Synthesis and cytotoxic activity of isocembrol and its hydroxy derivatives
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Synthesis and cytotoxic activity of isocembrol and its hydroxy derivatives Sh. M. Salikhov, L. Kh. Faizullina, and F. A. Valeev Ufa Institute of Chemistry, Ufa Federal Research Centre, Russian Academy of Sciences, 71 prosp. Oktyabrya, 450054 Ufa, Russian Federation. Fax: +7 (347) 235 6066. Е-mail: [email protected] The synthesis of 2- and 3-hydroxy derivatives of isocembrol was accomplished by the epoxidation of isocembrol with tert-butyl hydroperoxide in the presence of a catalytic amount of VO(acac)2 followed by the epoxide ring opening in the presence of LiAlH4. The 13-hydroxy derivative of isocembrol was synthesized by the allylic oxidation in the SeO2—ButOOH system. Using the PASS software, the 13-hydroxy derivative was predicted to be the most effective cytotoxic agent, which was esterified to form N-methylurocanate. Isocembrol exhibited the highest in vitro antitumor activity against the LOX IMVI (melanoma) and UO-31 (renal cancer) cells, causing up to 25.77 and 75.65% cell death, respectively. N-Methylurocanate led to the death of up to 51.04% UO-31 cells (renal cancer). Key words: isocembrol, allylic oxidation, N-methylurocanic acid, cytotoxicity.
Cembrane-type diterpenoids are widespread in nature, and many of them exhibit high and various biological activities. 1—24 Cembranoids contain a 14-membered carbon macrocycle bearing various functional groups in different mutual positions. These compounds are considered as biogenetic precursors of many polycyclic diterpenoids, in particular, of two closely related branches of oxygenated metabolites of eunicellins and eleuthesides.10 Representatives of eunicellanes also showed unique biological properties.25,26 Eleuthesides are a small group of compounds;27 one representative of these compounds, eleutherobin, exhibits cytotoxic activity comparable to that of taxol with a taxol-like mechanism of cytotoxic action.28,29 Due to the practical importance of this series of compounds, the total syntheses of eleutherobin and sarcodictyins have been developed over a short period of time,27,30—39 and the structure—activity relationship was established for the series of sarcodictyin analogues.40 One of the fundamental conclusions is that the replacement of the N-methylurocanic acid residue by other acids or the replacement of the N-methylimidazole moiety by other heterocycles with the retention of the ,-conjugated system leads to the complete loss or significant decrease in activity.32,40 This conclusion indirectly accounts for the lack of data on cytotoxic activity of valdivones — eleuthesides, which do not belong to urocanates.41 Urocanic acid, being a histidine metabolite, displays the immunosuppressive effect.42 This acid is sparingly soluble in organic solvents and water, which hinders a more detailed evaluation of its biological properties.43 The complexity of the chemical synthesis of eleuthesides and, as a consequence, the difficulty in practical applications of the results of the synthesis27 have spurred
the search for more readily available eleutheside analogues
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