Novel Benzosuberone-quinazolinone Derivatives: Synthesis and Antitumour Activity
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ovel Benzosuberone-quinazolinone Derivatives: Synthesis and Antitumour Activity N. J. P. Subhashinia,*, L. Jillaa, and P. Kumar Kolluria a
Department of Chemistry, University College of Science, Osmania University, Hyderabad, Telangana, 500007 India *e-mail: [email protected] Received December 27, 2019; revised January 20, 2020; accepted February 11, 2020
Abstract—Novel benzosuberone-quinazolinones hybrids have been synthesized efficiently in high yields, and their structures have been confirmed by 1H and 13C NMR, ESI-MS, and HRMS spectra. According to the in vitro tests of products for their antiproliferative activity against HeLa, MDA-MB-231, A549, and MIAPACA cancer cell lines, the compound 9b demonstrates significant cytotoxicity against A549 with GI50 value 0.4 μM and compound 8a exhibits activity against MIAPACA with GI50 value 0.6 μM. Keywords: benzosuberone, quinazolinone, 2-aminobenzamide, anticancer activity
DOI: 10.1134/S1070363220100199 INTRODUCTION Colchicine was the first natural drug for which anticancer activity was discovered. Benzosuberone nucleus contains the core structure of colchicine, and it demonstrated anticancer activity [1, 2] along some pharmacological activites more [3–6]. Quinazolinone is embedded in the structures of some natural products containing alkoloids like Luotonin A, Rosettacin, Camptothecin, Alloqualone, and were clinically proved to be anticancer agents [7–10]. Some synthetic compounds containing benzosuberone and quinazolinone scaffolds characterized by antiproliferation activity are representated in Fig. 1 [11–15]. The current study was driven by the idea of combining these moieties in a single motiff characterized by significant biological potential. In continuation of our previous research on benzosuberone [4], a novel series of compounds 3a, 3b, 4a, 4b, 6a, 6b, 7a, 7b, 8a, 8b, and 9a, 9b were synthesized by condensation of benzosuberone with 2-aminobenzamide. All synthesized compounds were screened for antitumour activity against four human cancer cell lines such as HeLa, MDA-MB-231, A549, and MIAPACA, and compared with ciprofloxacin. RESULTS AND DISCUSSION Substitued benzosuberones 1a, 1b were synthesized according to the Friedel-Crafts acylation of o-xylene with glutaric anhydride leading to γ-(3,4-dimethylbenzoyl)-
butyric acid. Clemmensen reduction of the obtained aryl butyric acid derivative followed by cyclization in presence of polyphosphoric acid generated 6,7,8,9-tetrahydro-2,3-dimethyl-(5H)-benzocyclohepten-5-one 1a, 1b. These substituted benzosuberones were treated with POCl3 and dimethyl formamide at 0–60°C for 4– 5 h to generate (Z)-9-chloro-6,7-dihydro-5H-benzo[5]annulene-8-carbaldehyde derivatives (2a, 2b) (Vilsmeier– Haack–Arnold reaction). Aminobenzamide reacted with a compound 2a or 2b in ethanol in presence of catalytic amount of ammonium chloride giving the corresponding dihydro quinazolinones 3a, 3b. These compounds were further oxidized with KMnO4 with formation of the corresponding products 4a, 4b. Also phenoxy derivatives 5aa, 5ba were
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