Design, Synthesis, and Biological Evaluation of Analogues of the Antitumor Agent, 2-{4-[(7-Chloro-2-quinoxalinyl)oxy]phenoxy}propionic Acid (XK469)

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.

Multi-gram Preparation of 7-Nitroquinoxalin-2-amine

“…By using phosphoryl chloride under refluxing conditions, we prepared the corresponding aryl chloride 2-chloro-7-nitroquinoxaline (4) in good yields by filtration after slowly addition of the reaction mixture into a mixture of ice and water. 6 Although the amination of 2-chloroquinoxaline is described as easily done, we could not reproduce chlorine substitution by an amino group at 7-nitroquinoxaline scaffold as previously described in literature. 3,7 Ammonia in methanolic solution at high temperatures, through nucleophilic aromatic substitution in similar procedure as described by Wolf et al 3 and by Gowenlock et al 7 did not yield the desired product.…”

“…1 H and 13 C NMR and DEPT-135 spectra were determined in DMSO-d 6 and br (broad signal). FTIR spectra were obtained using a Thermo Scientific Nicolet's Avatar iS10 spectrometer equipped with smart endurance diamond ATR unit for direct measurements.…”

“…were added to a solution of 2-chloro-7-nitroquinoxaline (4) (10.13 g, 48 mmol) in ethanol (160 mL). The reaction mixture was refluxed for 3 h. The solution was evaporated and the solids were filtered and washed with water to obtain an orange colored solid (13.94 Procedure for the synthesis of 7-nitroquinoxalin-2-amine (6) N-(4-Methoxybenzyl)-7-nitroquinoxalin-2-amine (5) (13.9 g, 45 mmol) was added to a round bottom flask containing trifluoroacetic acid (85 mL). The mixture was heated at 50 ºC for 24 h. Trifluoroacetic acid was evaporated and brine was added to the flask and a dark brown solid was obtained after filtration.…”

A Chalcone‐Based Highly Selective and Sensitive Chromofluorogenic Probe for Trivalent Metal Cations

“…Quinoxalines, also called benzopyrazines, and their derivatives show a broad spectrum of biological activity including antitumor [15], antiviral [16], antituberculosis [17], anti-inflammatory [18,19], anti-protozoal, anti-HIV [20,21], and have been evaluated as anticancer and anthelmintic agents [22].…”

Oxalic acid as an efficient, cheap, and reusable catalyst for the preparation of quinoxalines via condensation of 1,2-diamines with α-diketones at room temperature

“…3 Moreover, quinoxaline ring is a part of various antibiotics, such as Echinomycin, Levomycin and Actinoleutin that are known to inhibit growth of gram positive bacteria 4 and are active against various transplantable tumors. 5 They have been also used as building blocks for the synthesis of organic semiconductors.…”