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Quinazoline-2,4(\(1H,3H\))-diones inhibit the growth of multiple human tumor cell lines

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Abstract

Quinazoline-2,4(\(1H,3H\))-diones exhibit a wealth of biological activities including antitumor proliferation. We established an improved method for the synthesis of quinazoline-2,4(\(1H,3H\))-dione derivatives with three points of molecular diversity. Data indicate that compounds 60 (average \(\text{ logGI}_{50} \!=\! -6.1\)), 65 (average \(\text{ logGI}_{50} \!=\! -6.13\)), 69 (average \(\text{ logGI}_{50} \!=\! -6.44\)), 72 (average \(\text{ logGI}_{50} \!=\! -6.39\)), and 86 (average \(\text{ logGI}_{50} = -6.45\)) significantly inhibited the in vitro growth of 60 human tumor cell lines tested. Structure–activity relationship analyses indicate that chlorophenethylureido is the necessary substituent at the \(\text{ D}_{3}\) diversity point (7-position of quinazoline-2,4(\(1H,3H\))-dione), in particular, \(o\)-chlorophenethylurea (69) achieved optimal activity. \(o\)- or \(m\)-Chlorophenethyl substitutions (69 and 72) at the \(\text{ D}_{2}\) diversity point (3-position of quinazo line-2,4(\(1H,3H\))-dione) gave the most potent compounds. Methoxyl and 4-methylpiperazin-1-yl substitution at the \(\text{ D}_{1}\) diversity point (6-position of quinazoline-2,4(\(1H,3H\))-dione skeleton) may yield better activity than other groups. The quinazoline-2,4(\(1H,3H\))-dione scaffold can be effectively replaced by 2\(H\)-benzo[b][1,4]thiazin-3(4\(H\))-one.

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Acknowledgments

The research is financially supported by the National Natural Science Foundation of China (No. 81161120402) and National 863 Program of China (No. 2012AA020303).

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Authors and Affiliations

  1. Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 2 Nanwei Road, Xuanwu District, Beijing, 100050, People’s Republic of China

    Xiaoli Zhou, Xilei Xie & Gang Liu

  2. Tsinghua-Peking Center for Life Sciences, School of Medicine, Tsinghua University, Haidian Dist., Beijing, 100084, People’s Republic of China

    Gang Liu

  3. Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Haidian Dist., Beijing, 100084, People’s Republic of China

    Gang Liu

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  1. Xiaoli Zhou
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Correspondence to Gang Liu.

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Zhou, X., Xie, X. & Liu, G. Quinazoline-2,4(\(1H,3H\))-diones inhibit the growth of multiple human tumor cell lines. Mol Divers 17, 197–219 (2013). https://doi.org/10.1007/s11030-012-9421-y

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