ORIGINAL PAPER Synthesis and UV absorption of new conjugated quinoxaline 1,4-dioxide derivatives anticipated as tumor imaging and cytotoxic agents Sameh R. El-Gogary • Mohamed A. Waly • Ismail T. Ibrahim • Osama Z. El-Sepelgy Received: 1 March 2009 / Accepted: 9 August 2010 / Published online: 8 September 2010 Ó Springer-Verlag 2010 Abstract New conjugated arylidine, enamine, and ann- elated pyrido derivatives of quinoxaline 1,4-dioxide were synthesized via utilization of an active allylic methyl group. Biodistribution studies were carried out by injecting a solution of an 125 I derivative of an enamine-substituted quinoxaline 1,4-dioxide in normal and tumor-bearing mice. The uptake in solid tumor was over 6% of the injected dose per gram tissue body weight at 4 h post injection. These data revealed localization of the tracer in the tumor tissues with a high percentage sufficient to show a radiotherapeutic effect and showed that this is a promising tool for diagnosis. Also the radiotoxicity of the 125 I-substituted compound on Ehrlich ascites carcinoma cells may encourage this behavior. Keywords Quinoxaline 1,4-dioxide Á Iodine-125 Á Labeling Á Biodistribution Á Cancer Introduction Quinoxaline-1,4-dioxide derivatives seem to have interest- ing anticancer activities [1], especially in solid tumor treatment [2, 3]. Quinoxaline derivatives may act by the concept of bioreductive alkylation [4], and could cleave the DNA under hypoxic conditions in the presence of xanthine and xanthine oxidase [5]. Labeling of some quinoxaline derivatives with different radioisotopes like technetium- 99 m or radioiodine was conducted for imaging or therapeutic purposes, respectively [6, 7]. Auger electron emitters are widely used in cellular radiation studies. The radiotherapeutic effectiveness of the radionuclides can be achieved by the incorporation of these radionuclides into cellular DNA leading to the breakage of the DNA double strand [8–11]. Extensive studies indicate that 3-aminoquinoxaline-2- carbonitrile 1,4-dioxide (AQCD, 2) is more susceptible to reductive activation than tirapazamine (1)[12] and causes redox-activated DNA damage [13]. This was attributed to the property of 2 to absorb the radiation strongly at longer wavelengths (k max C 350 nm) [14]. One of the great challenges of photodynamic therapy (PDT) is to find drugs that can be activated at longer wavelengths, which in turn will increase the penetration of the tumor by photodynamic therapy [15–19]. At longer wavelengths of light, absorption by heme proteins and other reactive compounds in the blood will not interfere during therapy. In this work, we attempted to prepare new conjugated quinoxaline 1,4-dioxide derivatives substituted at position 3 of the quinoxaline ring, which could absorb radiation at longer wavelengths (around k max C 350 nm). In addition, this study was conducted to find a model for labeling [(dimethylamino)vinyl]quinoxaline 1,4-dioxide (AVQD) as a vehicle to carry iodine-125 to tumor cells. In vitro radiotoxicity, in vitro stability, and in vivo biodistribution of 125 I-AVQD on Ehrlich ascites carcinoma (EAC) were investigated. 2-(Ethoxycarbonyl)-3-methylquinoxaline 1,4-dioxide (3)[20, 21], bearing an active methyl group at position 3, was selected to carry out these syntheses (Scheme 1). S. R. El-Gogary Á M. A. Waly (&) Á O. Z. El-Sepelgy Faculty of Science (Damiatta), Chemistry Department, Mansoura University, Damiatta, Egypt e-mail: mohamedwaly7@yahoo.com I. T. Ibrahim Hot Laboratories Center, Atomic Energy Authority, Cairo, Egypt 123 Monatsh Chem (2010) 141:1253–1262 DOI 10.1007/s00706-010-0386-1