A-ring unsubstituted nor the B-ring 3-chloro-regioisomer of XK469 showed antitumor activity. The modulating antitumor effect(s) of substituents of differing electronegativities, located at the several sites comprising the A-ring of region I, were next ascertained. Thus, a halogen substituent, located at the 7-position of a 2-(4-[(2-quinoxalinyl)oxy]phenoxy)propionic acid, generated the most highly and broadly active antitumor agents. A methyl, methoxy, or an azido substituent at this site generated a much less active structure, whereas 5-, 6-, 8-chloro-, 6-, 7-nitro, and 7-amino derivatives all proved to be essentially inactive. When the connector linkage (region II) of 1 was changed from that of a hydroquinone to either a resorcinol or a catechol derivative, all antitumor activity was lost. Of the carboxylic acid derivatives of XK469 (region III), i.e., CONH2, CONHCH3, CON(CH3)2, CONHOH, CONHNH2, CN, or CN4H (tetrazole), only the monomethyl- and N,N-dimethylamides proved to be active.

XK469 (1) is among the most highly and broadly active antitumor agents to have been evaluated in our laboratories. Subsequent developmental studies led to the entry of (R)-(+) 1 (NSC 698215) into phase 1 clinical trials (NIH UO1-CA62487). The antitumor mechanism of action of 1 remains to be elucidated, which has prompted a sustained effort to elaborate a pharmacophoric pattern of 1. The present study focused on a strategy of synthesis and biological evaluation of topologically based, bioisosteric replacements of the quinoxaline moiety in the lead compound (1) by quinazoline (4a-d), 1,2,4-benzotriazine (12a-18b), and quinoline (21a-g) ring systems. The synthetic approach to each of the bioisosteres of 1 utilized the methodology developed in previous work (see Hazeldine, S. T.; Polin, L.; Kushner, J.; Paluch, J.; White, K.; Edelstein, M.; Palomino, E.; Corbett, T. H.; Horwitz, J. P. Design, Synthesis, and Biological Evaluation of Analogues of the Antitumor Agent 2-(4-[(7-Chloro-2-quinoxalinyl)oxy]phenoxy)propionic acid (XK469). J. Med. Chem. 2001, 44, 1758-1776.), which is extended to the procurement of the benzoxazole (23a,b), benzthiazole (23c,d), pyridine (25a,b), and pyrazine (27) congeners of 1. Only quinoline analogues, bearing a 7-halo (21a,b,d,e) or a 7-methoxy substituent (21g), showed antitumor activities (Br > Cl > CH(3)O > F approximately I), at levels comparable to or greater than the range of activities manifested by 1 and corresponding analogues. At high individual dosages, the (S)-(-) enantiomers of 1 and 21b,d all produce a reversible slowing of nerve-conduction velocity in the mice, the onset of which is characterized by a distinctive dysfunction of the hind legs, causing uncoordinated movements. The condition resolves within 5-10 min. However, at higher dosages, which approach a lethal level, the behavior extended to the front legs, lasting from 20 min to 1 h. By contrast, the (R)-(+) forms of these same agents did not induce the phenomenon of slowing of nerve-conduction velocity.