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Send Orders for Reprints to [email protected] Anti-Cancer Agents in Medicinal Chemistry, 2015, 15, 000-000
Different 6-Aryl-Fulvenes Exert Anti-proliferative effects on Cancer Cells Esther Sirignano1,§, Assunta Pisano2,§, Anna Caruso2,3, Carmela Saturnino1,*, Maria Stefania Sinicropi2,*, Rosamaria Lappano2, Antonio Botta1, Domenico Iacopetta2, Marcello Maggiolini2 and Pasquale Longo4 1
Department of Pharmacy, University of Salerno, via Giovanni Paolo II, 132, 84084 Fisciano (SA), Italy; 2Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Arcavacata di Rende, (CS), Italy; 3Department of Computer Engineering, Modeling, Electronics and Systems, University of Calabria, 87036 Rende (CS), Italy; 4Department of Sciences, University of Salerno, via Giovanni Paolo II, 132, 84084 Fisciano (SA), Italy Abstract: Fulvenes represent a class of molecules very interesting under a chemical point of view because are easily accessible starting materials and are still poorly characterized for their biological activities, with the exception of acylfulvene and irofulvenes which have been reported to exert cytotoxic properties. Here, we describe the synthesis and characterization of several aryl-fulvenes together with their effects on cancer cell growth by MTT method. The cytotoxic potential was investigated on a panel of tumor cell lines such as breast MCF7 and SkBr3, endometrial Ishikawa, prostate LnCaP and lung A549, in comparison with the cis-diamminedichloroplatinum(II) (cisplatin) which is largely used for the treatment of different types of cancer. The evaluation of the cytotoxic activity of these compounds indicated that they are able to inhibit the proliferation of the aforementioned cancer cell types. In particular, the compound 4 exhibited the most powerful antiproliferative activity on all tumor cells evaluated with higher inhibitory effects respect to cisplatin and without altering the proliferation of human mammary MCF-10A epithelial cells.
Keywords: Antiproliferative activity, A549, Fulvenes, Ishikawa, LnCaP, MCF-10A, MCF7, SkBr3. INTRODUCTION Fulvenes are molecules characterized by a "cross-conjugated" structure (Fig. 1a), with substituents (R groups) that can be alkyls, aryls, etc. . The "cross-conjugation" represents a type of conjugation in which only two π bonds over three interact (while the third π bond is excluded from the conjugation ), moreover it influences the reactivity and molecular electronic transitions and is also typical of molecules such as benzophenones and p-quinones. Fulvenes are not aromatic, but the suitably substitution with electron-donor or electron-withdrawing groups on the five-membered ring allows to obtain the typical characteristics of an aromatic system  and the presence of a significant dipole moment (Fig. 1b). Literature data regarding the biological properties of the fulvenes are, to date, quite scarce, only acylfulvene (Fig. 2a and 2b) [4-7] and irofulvenes [8-11] (Fig. 2d) have been shown to exhibit interesting cytotoxic properties. The acylfulvene is a cytotoxic toxin correlated with Illudins, which are sesquiterpenes produced by mushroom Omphalotus illudens and related species of basidiomycetes, having antimicrobial and anticancer properties. In their isolated form, the Illudins have been shown to be particularly effective against hematopoietic and solid tumor cells . Beside these positive effects, some Illudins, as for instance Illudin S (Fig. 2c), exerted a high toxicity which made useless their use in vivo , so that more efficient, and with lower side effects, analogues were synthesized, i.e. acylfulvenes. The latters have been used in a lung xenograft model and, moreover, 6-hydroxymethylacylfulvene has shown a marked efficacy in several in vivo models, as the MV522 lung carcinoma, MX1 breast *Address correspondence to these authors at Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Arcavacata di Rende, (CS), Italy; Tel.: +39 0984 493200; Fax: +39 0984 493298; E-mail: [email protected] and Department of Sciences, University of Salerno, via Giovanni Paolo II, 132, 84084 Fisciano (SA), Italy; Tel: +39 089 969602; Fax: +39 089 969769; E-mail: [email protected] § These authors equally contributed to the manuscript
carcinoma, KB epidermic carcinoma, and HT29 colon carcinoma xenograft models [4-7], and is currently in phase II chemotherapeutic clinical trials .
Fig. (1). Cross conjugated (a) and aromatic (b) resonance structures of fulvene
Fig. (2). Structures of (a) acylfulvene (R = H) and substituted (R =alkyl, aryl, etc.), (b) acylfulvene dimer (c) Illudin S and (d) Irofulven
cancer cells respect to normal cells, and blocks the growth of endothelial tumors, including hemangiomas, in mice .
Fig. (3). Fulvene 5.
Given the interesting antitumor effectiveness of these fulvene derivatives, in this paper we report the synthesis and characterization of twelve fulvenes and some interesting preliminary data on their biological usefulness on selected cancer cell lines, i.e. MCF7, SkBr3, Ishikawa, LnCap and A549. The library of selected compounds possessing varied steric hindrance, different lipophilicity and different polar substituents may provide some valuable indications for a further development of this class of compounds which may represent a valid alternative in the arsenal of anticancer drugs. MATERIAL AND METHODS Chemistry The elemental analyses for C, H, N, were recorded on a ThermoFinnigan Flash EA 1112 series and performed according to standard microanalytical procedures. 1H NMR, homodecoupled 1H NMR, 1H COSY and 13C NMR spectra were recorded at 298 K on a Bruker Avance 300 Spectrometer operating at 300 and 75 MHz for 1 H and 13C, respectively. The 1H and 13C chemical shifts are referred to internal tetramethylsilane (δ = 0 ppm). Molecular weights were determined by ESI mass spectrometry. ESI-MS analysis in positive and negative ion mode, were made using a Finnigan LCQ ion trap instrument, manufactured by Thermo Finnigan (San Jose, CA, USA), equipped with the Excalibur software for processing the data acquired. The sample
was dissolved in acetonitrile and injected directly into the electrospray source, using a syringe pump, which maintains constant flow at 5 µl/min. The temperature of the capillary was set at 220 °C. Melting point measurements have been carried out on a differential scanning calorimeter (DSC) 2920 apparatus manufactured by TA Instruments, calibrated against an indium standard (Tm = 156.6 8C), with heating scans from -10 to 200 °C, at a 10 °C/min heating rate, under a flowing nitrogen atmosphere. Specimens were sealed in aluminum pans. All manipulations were carried out under oxygen- and moisture-free atmosphere in an MBraun MB 200 glove-box. All the solvents were thoroughly deoxygenated and dehydrated under argon by refluxing over suitable drying agents, while NMR deuterated solvents (Euriso-Top products) were kept in the dark over molecular sieves. All chemicals were obtained from Aldrich chemical Co. and used without further purification. Cyclopentadiene was obtained by freshly cracked dicyclopentadiene. Compounds 1-8 were prepared following the procedures already published [6, 24-27]. General Procedure for the Preparation of Compounds 9 and 10 The synthesis was carried out under nitrogen. Pyrrolidine (2.5 ml, 30.0 mmol) was added to a solution of the suitable acetophenone (20 mmol) and cyclopentadiene (4.1 ml, 50.0 mmol) in 30 ml of methanol. After addition, the solution turned from colorless to redorange color. After 20 hours, acetic acid (1.8 ml, 32.0 mmol) was added. The reaction mixture was diluted with 20 ml of a mixture of diethyl ether and water (1:1). The resultant organic layer was separated and the aqueous layer was washed with diethyl ether (3 x 20 ml). The combined organic extracts were washed with a saturated aqueous NaCl solution. The organic solution was dried over magnesium sulfate. Both products were purified by column chromatography over silica gel and a mixture of n-hexane/ethyl acetate (9:1) as the eluent. The yields are 20% for compound 9 and 31% for compound 10. 6-Methyl-6-(4’-methoxyphenyl)fulvene (9) 1 H NMR (δ ppm CDCl3): 7.38-6.91 (m, 4H, C6H4); 6.63-6.23 (m,...