Daunomycin Synthesis Essay

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  • 1. Introduction

    Anthraquinone compounds, especially anthracyclines, have long been used as effective anticancer drugs. Depending on their chemical structure, anthraquinone drugs can kill tumor cells by diverse mechanisms, involving different initial intracellular targets that normally contribute to drug-induced toxicity [1,2,3]. Anthraquinones are known as “multipotent antioxidants”, as they are molecules that besides antioxidant activity possess additional pharmacological activities such as inhibition of platelet-aggregation or display antineoplastic and anticancer activities [4,5]. Many anthraquinones also display various biological activities such as antimicrobial, antifungal, hypotensive, analgesic, antimalarial [6,7,8,9,10,11], antileukemic, mutagenicity and anti-inflammatory properties [12,13,14]. Natural anthraquinones from Damnacanthus subspinosus and Morinda parvifolia have long been used in traditional medicine for the treatment of cancer [15]. The discovery of new compounds with antitumor activity has become one of the most important challenges in medicinal chemistry. The detail study on anthraquinones has revealed that a range of DNA-recognizing molecules that act as antitumor agents, including groove binders, alkylating and intercalator compounds. DNA intercalators have attracted particular attention because of their antitumor activity. For example, a number of acridine and anthracycline compounds are excellent DNA intercalators that are now on the market as chemotherapeutic agents [15,16]. Substituted anthraquinones such as rubiadin, subspinosin and morindaparvin are widely distributed in nature and are known to display various pharmacological activities [17,18,19,20,21]. Previously, we have reported the antitumor and anti-oxidant activities of anthraquinones isolated from Morinda elliptica [22].Recently, we have also reported the cytotoxic and immunomodulatory effects of damnacanthal and nordamnacanthal against different cell lines [23,24]. Damnacanthal and nordamnacanthal were originally isolated from Damnacanthus major [25]. Previous studies on the synthesis of damnacanthal and nordmnacanthal were reported by Hirose, Roberts and Saha [26,27,28]. The current study describes the total synthesis of damnacanthal (1) and nordamnacanthal (2) with modified reaction steps, their cytotoxic activities of against MCF-7 and K-562 cancer cell lines and their structure activity relationships (SARs).

    2. Results and Discussion

    Anthraquinone skeletons are generally synthesized by Friedel-Crafts acylation condensation between phthalic anhydride and benzene derivatives [29]. 1,3-Dihydroxy-2-methylanthraquinone (3) was used as the common precursor for the synthesis of damnacanthal (1) and nordamnacanthal (2). This was synthesized by mixing of phthalic anhydride and 1,3-dihydroxy-2-methylbenzene in a molten mixture of AlCl3/NaCl [29,30].

    The synthesis of nordamnacanthal (2) was accomplished by first acetylating the precursor compound 3 with acetic anhydride and potassium carbonate to afford the monoacetylated intermediate 8. Upon methylation of compound 8 with K2CO3/(CH3)2SO4 in dry acetone to afforded 1,3-dimethoxy-2-methylathraquinone (4), which was then brominated with Wohl-Ziegler’s reagent (N-bromosuccinimide) in dry CCl4 to yield 2-bromomethyl-1,3-dimethoxyathraquinone (5) [25,31,32] and structure was confirmed by single X-ray diffraction (Figure 1). It is noteworthy that the use of a catalytic amount of benzoyl peroxide in this reaction gave 2-dibromomethyl-1,3-dimethoxyanthraquinone [26]. Compound 5 was hydrolyzed by refluxing it in acetic acid-water (8:2) to give the desired 2-hydroxymethyl-1,3-dimethoxyanthraqunone (6) in quantitative yield [26,31]. Compound 6, which contains a hydroxymethyl moiety, was converted into the corresponding aldehyde 7 in 92.3% yield using a mild oxidizing agent [pyridinium chlorochromate (PCC) in dry CH2Cl2 at 20–25 °C]. The use of an excess amount (1.5 equiv.) of PCC also gave the undesired 1-hydoxy-3-methoxyanthraquinone-2-carboxylic acid. Upon treating compound 7 with AlCl3/CH2Cl2, nordamnacanthal (2) was obtained in 28% yield. The detailed reaction conditions are shown in Scheme 1.

    The synthesis of damnacanthal (1) was accomplished by first acetylated the precursor compound 3 with (CH3)2SO4 and potassium carbonate to afforded monoacetylated derivative 8. Upon methylation of compound 8 with K2CO3/CH3I compound 9 was obtained, which then brominated with NBS to yield 1-methoxy-3-aectoxy-2-bromomethyl-1-methoxyathraquinone (10) [25,32]. The bromo derivative 10 was converted into ethoxymethyl derivative 11 by dissolving it in a mixture of aq. NaOH/ethanol and followed by reflux in acidic media. Compound 11 was acetylated using acetic anhydride and K2CO3 to afforded 12, which on oxidation with PCC in CH2Cl2 to give damnacanthal (1) in good yield. Thus the synthesis of damnacanthal (1) was achieved through modified steps as shown in Scheme 2.

    Figure 1. The ORTEP diagram of 2-bromomethyl-1,3-dimethoxy-9,10-athraquinone (5).

    Figure 1. The ORTEP diagram of 2-bromomethyl-1,3-dimethoxy-9,10-athraquinone (5).

    Scheme 1. Reactions pathway for synthesis of nordamnacanthal (2).

    Scheme 1. Reactions pathway for synthesis of nordamnacanthal (2).

    Reagents and conditions: (a) anhydrous AlCl3, NaCl, 165–175 °C, 1 h; (b) Anhydrous K2CO3 (CH3)2SO4, dry acetone, refluxed, 22 h; (c) NBS/CCl4 refluxed for 30 h; (d) 80% acetic acid refluxed 24 h; (e) PCC, CH2Cl2 stir. 2–4 h. rt; (f) AlCl3 /CH2Cl2, HCl.

    Scheme 2. Reactions pathway for synthesis of damnacanthal (1).

    Scheme 2. Reactions pathway for synthesis of damnacanthal (1).

    Reagents and conditions: (a) anhydrous K2CO3 /Ac2O, acetone; (b) anhydrous K2CO3/(CH3)2SO4 acetone, refluxed 22 h; (c) NBS/CCl4 refluxed 30 h; (d) 10% aq. NaOH/EtOH, aq. HCl; (e) Ac2O/ K2CO3 stirred for 24 h; (f) PCC, CH2Cl2 stir 2–4 h. rt.

    For the SARs additional anthraquinone analogous 13ah were synthesized by Friedel-Crafts acylation of phthalic anhydride with resorcinol or catechol to yielded respective anthraquinones [29,30] as shown in Figure 2. All compounds showed significant in vitro cytotoxicity against two cancer cell lines, indicating that anthraquinone is an interesting class of compounds for cancer therapy. The compound damnacanthal (1) contains methoxy, formyl and hydroxyl groups at the 1, 2 and 3 positions that might be important for the cytotoxicity since the standard drug doxorubicin [33] also possesses an anthraquinone moiety. However, nordamnacanthal (2), 3, 8, 13a, 13c, 13f and 13h exhibited less cytotoxic effects on both the MCF-7 and K-562 cell lines, suggesting that a protected OH group at position 1 and 3 increase the solubility and might make it easy for the compounds to diffuse across the cellular membrane as investigated by a theoretical study of 188 drug-like compounds by MI-QSAR analysis [34,35], while for poorly soluble drugs dissolution could be the rate limiting step in the absorption process. The methylated compound 13b (IC50 = 24.25 ± 2.46 μM and 22.01 ± 3.54 μM) showed the stronger cytotoxicity than 13a (IC50 = 82.08 ± 1.46 and 60.42 ± 5.33 μM) and 13c (IC50 = 87.80 ± 2.01 and 64.96 ± 1.57μM). Other derivatives 13e (IC50 = 43.64 ± 2.12 and 46.61 ± 12.37) and 2-hydroxymethylanthraquinone (13d) (IC50 = 49.58 ± 12.61and 50.84±14.12) showed poor cytotoxicity as shown in Table 1. However, previously synthesized compounds 13fh with mono or dihydroxyl groups at the 1 and 2 positions exhibited moderate cytotoxic activity [36]. Further derivatives as exemplified by compounds 13ch indicated that this series of compounds only exhibited moderate activities not exceeding that of damnacanthal (1), suggesting that functional groups such as formyl at C-2, methoxy at C-1, hydroxyl groups at C-3 (damnacanthal) and bromomethyl at C-2 are important pharmacophores for the anticancer activity. However, the active compound 5 ((IC50 = 15.83 ± 0.58 and 23.61 ± 3.28 μM) might involve another mechanism like perfusion. The overall cytotoxic compounds (1, 5, 13b) showed more selectivity towards cancer cell lines because of their side chains and might fulfill the Lipinski rule-of-5 and drug-like properties.

    Figure 2. Structure of compounds 13a to 13h.

    Figure 2. Structure of compounds 13a to 13h.

    Table 1. IC50 values of compounds 1 to 13h against MCF-7 and K-562 cell lines.

    Compound No.IC50 value (μM)
    Chemical StructureMCF-7K562
    113.48 ± 2.0219.50 ± 4.47
    260.07 ± 6.4632.46 ± 8.73
    390.78 ± 1.49100.71 ± 2.80

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