Constantinou-Kokotos, George

Constantinou-Kokotou, Violetta

Smyrniotoua, Anneta

Digital Repository of Hellenic Managing Authority of the Operational Programme &quot;Education and Lifelong Learning&quot; (EDULLL)

SYNTHESIS OF POLYFLUOROKETONES CONTAINING AN INDOLE RING AS INHIBITORS OF HUMAN Ca2+- INDEPENDENT PHOSPHOLIPASE A2 Anneta Smyrniotoua, Violetta Constantinou- Kokotoua, George Kokotosb aChemical Laboratories, Agricultural University of Athens, Athens, Greece; bDepartment of Chemistry, University of Athens, Athens, Greece Introduction Phospholipase A2 (PLA2) enzymes catalyze the hydrolysis of the sn-2 ester bond of glycerophospholipids producing free fatty acids and lysophospholipids.1 The main representative of these fatty acids is arachidonic acid, which can be transformed into eicosanoids (prostaglandins, leukotriens, etc) by the action of other enzymes. Lysophospholipids are precursors for other bioactive compounds, such as platelet-activating factor (PAF). PAF and eicosanoids constitute basic mediators of inflammation and other pathophysiological routes. In the superfamily of PLA2 enzymes, three are the predominant groups found in human tissues; the cytosolic PLA2 (cPLA2), the calcium-independent PLA2 (iPLA2) and the secreted PLA2 (sPLA2).1  We have recently demonstrated that Ca2+-independent phospholipase A2 (GVIA iPLA2) plays a key-role in experimental autoimmune encephalomyelitis and that GVIA iPLA2 is a novel target for the development of new therapies for multiple sclerosis.2  A series of fluoroketones of the general structure 1 has been presented as iPLA2 inhibitors and the structure-activity relationship has been evaluated.3,4 Polyfluoroketones FKGK11 and FKGK18 proved to be potent and selective inhibitors of GVIA iPLA2 (Table 1). Therefore, to extend this research, we synthesized a variety of polyfluoroketones containing an indole ring and a four carbon atom chain between the ring and the polyfluoroketone group.                   Table 14 No Ar Rf XI(50) for iPLA2 FKGK11 C2F5 0.0014 ± 0.0001 FKGK18 CF3 0.0002 ± 0.0000 Acknowledgments This research has been co-financed by the European Union (European Social Fund – ESF) and Greek national funds through the Operational Program "Education and Lifelong Learning" of the National Strategic Reference Framework (NSRF) - Research Funding Program: Heracleitus II. Investing in knowledge society through the European Social Fund. Synthesis Indole-3-carboxaldehyde (2) was obtained from indole using the Vilsmeier - Haack reaction and then it was protected with the tosyl or the methyl group (Scheme 1). These two protected aldehydes along with commercially available indole-5-carboxaldehyde underwent a Horner – Wadsworth – Emmons reaction with triethyl-4-phosphonocrotonate in the presence of a strong base (1,1,3,3-tetramethyl guanidine or NaH) to produce the corresponding unsaturated esters 4a-c (Scheme 2). After catalytic hydrogenation, we received the saturated esters 5a-d; in the case of ester 5d the indole ring was also hydrogenated along with the double bonds. After saponification with NaOH 1N in ethanol, we acquired the corresponding carboxylic acids 6a-d which were converted to acyl chlorides with the method of oxalyl chloride/DMF. In situ, the acyl chlorides were treated with pyridine and trifluoroacetic anhydride or pentafluoropropionic anhydride to provide the trifluoromethyl ketone 8d, and pentafluoroethyl ketones 7a-c. In the case of pentafluoroethyl ketone 7c the reaction conditions of the last step were in consistency with the Vilsmeier – Haack reaction and as a result we obtained the aldehyde derivative (Scheme 3).   Scheme 1: Synthesis of protected indole-3-carboxaldehyde       Reagents and conditions: a) DMF, (COCl)2, NaOH 9N, H2O,  b) TsCl, NaOH, CH2Cl2, r.t. to 35 °C, c) NaH, CH3I, THF.   Scheme 2: Synthesis of polyfluoroketones 3 R a SO2C6H4CH3 b CH3 Reagents and conditions: a) C2H5OOCCH=CHCH2P(=O)(OC2H5)2, i) NaH, THF, 0 oC to r.t. for a,b or ii) TMG, THF, -15 oC to r.t. for c,  b) H2, 10% Pd/C, EtOH, c) NaOH 1N, EtOH, d) (COCl)2, DMF, CH2Cl2, e) pyridine, (CF3CF2CO)2O, CH2Cl2, 0 oC to r.t., f) pyridine, (CF3CO)2O, CH2Cl2, 0 oC to r.t. 3-8 Ar a b c d Scheme 3  Conclusion Five novel polyfluoroketones were synthesized containing an indole ring and the evaluation of their inhibitory activity is in progress. References 1.Dennis, E.A.; Cao, J.; Hsu, Y.-H.; Magrioti, V.; Kokotos, G. Chem. Rev. 2011, 111, 6130–6185. 2.Kalyvas, A.; Baskakis, C.; Magrioti, V.; Constantinou-Kokotou, V.; Stephens, D.; Dennis, E. A.; Kokotos G.; David, S. Brain 2009, 132, 1221-1235. 3.Baskakis, C.; Magrioti, V.; Cotton, N.; Stephens, D.; Constantinou-Kokotou, V.; Dennis, E.A.; Kokotos, G. J. Med. Chem. 2008, 51, 8027–8037. 4. Kokotos, G.; Hsu, Y.-H.; Burke, J. E.; Baskakis, C.; Kokotos, C.G.; Magrioti, V.; Dennis, E. A. J. Med. Chem. 2010, 53, 3602-361.   

Synthesis of polyfluoroketones containing an indo ring as inhibitors of human Ca2+- independent phospholipase A2

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Synthesis of polyfluoroketones containing an indo ring as inhibitors of human Ca2+- independent phospholipase A2

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Digital Repository of Hellenic Managing Authority of the Operational Programme "Education and Lifelong Learning" (EDULLL)

Synthesis of polyfluoroketones containing an indo ring as inhibitors of human Ca2+- independent phospholipase A2

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Digital Repository of Hellenic Managing Authority of the Operational Programme &quot;Education and Lifelong Learning&quot; (EDULLL)

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