Design, Synthesis, and Anticancer Activity of Substituted Styryl Incorporated Quinazoline Derivatives
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esign, Synthesis, and Anticancer Activity of Substituted Styryl Incorporated Quinazoline Derivatives Pruthu Kalaa and Dittakavi Ramachandrana,* a
Department of Chemistry, Acharya Nagarjuna University, Nagarjuna Nagar, Andhra Pradesh, 522510 India *e-mail: [email protected] Received November 17, 2019; revised June 7, 2020; accepted June 11, 2020
Abstract—A novel series of substituted aryl ethynyl incorporated quinazolines has been synthesized, and their molecular structures have been characterized by 1H and 13C NMR, and mass spectra. The products have been tested for their preliminary anticancer activity against human cancer cell lines like MCF-7 (human breast cancer), A549 (human lung cancer), DU-145 (human prostate cancer), and MDA MB-231 (human breast cancer). Some compounds are characterized by potent activity. Keywords: quinazoline, styryl, anticancer activity
DOI: 10.1134/S1070363220100187 INTRODUCTION Compounds containing the quinazoline structure demonstrated biological activities including antioxidant [1], anti-TB [2], analgesic [3], anti-inflammatory [4], antiviral [5], antibacterial [6], anticancer [7], and some more. FDA has approved clinic compounds like Gefitinib (1, Fig. 1) [8] and Erlotinib (2) [9] as anticancer drugs. Styryl derivatives, such as Rigosertib (3), are well known for a wide variety of biological activities. In view of the above we put some effort in design and synthesis of novel N-(3,4,5-trimethoxyphenyl)-7-
styrylpyrimido[4,5-d]pyrimidin-4-amine derivatives containing a substituted styryl core directly attached to the C7 position. Structures of the compounds were elucidated from 1H and 13C NMR, and mass spectral data. All products were tested for their anticancer activity against four human cancer cell lines. RESULTS AND DISCUSSION The novel series of structurally modified quinazoline derivatives 11a–11j was prepared as outlined in Scheme 1. A mixture of ethyl 4-amino-2-methylpyrimidine-5carboxylate (4) with formamide 5 was refluxed upon
F O
HN N
O
Cl
HN
N
MeO
O
O
N
O
N
O
1
N 2
OMe
OMe
O S
N H
O MeO
OMe
ONa O
3 Fig. 1. Structures of Gefitinib (1), Erlotinib (2) and Rigosertib (3).
1955
1956
PRUTHU KALA, DITTAKAVI RAMACHANDRAN Scheme 1. Synthetic approach to substituted styryl incorporated quinazoline derivatives.
stirring for 10 h to give 7-methylpyrimido[4,5-d]pyrimidin-4(3H)-one (6). This intermediate was reacted with thionyl chloride and catalytic amount of DMF upon refluxing for 5 h to afford the corresponding 5-chloro-2-methylpyrimido[4,5-d]pyrimidine (7), which was subjected to coupling reaction with 3,4,5-trimethoxybenzenamine (8) in presence of potassium carbonate to give pure N-(3,4,5-trimethoxyphenyl)-7methylpyrimido[4,5-d]pyrimidin-4-amine (9). Finally, the intermediate 9 was condensed with various types of aromatic aldehydes 10a–10j in presence of acetic acid to give the corresponding pure target compounds 11a–11j. In vitro cytotoxicity. In this study, anticancer activity of the target compounds 11a–11j towards four human cancer cell lines
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