Chemical modification of ascorbic acid and evaluation of its lipophilic derivatives as inhibitors of secretory phospholipase A(2) with anti-inflammatory activity.
The halo 6-fatty acid esters of L-ascorbic acid 3a, 3b and 6-fatty acid esters of L-ascorbic acid 5a-g were achieved from L-ascorbic acid 1. Compounds 3a, 3b and 5a-g were evaluated for anti-oxidant, anti-lipid peroxidation, and secretory phospholipase A(2) (sPLA(2)) inhibition in vitro, and sPLA(2) induced mouse paw edema. All the derivatives retained their anti-oxidant property compared to ascorbic acid at 6 × 10(-4)M and are good inhibitors of lipid peroxidation at 1 mg ml(-1) as evaluated by 2, 2-Diphenyl-1-picrylhydrazyl radical and thio-barbituric acid methods, respectively. Compounds 5e and 5f significantly inhibited purified group I sPLA(2) from Naja naja and group II sPLA(2) from Vipera russelli, human synovial fluid and human pleural fluid with IC(50) value ranging from 64 ± 1.95 to 82 ± 1.3 and 48 ± 2.27 to 61 ± 2.23 μM, respectively. The compounds 5e and 5f also showed varying degree of potency in neutralizing indirect hemolytic activity of sPLA(2) at 50 μM concentration, and sPLA(2) induced mouse paw edema at the dose 3 mg/kg. Further docking studies also confirmed that compounds 5e and 5f have maximum interaction with increasing negative energy value. Single molecule possessing both anti-oxidant and anti-inflammatory activities is of great therapeutic significance in inflammatory disorders.
Mohamed
Riyaz
R
Department of Studies in Biochemistry, University of Mysore, Mysore, 570006, India.
Dharmappa
K K
KK
Tarannum
Shaista
S
Jameel
N M
NM
Kannum
S A
SA
Ashrafulla
H S
HS
Rai
Lokanath
L
Souza
Cletus Jmd'
CJ
Shekhar
M A
MA
Vishwanath
Bannikuppe S
BS
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000737:chemistry; D000975:Antioxidants / Q000138:chemical synthesis; D001205:Ascorbic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D005227:Fatty Acids / Q000737:chemistry* / Q000494:pharmacology; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D015227:Lipid Peroxidation; D051379:Mice; D054497:Phospholipases A2, Secretory / Q000037:antagonists & inhibitors* / Q000302:isolation & purification; D011485:Protein Binding; D012910:Snake Venoms / Q000201:enzymology; D013329:Structure-Activity Relationship
D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D005227:Fatty Acids; D012910:Snake Venoms; D054497:Phospholipases A2, Secretory; D001205:Ascorbic Acid