Synthesis of new benzo[ f ]chromene-based heterocycles targeting anti-proliferative activity
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ORIGINAL PAPER
Synthesis of new benzo[f]chromene‑based heterocycles targeting anti‑proliferative activity Fatma S. M. Abu El‑Azm1 · Manal M. El‑Shahawi1 · Amna S. Elgubbi2 · Hassan M. F. Madkour1 Received: 10 April 2020 / Accepted: 9 October 2020 © Iranian Chemical Society 2020
Abstract In this article β-enaminonitrile 1 undergoes intramolecular cyclocondensation reaction under acidic conditions to generate novel chromeno[2,3-b]azet-9-one derivative 2 in good yield. Ring expansion of the four membered ring of the azet-2(1H)-one derivative 2 to six and/or seven membered rings was achieved via reaction of compound 2 with different nitrogen nucleophiles. A new series of benzochromeneone, benzochromenopyrimidine, and benzo[f]coumarin derivatives were prepared via reaction of β-enaminonitrile 1 with different C-electrophiles. The structures of the products have been affirmed on the basis of analytical and spectral data. The anti-proliferative activity of the newly synthesized compounds against two human epithelial cell lines; liver (HepG2) and breast (MCF-7) in addition to normal fibroblasts (WI-38) was investigated. Derivatives 4 and 10 had significant and selective anti-proliferative activity against liver and breast cancer cell lines without harming normal fibroblasts. Graphic abstract Ar O
Ar
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Ar N
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CN NH O
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Extended author information available on the last page of the article
13
Vol.:(0123456789)
Journal of the Iranian Chemical Society
Keywords Benzo[f]chromene · Chromeno[2,3-b]azet-9-one · Benzo[f]chromeno[2,3-d]pyrimidines · Benzo[f] chromeneone · Benzo[f]coumarin · Intramolecular cyclocondensation · Anti-proliferative activity
Introduction Benzochromenes and fused chromenes are significantly established molecules that display diverse biological activities, like antileishmanial [1], antibacterial, antifungal [2–4], anti-proliferative agents [5], hypolipidemic [6], blood platelet antiaggregating [7], vascular-disrupting [8], antioxidant [9, 10] effects and activities. Furthermore, benzochromenes were considered as an emboldening skeleton for the development of potent antitumor agents. For example, β-enaminonitrile/esters (A) [11–14] are classified as effective antiproliferative agents, while β-enaminonitriles (B) [15] have efficacious apoptotic and cytotoxic behaviors against different cell lines: MCF-7, HepG-2, MDAMB-231, T-47D, KB, PC3, and SK-N-MC. Additionally, β-enaminonitriles (C) represent antiproliferative and c-Src kinase inhibitory activities [16], as shown in Fig. 1. Moreover, benzochromenopyrimidines exhibit antitumor activities. For example, the methylimino compounds (D) [13, 17], amino–imino compounds (E) [13, 14, 17, 18], and the amino–imino compounds (F) [13, 14, 17] have higher considerable strong anticancer activities against MCF7, HepG-2, and HCT-116, in comparison to the different standard drugs: Vinblastine, Colchicine, and Doxorubicin, as presented in Fig. 2. These promisin
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