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Synthesis and Characterization of Some New Coumarins with in Vitro Antitumor and Antioxidant Activity and High Protective Effects Against DNA Damage

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Synthesis and Characterization of Some New Coumarins with in Vitro Antitumor and Antioxidant Activity and High Protective Effects Against DNA Damage molecules Article Synthesis and Characterization of Some New Coumarins with In Vitro Antitumor and Antioxidant Activity and High Protective Effects against DNA Damage Mounir A. I. Salem 1,†, Magda I. Marzouk 1,*,† and Azza M. El-Kazak 2,† 1 Synthetic Organic Chemistry Laboratory, Chemistry Department, Faculty of Science, Ain Shams University, Abassia, Cairo 11566, Egypt; [email protected] 2 Faculty of Education; Ain Shams University, Roxy, Cairo 11711, Egypt; [email protected] * Correspondence: [email protected]; Tel.: +20-2-0122-330-9974 † All the authors contributed equally to this work. Academic Editor: Pascal Richomme Received: 23 December 2015 ; Accepted: 17 February 2016 ; Published: 22 February 2016 Abstract: Coumarins are naturally occurring oxygen heterocyclic compounds having multifarious medicinal properties, hence used as lead compounds for designing new potent analogs. The chromene butenoic acid 3 and the benzochromene butenoic acid 4 which are derived from the reaction of glyoxalic acid with 3-acetylcoumarin and 3-acetylbenzocoumarin, respectively, were reacted with different nitrogen and carbon nucleophiles to give new heterocyclic compounds. The structures of the prepared compounds were elucidated by IR, 1H-NMR, and mass spectroscopy. Some of the newly prepared compounds were tested in vitro against a panel of four human tumor cell lines namely; hepatocellular carcinoma (liver) HepG2, colon cancer HCT-116, human prostate cancer PC3, and mammary gland breast MCF-7. Also they were tested as antioxidants. Almost all of the tested compounds showed satisfactory activity. Keywords: functionalized coumarin; antitumor activity; antioxidant activity 1. Introduction Coumarins are an important class of compounds of both natural and synthetic origin. Many compounds which contain the coumarin moiety exhibit useful and diverse pharmaceutical and biological activities, often depending on the substituents they bear in the parent benzopyran moiety [1,2] and, there has been a growing interest in their synthesis [3]. Some of these coumarin derivatives have been found useful in photochemotherapy, antitumor [4], anti-HIV therapy [5,6], as CNS-stimulants [7], antibacterial [8–10], anticoagulants [11–13], antifungal [14,15], antioxidant [16] agents and as dyes [17]. Natural, semi-synthetic and synthetic coumarins are useful substances in drug research [18]. Coumarins can be used not only to treat cancer, but to treat the side effects caused by radiotherapy [19,20]. Coumarin derivatives can possess not only cytostatic, but cytotoxic properties as well [21], as they can inhibit growth in human cancer cell lines [22] such as A549 (lung), ACHN (renal), H727 (lung), MCF7 (breast) and HL-60 (leukemia) and in some clinical trials they exhibited anti-proliferative activity in prostate cancer [23] malignant melanoma [24] and renal cell carcinoma [25]. Coumarin itself also exhibited cytotoxic effects against Hep2 cells (human epithelial type 2) in a dose dependent manner and showed some typical characteristics of apoptosis with loss of membrane microvilli, cytoplasmic hypervacualization and nuclear fragmentation [26]. Molecules 2016, 21, 249; doi:10.3390/molecules21020249 www.mdpi.com/journal/molecules Molecules 2016, 21, 249 2 of 20 [27]. Cinnamoyl-coumarin derivatives were especially effective in oestrogen-dependent cancers, such as breast (MCF7) and ovarian (OVCAR) cancer cell lines. These compounds are selective nonsteroidal inhibitors of 14β-hydroxysteroid dehydrogenase type 1, an enzyme that catalyzes NADPH-dependent Moleculesreduction2016 of, the21, 249 weak oestrogen, oestrone, into the most potent oestrogen, oestradiol [28]. Seidel et al.2 of [29] 20 synthesized a series of coumarin derivatives which carry α,β-(mono- or bis)-unsaturated ketones at the C3 or C4 position such as compound I (Figure 1) which strongly inhibits proliferation in the chronic myeloidThe leukemia hormone K-562 oestrogen and histiocytic plays the cruciallymphoma role U-937 in the cell development lines. This compound of the breast also cancer, inhibited the mostthe activity frequent of histone malignant deacetylase disease (HDAC), in women. an enzyme Therefore crucial many in therapies cancer development. are designed to block its activitySashidhara [27]. Cinnamoyl-coumarin et al. [27] developed new derivatives hybrid coumarin-m were especiallyonastrol effective molecules in oestrogen-dependent such as compound II cancers,(Figure 1) such which as breast showed (MCF7) the most and potent ovarian selective (OVCAR) activity cancer against cell lines. breast These cancer compounds cell lines areMCF-7 selective and β nonsteroidalMDA–MB-231. inhibitors This compound of 14 -hydroxysteroid induced caspase-3 dehydrogenase activation and type apoptosis 1, an enzyme and caused that catalyzesarrest of NADPH-dependentMCF-7 cell cycle at G1 reduction phase. of the weak oestrogen, oestrone, into the most potent oestrogen, α β oestradiolFrom [Korean28]. Seidel Angelicaet al. [gigas29] synthesized root Kim et aal. series [30] isolated of coumarin pyranocoumarin derivatives which decursin carry III (Figure, -(mono- 1), orwhich bis)-unsaturated inhibited proliferation ketones at in the bladder C3 or C4cancer position 235J suchcells asand compound also in colonI (Figure cancer1) HCT-1116 which strongly cells. inhibitsDecursin proliferation induced apoptosis in the chronicin both cancer myeloid cell leukemia lines through K-562 expression and histiocytic of Bax lymphoma protein and U-937 reduced cell lines.Bcl-2 protein This compound levels. Amin also et inhibited al. [31] synthesized the activity ofcoumarins histone deacetylase IV attached (HDAC), to pyrazoline an enzyme rings (Figure crucial in1) cancerthat have development. anticancer activity against the HepG2 cell line. Figure 1. Structure of some anticancer derivatives (I–VI) and some of the designed target compounds Figure 1. Structure of some anticancer derivatives (I–VI) and some of the designed target compounds 3, 4, 5a,b, 7a,b, 9a,b, 13b, 15a,b, 16a and 18a. 3, 4, 5a,b, 7a,b, 9a,b, 13b, 15a,b, 16a and 18a. Molecules 2016, 21, 249 3 of 20 Sashidhara et al. [27] developed new hybrid coumarin-monastrol molecules such as compound II (Figure1) which showed the most potent selective activity against breast cancer cell lines MCF-7 and MDA–MB-231. This compound induced caspase-3 activation and apoptosis and caused arrest of MCF-7 cell cycle at G1 phase. From Korean Angelica gigas root Kim et al. [30] isolated pyranocoumarin decursin III (Figure1), which inhibited proliferation in bladder cancer 235J cells and also in colon cancer HCT-1116 cells. Decursin induced apoptosis in both cancer cell lines through expression of Bax protein and reduced Bcl-2Molecules protein 2016, 21 levels., 249 Amin et al. [31] synthesized coumarins IV attached to pyrazoline rings (Figure3 of1 20) that have anticancer activity against the HepG2 cell line. DrugsDrugs containingcontaining 1,2,3-triazine rings [[32]32] originated from natural and synthetic sources are exemplifiedexemplified by tubercidin (Va),), toyocamycintoyocamycin ((VbVb)) andand sangivamycinsangivamycin ((Vc)) (Figure(Figure1 1),), which which have have significantsignificant pharmacological activities. Tubercidin (Va)) andand itsits 5-substituted5-substituted derivativesderivatives inhibitinhibit bothboth DNA and RNA viruses at thethe concentrationsconcentrations that inhibit DNA, RNA and proteinprotein synthesissynthesis in micemice and humanhuman cellcell lines.lines. Toyocamycin ((VbVb)) isis aa knownknown antineoplasticantineoplastic antibioticantibiotic withwith specificspecific antitumorantitumor activity. Sangivamycin ((VcVc)) isis active against L1210 leukemia, P338 leukemia and Lewis lung carcinoma and under clinical trials against colon cancer, gallgall bladderbladder cancercancer andand acuteacute myelogenousmyelogenous leukemialeukemia inin humans.humans. 2-Azaadenosine VI (Figure 11)) exhibitsexhibits fivefivetimes times greater greater cytotoxicity cytotoxicity thanthan 8-azapurine 8-azapurine against human epidermis carcinomacarcinoma cellscells inin vitrovitro.. InIn continuationcontinuation ofof ourour previousprevious investigationsinvestigations [[33–37],33–37], some heterocyclic compounds bearingbearing thethe coumarin moiety were utilizedutilized herein forfor thethe synthesissynthesis ofof valuablevaluable heterocyclicheterocyclic ringring systemssystems havinghaving satisfactory antitumorantitumor andand antioxidantantioxidant activities.activities. 2. Results Results and and Discussion Discussion 2.1. Chemistry InIn thethe present present investigation investigation we we report report the synthesesthe syntheses of some of newsome coumarin new coumarin derivatives derivatives having antitumorhaving antitumor and antioxidant and antioxidant activities. activities. 4-Oxo-4-(2-oxo-2 4-Oxo-4-(2-oxo-2H-chromen-3-yl)but-2-enoicH-chromen-3-yl)but-2-enoic acid acid (3(3)) waswas synthesized by by Tolstoluzhsky Tolstoluzhsky etet al. al. [38][38 ]using using glyoxalic glyoxalic acid acid and and acetic acetic anhydride anhydride in inthe the presence presence of ofytterbium ytterbium triflate triflate as asa acatalyst catalyst under under microwav microwavee conditions. conditions. Herein Herein we we synthesized synthesized the targettarget compounds 3 and 44 byby thethe reactionreaction ofof 3-acetyl-23-acetyl-2HH-chromen-2-one-chromen-2-one ((1a1a)) andand 2-acetyl-32-acetyl-3HH-benzo[-benzo[ff]-]- chromen-3-one (1b)) withwith glyoxalicglyoxalic
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