Original article Copper(II) chloride mediated synthesis and DNA photocleavage activity of 1-aryl/heteroaryl-4-substituted-1,2,4-triazolo[4,3-a]quinoxalines Ranjana Aggarwal a, * , Garima Sumran a,1 , Virender Kumar a , Ashwani Mittal b a Department of Chemistry, Kurukshetra University, Kurukshetra 136119, India b Biochemistry Department, University College, Kurukshetra University, Kurukshetra 136119, India article info Article history: Received 31 August 2011 Received in revised form 4 October 2011 Accepted 14 October 2011 Available online 21 October 2011 Keywords: Triazolo[4,3-a]quinoxalines Copper(II) chloride Oxidative cyclization Plasmid DNA Photocleavage AM1 calculations abstract A new class of photonucleases, 1-aryl/heteroaryl-4-substituted-1,2,4-triazolo[4,3-a]quinoxalines (4) was synthesized in a facile and efficient manner via copper(II) chloride mediated oxidative intramolecular cyclization of 2-(arylidenehydrazino)-3-substituted-quinoxalines (3). DNA cleavage potency of compounds 4aed (40 mg each) was quantitatively evaluated on supercoiled plasmid FX174 under UV irradiation (312 nm, 15 W) without any additive. Compound 4c was found to be the most efficient DNA photocleaver which had converted supercoiled DNA (form I) into the relaxed DNA (form II) at 30 mg and the DNA photocleavage activity increases with increase in concentration of 4c. Ó 2011 Elsevier Masson SAS. All rights reserved. 1. Introduction The design of novel photonucleases, which selectively cleave DNA under irradiation with a specific light under mild conditions without any additives such as metals and reducing agents, is very interesting from chemical and biological standpoints and offers a significant potential in medicine especially in post-genome era [1]. Research in this area has revealed that photocleavage is a promising approach for new antitumor and antiviral therapeutic strategies. Several heterocyclic DNA photocleaving molecules such as thiazo- or thiadiazo-naphthalene carboxamides [2] and isoquino [4,5-bc]acridines [3] exhibit antitumor activity whereas iso- quinolino[5,4-ab]phenazine derivatives [4] could be used as topo- isomerase I targeted antitumor agents. Other photosensitive DNA cleavers which have been reported include antitumor agents, 3- amino-1,2,4-benzotriazine 1,4-dioxide, (tirapazamine, WIN 59075, SR4233) [5] and chlorobithiazoles derivatives structurally related to bleomycin [6]. In addition, DNA photocleaving molecules find potential use for the design of photofootprinting agents to map the sequence specific sites of DNA binding drugs and proteins or as site- directed photonucleases for accessing structural and genetic information. Wender et al. [7] demonstrated that benzotriazoles when combined with a DNA recognition subunit can upon photo- activation cleave DNA via radical mechanism in a potent and selective fashion. The conjugated C]N bond in aromatic hetero- cycles was reported to generate the photoexcited [8] (nep*) state, which would have radical character and could be able to cleave DNA photochemically [8]. Triostin A and echinomycin, members of the quinoxaline family of antitumor antibiotics, bind to DNA and exhibit high level of cytotoxicity [9]. Prompted by these reports, it seemed worthwhile to synthesize and explore the photochemical DNA cleaving properties of 1,2,4-triazolo[4,3-a]quinoxalines as this nucleus exhibits diverse pharmacological activities, viz., antitumor [10], antimicrobial [11,12], and antidepressants [13]. Traditional routes to 1,2,4-triazolo[4,3-a]quinoxalines include the reaction of 2-hydrazinoquinoxaline with acid chlorides/acids/ acid anhydrides at elevated temperature [14]; ring closure of 2- hydrazino-3-chloroquinoxalines with triethyl orthoalkanoates [14]; pyrolysis of hydrazones [14,15]; cyclodehydration of aroylhy- drazine with phosphorus oxychloride [15]; reaction of 2- chloroquinoxaline with mono or diacylhydrazine [14,16]; dehy- drogenative cyclization of Schiff’s bases with DDQ [17]. Unfortu- nately, such methods are often limited due to inevitably poor conversions, multistep synthesis, harsh reaction conditions, long * Corresponding author. Tel.: þ91 1744238734; fax: þ91 1744238277. E-mail address: ranjana67in@yahoo.com (R. Aggarwal). 1 Present address: Technology Education & Research Integrated Institutions, Kurukshetra 136 119, India. Contents lists available at SciVerse ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech 0223-5234/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmech.2011.10.032 European Journal of Medicinal Chemistry 46 (2011) 6083e6088