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(12) Patent Application Publication (10) Pub. No.: US 2011/0190389 A1 Arterburn Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2011/0190389 A1 Arterburn Et Al US 2011 0190389A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0190389 A1 Arterburn et al. (43) Pub. Date: Aug. 4, 2011 (54) OXYLIPINS FROM LONG CHAIN C07C 57/03 (2006.01) POLYUNSATURATED FATTY ACDS AND A6IP 29/00 (2006.01) METHODS OF MAKING AND USING THE CI2P 7/64 (2006.01) SAME CI2P I 7/02 (2006.01) C07D 303/38 (2006.01) (76) Inventors: Linda Arterburn, Ellicott City, A6IP 25/28 (2006.01) MD (US); William Barclay, Boulder, CO (US); Bindi Dangi, (52) U.S. Cl. ......... 514/475: 514/560; 554/124; 435/134; Elkridge, MD (US); James Flatt, 435/123:549/561 Colorado Springs, CO (US); Jung Lee, McLean, VA (US); Dutt (57) ABSTRACT Vinjamoori, Chesterfield, MO Disclosed are novel oxylipins, referred to herein as (US); Mary Van Elswyk, docosanoids and eicosanoids, that are derived from C22 poly Longmont, CO (US) unsaturated fatty acids and from C20 polyunsaturated fatty acids, respectively, and methods of making and using Such (21) Appl. No.: 12/531,344 oxylipins. Also disclosed is the use of docosapentaenoic acid 1-1. (C22:5n-6) (DPAn-6), docosapentaenoic acid (C22:5n-3) (22) PCT Filed: Feb. 20, 2008 (DPAn-3), and docosatetraenoic acid (DTAn-6: C22:4n-6), (86). PCT No.: PCT/USO8/54.456 docosatrienoic acid (C22:3n-3) (DTrAn-3), docosadienoic acid (C22:2n-6) (DDAn-6), eicosatrienoic acid (C20:3n-3) S371 (c)(1), (ETrAn-3) eicosapentaenoic acid and arachidonic acid as (2), (4) Date: Feb. 15, 2011 substrates for the production of novel oxylipins, and to the oxylipins produced thereby. Also disclosed is the use of Related U.S. Application Data DPAn-6, DPAn-3, DTAn-6, and/or the oxylipins derived therefrom, and/or novel docosanoids derived from the struc (60) Provisional application No. 60/890,701, filed on Feb. tures of C22 fatty acids in therapeutic and nutritional or 20, 2007. cosmetic applications, and particularly as anti-inflammatory O O or anti-neurodegenerative compounds. The invention also Publication Classification relates to novel ways of producing long chain polyunsatu (51) Int. Cl. rated acid (LCPUFA)-rich oils and compositions that contain A6 IK3I/336 (2006.01) enhanced and effective amounts of LCPUF A-derived oxy A6 IK 3L/202 (2006.01) lipins, and particularly, docosanoids. Patent Application Publication Aug. 4, 2011 Sheet 1 of 48 US 2011/O190389 A1 Fig. 1 120 Yom 1 OO - . 80 - 6 O r t O 5 O 15 2O 25 30 35 Time (minutes) Patent Application Publication Aug. 4, 2011 Sheet 2 of 48 US 2011/O190389 A1 Fig. 2A Y Y YYcoo- -N-V-N-Noo - - - Max-a- Y - more - /N w Docosahexaenoic acid (DHA) 17-hydroxyO DHA O- / N. OH W COO 2 COO - /N r - /N O O 10,17-dihydroxy DHA 7,17-dihydroxy DHA Patent Application Publication Aug. 4, 2011 Sheet 3 of 48 US 2011/O190389 A1 40 ro COO 90.6 o rts .. i O4 245 OH: & 273 o 2. O.2 O in ar M-H --- 2OO O 80 300 343 Wavelength (nm) s as o 1.5 - r w o av 4-2 wa . w 1.0 - 0.5 - a- M D 245 -H2O M-H -CO2 273 -co M-H -H2O m O -CO2 281.5 -CO2 3256 w- 2453 2.99.S. 229 OO 50 200 250 300 350 400 Patent Application Publication Aug. 4, 2011 Sheet 4 of 48 US 2011/O190389 A1 Fig.2C . 4. O. 2 270 320 Wavelength (nm) c OO 50 2OO 2SO BOO 350 4OO Patent Application Publication Aug. 4, 2011 Sheet 5 of 48 US 2011/O190389 A1 Fig. 2D 175 S 2500 C 125 es 75 25 200 240 280 320 360 M-H -H2O 2OOO 26 Wavelength (nm) 34. -H2O -CO2 98.9 en o M-H 1500 -CO2-H2O s 29. 2g t M-H O.9 -CO2 1000- -2H2O - 29. 26 26 -CO2 26 M-H 359. 'oo289 -HOft2 -CO2 09 -H2O243 BS. 133 529 92 | w l 100 150 2OO 250 300 350 AOC Patent Application Publication Aug. 4, 2011 Sheet 6 of 48 US 2011/O190389 A1 Fig. 3A COO - / YTY COO oard A rar - /N DoCosapentaenoic n-6 acid OH (DPAn-6) 17-hydroxy DPAn-6 OI - N. OH W COO - N2 WWW COOT OH O 10,17-dihydroxy DPAn-6 7,17-dihydroxy DPAn-6 Patent Application Publication Aug. 4, 2011 Sheet 7 of 48 US 2011/O190389 A1 Fig. 3B BOOO 0.6 245 O 304 LM-H 345. 25 its o.2 M-H H2O 200 240 280 300 3272 Wawelegth (iii) e 2OCO w ww. e is 1500 J 1 OOO 245 -CO2 2014 SOO 3.2 their tly | | | | | | | It OO SO 2OO 2SO 3. 35C 4. Patent Application Publication Aug. 4, 2011 Sheet 8 of 48 US 2011/O190389 A1 Fig. 3C 2000 8 0. 4. O, 2 1500 270 320 Wavelength (nm) 1000 100 150 OO 25 3OO 350 400 m/z Patent Application Publication Aug. 4, 2011 Sheet 9 of 48 US 2011/O190389 A1 Fig. 3D 70 2 3d 50 600 3. ac 9 30 it. 9. m 10 200 240 280 320 38 Wavelength (nm) 2. M-H) -H2O 5 400 -CO2 261 299 H2O t -CO2 2 1989 200 - (M-H -2H2O -CO2 H 261 2811 t - -CO2 2610 M 217 ly. ...A.TT OO 150 2O) 25 300 m/z. Patent Application Publication Aug. 4, 2011 Sheet 10 of 48 US 2011/O190389 A1 Fig. 4A ( YCOO or or COO - /N ---------- DoCosapentaenoic n-3 acid O (DPAn-3) 17-hydroxy DPAn-3 O / N OH W area COO" - N2 COO r N - /N OH OH 10,17-dihydroxy DPAn-3 7,17-dihydroxy DPAn-3 Patent Application Publication Aug. 4, 2011 Sheet 11 of 48 US 2011/O190389 A1 Fig. 4B 100 2500 1500 oH 80 275 M-H 345.2 200 240 280 320 360 380 247 6 O Wavelength (nm) 4. 0 -CO2 20 283 247 275 121 -CO2 -CO2 203.1 231 OO 150 200 250 300 350 moz Patent Application Publication Aug. 4, 2011 Sheet 12 of 48 US 2011/O190389 A1 Fig. 4C 7000 0.4 COO 6OO s s g O. & 5OOO 343 210 270 Wavelength (nm) 400 M-H N 36 3OOO 83 S C y 2000 2632 (M-H -2H2O M-H 325, 263 --O COO -H2O M-H 26, 45. -2H2O , -CO2 155 23. I all39 11,97 all | 28| || | ------ | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | 100 150 200 250 3OO 350 400 Patent Application Publication Aug. 4, 2011 Sheet 13 of 48 US 2011/O190389 A1 Fig. 4D 5000 60 C as as 40 al AOO 20 20 240 280 32O 34 Wavelength (nm) ty 3000 w .2 c. S s C. 2OO 13 OO 263 -H2O CO2 29 12 -CO4. rth riskT O 150 2O 250 BOO 350 400 Patent Application Publication Aug. 4, 2011 Sheet 14 of 48 US 2011/O190389 A1 Fig. 5A C YCOO --> ( ) N/ N/\oo ww. - 1N DOCOSatetraenoic n-6 acid O (DTAn-6) 17-hydroxy DTAn-6 OF - N2 COO" - /N OH 7,17-dihydroxy DTAn-6 Patent Application Publication Aug. 4, 2011 Sheet 15 of 48 US 2011/O190389 A1 Fig.5B 4 OO 60 O 20 240 280 320 360 Wavelength (nm) 00 50 2OO 2SO 300 350 400 infz Patent Application Publication Aug. 4, 2011 Sheet 16 of 48 US 2011/O190389 A1 Fig.5C 8000 -T- 2OG 240 230 280 320 350 Wavelength (nm) 6000 263 es -H2O "a -CO2 l 20 9. 2. 4000 2000 O) 150 200 250 3OO 3SO 400 Patent Application Publication Aug. 4, 2011 Sheet 17 of 48 US 2011/O190389 A1 Fig.6 O co -> COO area Xaaaaaaa - /N OH DPA n-6 /uninhemoglobin17-hydroxy DPAn-6 N. O- w - /N N O- OH O 10,17-dihydroxy DPAn-6 13,17-dihydroxy DPAn-6 No ro trihydroxy DPAn-6 Patent Application Publication Aug. 4, 2011 Sheet 18 of 48 US 2011/O190389 A1 Fig. 7 M-H M-H-H2O M-H-CO2 M-H-CO2-H2O fragment fragment 8-CO2 COOT 325 M.H.H2O 299 MH-CO2 281 M-H-CO2-H2O -H. 193 fragment OH 22 22 fragment 13-hydroxy DHA M-H COO M-H-H2O M-H-CO2 M-H-CO2-H2O 233, i fragment OH -Fi fragment 26 233-CO2 16-hydroxy DHA 343 M-H 32.5 M-H-H2O a 2.99 M-H-CO2 COO 28 M-H-CO2H2O 193 fragment 149 fragment 65 fragment 165-CO2 M-H M-H-H2O M-H-CO2 M-H-CO2H2O M.H.CO2-2H2O fragment fragment fragment 301 -CO2 301-CO2H2O 10, 20-dihydroxy DHA 18-CO Patent Application Publication Aug. 4, 2011 Sheet 19 of 48 US 2011/O190389 A1 Fig. 8 M-H M-H-H2O M-H-CO2 M-H-CO2-H2O fragment fragment 181-CO2 10-hydroxy DPAn-6 error Yor Patent Application Publication Aug . 4, 2011 Sheet 20 of 48 US 2011/O190389 A1 161 183 fragment fragment fragment 345 M-H 327 M-H-H2O 301 M-H-CO2 COO" 283 M-H-CO2-H2O 195 fragment fragment COO M-H M-H-H2O M-H-CO2 235 litti. ; M-H-CO2H2O O-I -H,- fragment 263 fragment 16-hydroxy DPAn-3 235-CO2 M-H COO M-H-H2O M-H-CO2 M-H-CO2-H2O fragment fragment fragment M-H M.HH2O M-H-CO2 COO M-H-CO2-H2O fragment fragment OH fragment 10, 20 dihydroxy DPAn-3 Patent Application Publication Aug.
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