Analgesic and anti-inflammatory activity of podophyllotoxin derivatives.
BACKGROUND
Podophyllotoxin is a natural product that inhibits the polymerization of tubulin and has served as a prototype for the development of diverse antitumor agents in clinical use, such as etoposide, teniposide and etopophos. Reumacon, another semisynthetic derivative, reached its clinical phase for the treatment of rheumatoid arthritis.


OBJECTIVE
This study investigated the analgesic and anti-inflammatory properties of three compound derivatives from podophyllotoxin.


METHODS
During a phytochemical study performed on Juniperus thurifera Linne (Cupressaceae) leaves, among other products, several cyclolignans, such as podophyllotoxin, deoxypodophyllotoxin, deoxypicropodophyllotoxin and thuriferic acid were isolated. These compounds, obtained afterwards through semisynthesis, were assayed as analgesic and anti-inflammatory agents. Additionally, the cytotoxic activity of thuriferic acid was evaluated in three cancer cell lines, P-388, A-549 and HT-29, and these data were compared with previous cytotoxicity results obtained for the other three compounds.


RESULTS
Analgesic activity results showed that deoxypicropodophyllin is as effective as deoxypodophyllotoxin to inhibit nociceptive perception induced by acetic acid in mice (77.8% ± 4.1% and 71.3% ± 6.5%, respectively), while its cytotoxicity [1.01 × 10(-7) (GI50 M)] is 100-fold less. Other set of experiments showed that thuriferic acid, a derivative of podophyllotoxin a thousand times less citotoxic [1.21 × 10(-5) (GI50 M)] than deoxypodophyllotoxin, caused significant inhibition of paw edema development in the carrageenan-induced inflammation test (63.4% ± 3.3%), effect comparable to those of deoxypodophyllotoxin (66.3% ± 4.4%), and the standard drug indomethacin (61.5% ± 2.5%).


CONCLUSIONS
We conclude that deoxypicropodophyllotoxin and thuriferic acid are effective in reducing edema formation. However, deoxypicropodophyllin is more related with analgesic activity than anti-inflammatory effect.
Departamento de Farmacología, Facultad de Medicina, Universidad de Panamá, Panama. guerrerodleon@gmail.com
Estela
E
Guerrero
Andrés
A
Abad
Gisela
G
Montenegro
Esther
E
Del Olmo
José Luis
JL
López-Pérez
Arturo
A
San Feliciano
D000700:Analgesics / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002227:Carbazoles / Q000494:pharmacology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004365:Drugs, Chinese Herbal; D019073:HT29 Cells; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy / Q000473:pathology; D018653:Juniperus / Q000737:chemistry; D008297:Male; D051379:Mice; D009281:Naphthalenes / Q000494:pharmacology; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D010146:Pain / Q000188:drug therapy / Q000503:physiopathology; D018515:Plant Leaves; D011034:Podophyllotoxin / Q000031:analogs & derivatives* / Q000494:pharmacology
D000700:Analgesics; D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D002227:Carbazoles; D004365:Drugs, Chinese Herbal; D009281:Naphthalenes; C452999:thuriferic acid; C014451:deoxypodophyllotoxin; D011034:Podophyllotoxin; D007213:Indomethacin