II. Synthesis and Biological Evaluation of Some Bioisosteres and Congeners of the Antitumor Agent, 2-{4-[(7-Chloro-2-quinoxalinyl)oxy]phenoxy}propionic Acid (XK469)

Abstract

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.

Microwave-Assisted Synthesis of Bioactive Six-Membered Heterocycles and Their Fused Analogues

“…Pyrazine is a six membered hetero-aromatic ring usually found in the structure of numerous natural products and synthetic compounds, some of which are used in the food industry for their flavor properties [222][223][224]. Moreover, they are versatile synthetic intermediates [225], and many functionalized pyrazines possess pharmacological activities, such as antiviral [226,227] (242, 243), ATR kinase inhibitor [228] (244), antitumor [229], vascular endothelial growth factor inhibitory activity [230], or as epithelial sodium channel blockers [231] (Figure 15). Pyrazine is a six membered hetero-aromatic ring usually found in the structure of numerous natural products and synthetic compounds, some of which are used in the food industry for their flavor properties [222][223][224].…”

“…Moreover, they are versatile synthetic intermediates [225], and many functionalized pyrazines possess pharmacological activities, such as antiviral [226,227] (242, 243), ATR kinase inhibitor [228] (244), antitumor [229], vascular endothelial growth factor inhibitory activity [230], or as epithelial sodium channel blockers [231] (Figure 15). Original synthetic heterocycles, such as substituted dicyanopyrazines 247, 248, have been synthesized using a domestic MW oven [232].…”

Structure Parameter Correlation of some Quinoxaline Derivatives through IR and ¹³C NMR Spectra

“…The important biological activities of quinoxalines are antibacterial [2,3], antiviral [4], anti-inflammatory [4], askinase inhibitors [4], anticancer [4], antimycobacterial [5,6], antifungal [7], anthelmintic [4,7], antidepressants [8] and antitumour [9,10]. Many kinds of synthetic methods including solvent-free and catalysts were reported in the literature for synthesis of quinoxalines by the condensation of 1,2-diamines and 1,2-dicarbonyl compounds [1,2,11].…”

Insect Antifeedant Potent Quinoxalines

“…The important biological activities of quinoxalines are antibacterial [2,3], antiviral [4], anti-inflammatory [4], askinase inhibitors [4], anticancer [4], antimycobacterial [5,6], antifungal [7], anthelmintic [4,7], antidepressants [8] and antitumor [9,10]. Many kinds of synthetic methods including solvent-free and catalysts were reported in the literature for synthesis of quinoxalines by the condensation of 1,2-diamines and 1,2-dicarbonyl compounds [1,2,11].…”