- Investigations on cytotoxicity and anti-inflammatory potency of licofelone derivatives
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A series of C5-substituted licofelone ([2,2-dimethyl-6-(4-chlorophenyl)-7- phenyl-2,3-dihydro-1H-pyrrolizin-5-yl]acetic acid) derivatives were developed by a parallel synthesis approach and investigated for cytotoxicity against MCF-7 and MDA-MB-231 cells as well as for anti-inflammatory potency in vitro and in vivo. Dependent on the C5-substituent, the compounds showed high selectivity for MCF-7 cells. Especially 2-oxoethyl benzoate derivatives were inactive at the MDA-MB-231 cell line and as active as 5-FU at MCF-7 cells. C5-acetyl (8a), -2-oxoethyl formiate (8e), -2-oxoethyl acetate (8f) and -2-oxoethyl propionate (8g) derivatives showed growth inhibition at both cell lines, comparable with cisplatin. Modifications significantly reduced the inhibitory potency at COX-1 and COX-2 in vitro and in the xylene-induced ear swelling assay in mice. Only compound 8a was equipotent to licofelone, ibuprofen and celecoxibe in vivo.
- Liu, Wukun,Zhou, Jinpei,Bensdorf, Kerstin,Zhang, Huibin,Liu, Haoran,Wang, Yubin,Qian, Hai,Zhang, Yanchun,Wellner, Anja,Rubner, Gerhard,Huang, Wenlong,Guo, Cancheng,Gust, Ronald
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p. 907 - 913
(2011/04/19)
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- Licofelone-nitric oxide donors as anticancer agents
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Five licofelone ([2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-1H- pyrrolizin-5-yl]acetic acid) nitric oxide donor conjugates were developed by a parallel synthesis approach. The biological screening revealed that compounds with a propyl (6b), butyl (6c), or octyl (6d) chain between licofelone and the nitric oxide donor exhibited high antiproliferative potency at MCF-7 and MDA-MB-231 breast cancer as well as at HT-29 colon cancer cells. Moreover, 6b-d possessed at least 2-fold higher cytotoxicity at MDA-MB-231 cells than the parent compound licofelone although they showed less inhibitory activity at COX-1 and COX-2. A correlation between COX inhibition and growth inhibitory properties is not visible. However, the high levels of nitric oxide production of the compounds may result in their high cytotoxic activity. Non-steroidal anti-inflammatory drugs possessing nitric oxide donors are promising anti-inflammatory and anticancer drugs. Herein, a series of licofelone-nitric oxide donors was synthesized and evaluated for their primary biological activities.
- Liu, Wukun,Zhou, Jinpei,Liu, Yinglin,Liu, Haoran,Bensdorf, Kerstin,Guo, Cancheng,Gust, Ronald
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p. 487 - 493
(2011/10/18)
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- Synthesis and biological evaluation of licofelone derivatives as anticancer and anti-inflammatory agents
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Two C5-substituted licofelone derivatives were developed and investigated for cytotoxicity against mammary (MCF-7 and MDA-MB 231) as well as colon carcinoma (HT-29) cancer cells. Both compounds were at least 2-fold more active than 5-fluorouracil (5-FU) and licofelone against mammary carcinoma cells. At HT-29 cells, they were less active, but nevertheless distinctly as active as 5-FU and still 2-fold more active than licofelone. However, variation of the C5- carboxylic group results in an occasionally remarkable decrease of anti-inflammatory potency in in vitro and in vivo.
- Liu, Wukun,Zhou, Jinpei,Zhang, Huibin,Qian, Hai,Yin, Jiahan,Bensdorf, Kerstin,Gust, Ronald
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experimental part
p. 911 - 917
(2012/07/03)
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- A NEW METHOD OF MANUFACTURING 2-(6-(4-CHLOROPHENYL)-2,2-DIMETHYL-7-PHENYL-2,3-DIHYDRO-LH-PYRROLIZINE-5-YL)ACETIC ACID (LICOFELONE)
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A method of manufacturing 2-(6-(4-chlorophenyl)-2,2-dirnethyl-7-phenyl-2,3-dihydro-lH- pyrrolizine-5-yl)acetic acid of formula I, wherein 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl- 2,3-dihydro-lH-pyrrolizine of formula II is alkylated with a iodo derivative of formula VII, wherein A is either the cyano group CN or an ester group COOR, wherein R is an (un)branched C1-C6 alkyl group, with the use of the Fenton reagent in the presence of a sulfoxide of formula R1-SO-R2, wherein R1 is an (un)branched C1-C12 alkyl group, R2 is either an (un)branched C1-C12 alkyl group, an aryl group or a substituted aryl group, or wherein R1, R2 are independently (CΗ2)mX(CΗ2)n, wherein X = CH2, O, S, NR3, m = 1-3, n = 1-3 and R3 is either an (un)branched C1-C12 alkyl group, an aryl group or a substituted aryl group, the reaction being carried out in the environment of the sulfoxide used or in its mixture with suitable solvents at a temperature of O 0C to 80 °C, preferably at temperatures in the range of 10 to 40 °C, and the resulting ester of formula IV or nitrile of formula VIII is hydrolyzed to the desired product of formula I either directly or in the case of the nitrile via the amide of formula (IX).
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Page/Page column 16
(2009/06/27)
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- A synthesis of licofelone using Fenton's reagent
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An efficient synthesis of licofelone, an anti-inflammatory drug currently undergoing phase-III clinical studies, based on Fenton-type radical alkylation of 2,3-dihydro-1H-pyrrolizine 3 with iodoacetonitrile or iodoacetates is reported. The iodoacetates can be replaced by NaI and by the corresponding bromoacetate.
- Rádl, Stanislav,?erny, Josef,Klecán, Ond?ej,Stach, Jan,Pla?ek, Luká?,Mandelová, Zuzana
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p. 5316 - 5318
(2008/12/22)
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- PROCESS FOR THE PREPARATION OF 6-(4-CHLOROPHENYL)-2,2-DIMETHYL-7-PHENYL-2, 3-DIHYDRO-1H-PYRROLIZIN-5-YL ACETIC ACID AND ITS INTERMEDIATES
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The present invention relates to a process for the preparation of 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2, 3-dihydro-1H-pyrrolizin-5-yl acetic acid, in which the key intermediate, 5-Benzyl-3,3-dimethyl-3,4-dihydro-2H-pyrrole is obtained by the hydrogenation of 2,2-dimethyl-4-oxo-5-phenyl-nitropentane. The invention also relates to the preparation of the intermediates occurring in the above process.
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Page/Page column 10-11
(2010/11/28)
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- POLYMORPHIC FORM OF 6- (4-CHLOROPHENYL) -2, 2-DIMETHYL-7-PHENYL-2, 3-DIHYDRO-LH-PYRROLIZIN-5-YLACETIC ACID
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The present invention relates to a new crystalline modification of 6- ( 4-chlorophenyl) -2, 2-dimethyl-7- phenyl-2, S-dihydro-lH-pyrrolizin-S-ylacetic acid which is referred to as polymorph B. It has a peak in the solid state 13C-NMR spectrum (with adamantane as external reference standard; CH group d = 29.45 ppm) in the range from 179.8 to 180.2 ppm and can be processed directly to a pharmaceutical formulation.
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Page/Page column 14-15
(2008/06/13)
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- Synthetic studies towards ML-3000: A concise synthesis of this non- steroidal anti-inflammatory drug
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ML-3000 was obtained from 1-chloro-3-phenyl-2-propyne in 8 steps with an overall yield of 19%. The key steps are a thermal acid-promoted bicyclization of an ω-acetylenic amino ester and a Suzuki cross-coupling reaction between a heteroaryl triflate and (4-chlorophenyl)boronic acid.
- Cossy, Janine,Belotti, Damien
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p. 5145 - 5156
(2007/10/03)
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- (6,7-Diaryldihydropyrrolizin-5-yl)acetic Acids, a Novel Class of Potent Dual Inhibitors of Both Cyclooxygenase and 5-Lipoxygenase
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A novel class of nonantioxidant dual inhibitors of both CO and 5-LO is described.The balance between the activity against CO and 5-LO can be shifted by modifying the substitution pattern of the phenyl moiety at the 6-position of the pyrrolizine ring.Structure-activity relationships are discussed.Compound 3e with a 4-Cl substituent (IC50 = 0.21 μM (CO); 0.18 μM (5-LO)) and 3n with a 4-OCH3 substituent (IC50 = 0.1 μM (CO); 0.24 μM (5-LO)) are the most potent and well-balanced dual inhibitors of both enzymes.The inhibition of CO was determined in a bovine thrombocyte intact cell assay and that of 5-LO using intact bovine PMNL.Compound 3e was also ivestigated in human cells.
- Laufer, Stefan A.,Augustin, Jan,Dannhardt, Gerd,Kiefer, Werner
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p. 1894 - 1897
(2007/10/02)
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