Anti-HIV-1 phorbol esters from the seeds of Croton tiglium

Inhibition of Cytopathic Effect of Human Immunodeficiency Virus Type-1 by Various Phorbol Derivatives.

“…Kubinski et al 33) reported that although chemically related compounds tend to change the properties of the microsomal membrane in a similar way, TPA (8) decreased the amount of bound DNA 5-fold, while phorbol 12,13-didecanoate, the second strongest promoter, increased this amount by about one-third. These discrepancies have been postulated to reflect a difference in the specific site of action, and led us to suggest that except for TPA (8), the inhibition of CPE and activation of PKC by these compounds are not parallel in potency, and that the anti-CPE activity shown by 4 and 6 is mediated through different receptor(s) other than/or in addition to PKC.…”

“…On the other hand, 4-deoxy-4a-phorbol derivatives (23a-c) were prepared from 23, while 24a-d and 25 were obtained from 23b (Chart 2). 19) 13-O-Acetylphorbol 20-octadecanoate (1), 4, 6 and 12-Otetradecanoylphorbol 13-acetate (8), showing appreciable inhibition of CPE, were selected for further modification. Compound 1 was treated with mesyl chloride in pyridine at room temperature to afford a ring fission product (1a), 20) and this was converted to 12-O-,13-O-diacetylphorbol 20-octadecanoate (1b) on acetylation.…”

“…Preparation of Phorbol (9), Isophorbol (14) and 4-Deoxy-4a a-isophorbol (23) A hexane-soluble fraction (50 g) of the methanol extract of the seeds of C. tiglium, as reported previously, 8) was mixed with a solution of Ba(OH) 2 · 8H 2 O (2.2% in MeOH, 500 ml) and stirred under an atmosphere of argon for 20 h at room temperature. The procedure was followed as reported previously 9,10) to obtain a crude phorbol fraction (10 g).…”

Artificial Analogs of Naturally Occurring Tumor Promoters as Biochemical Tools and Therapeutic Leads

“…[43][44][45] Among these, 12-O-acetylphorbol 13-decanoate (18) was found to be the most effective inhibitor of HIV-1, but detailed biological studies found that the inhibitory activity of 18 against HIV-1 was strikingly reduced after incubation with mouse plasma, probably due to hydrolysis of the 12-O-acetyl group by esterases. To improve the stability of 18 under physiological conditions, Nemoto and coworkers synthesized new analogs with ethereal side chains at position 12 (19)(20)(21)(22).…”

Biotransformation of Phorbol by Human Intestinal Bacteria.

“…Although many biological activities of phorbol esters are mediated through their direct interaction and the activation of protein kinase C (PKC), there are some phorbol esters that are active without being tumor promoters, such as ostodin and prostratin. 6,7) Recently, Hattori et al reported that 12-Oacetylphorbol 13-decanoate potently inhibited the cytopathic effects of human immunodeficiency virus type 1 without appreciable activation of protein kinase C. 8,9) Phorbol (1) has been synthesized, 10) and the total synthetic approach can be modified in ways which might lead to biologically improved versions of the molecule. Microbial transformation studies have been conducted successfully as model systems to predict metabolic pathways in humans or to increase the efficiency of drugs by metabolic activation.…”