Inhibition of cytopathic effect of human immunodeficiency virus type-1 by various phorbol derivatives.
Forty-eight derivatives of phorbol (9) and isophorbol (14) were evaluated for their inhibition of human immunodeficiency virus (HIV)-1 induced cytopathic effects (CPE) on MT-4 cells, as well as their activation of protein kinase C (PKC), as indices of anti-HIV-1 and tumor promoting activities, respectively. Of these compounds, the most potent inhibition of CPE was observed in 12-O-tetradecanoylphorbol 13-acetate (8) and 12-O-acetylphorbol 13-decanoate (6). The former also showed the strongest PKC activation activity, while the latter showed no activity at 10 ng/ml. Both activities were generally observed in those phorbol derivatives with an A/B trans configuration, but not in the isophorbol derivatives with an A/B cis configuration. Acetylation of 20-OH in the phorbol derivatives significantly reduced the inhibition of CPE, as shown in 12-O-, 20-O-diacetylphorbol 13-decanoate (6a) (IC100=15.6 microg/ml) vs. compound 6 (IC100=0.0076 microg/ml), and 12-O-tetradecanoylphorbol 13,20-diacetate (8a) (IC100=15.6 microg/ml) vs. 12-O-tetradecanoylphorbol 13-acetate (8) (IC100=0.00048 microg/ml), except in the case of 12-O-decanoylphorbol 13-(2-methylbutyrate) (4) and phorbol 12,13-diacetate (9c). The reduction of a carbonyl group at C-3 abruptly reduced the inhibition of CPE, as observed in 3beta-hydroxyphorbol 12,13,20-triacetate (9f) (IC100=500 microg/ml) vs. phorbol 12,13,20-triacetate (9d) (IC100=62.5 microg/ml). Although 8 was equipotent in the inhibition of CPE, and activation of PKC, both activities were abruptly decreased by the acetylation of 20-OH and methylation of 4-OH [as in 8a and 4-O-methyl-12-O-tetradecanoylphorbol 13,20-diacetate (8b), respectively]. On the other hand, its positional isomer (12-O-acetylphorbol 13-tetradecanoate (8c) showed neither activities. The removal of a long acyl group in 8 led to a substantial loss of both activities, as shown in phorbol 13-acetate (9b). Of the 12-O-acetyl-13-O-acylphorbol derivatives, the highest inhibition of CPE was observed in 6, which has a dodecanoyl residue at C-13. Both an increase and decrease in the number of fatty acid carbon chains resulted in significant reduction of the inhibition of CPE.
El-Mekkawy
Sahar
S
Institute of Natural Medicine, Toyama Medical and Pharmaceutical University, Sugitani, Japan.
Meselhy
Meselhy Ragab
MR
Abdel-Hafez
Atef Abdel-Monem
AA
Nakamura
Norio
N
Hattori
Masao
M
Kawahata
Takuya
T
Otake
Toru
T
D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001921:Brain / Q000201:enzymology; D002460:Cell Line; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D004789:Enzyme Activation; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D007938:Leukemia; D010704:Phorbols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D013601:T-Lymphocytes / Q000187:drug effects / Q000821:virology
D019380:Anti-HIV Agents; D010704:Phorbols; D011493:Protein Kinase C