Betulinic Acid And Its Derivatives With Antitumor Activity

Betulinic acid and its derivatives were potential antitumor agents, which displayed a selective cytotoxicity on tumor cell lines but not on normal cells. Research and development of betulinic acid as a therapeutic agent has been hindered because 1) betulinic acid presently is available in very limited quantities and at a very high cost; 2) betulinic acid suffers a low water solubility, resulting in inefficient biological efficacy. It was envisioned that providing commercial quantity of betulinic acid and improving the water solubility by synthesized a number of potentially important derivatives, which may be developed as antitumor agents, could resolve the problems.First, we studied the method of extracting betulinic acid from Semen Ziziphi Spinosae and obtained fine needles betulinic acid, purity>95%, yield 0.15%.Next, betulin was extracted and isolated from the bark of Betula alba in significant quantity. After recrystallized from ethanol pure betulin(>95%)was obtained, yield 20%. Then, it was synthetically converted to betulinic acid by Jones'oxidation and sodium borohydride reduction.Third, four amino acid (L-alanine D-alanineβ-amino-propanoic acid andγ-amino-butanoic acid) conjugates of betulinic acid and ten amino acid (glycine L-alanine D-alanine,β-amino-propanoic acidγ-amino-butanoic acid L-valine L-glutamic acid L-isoleucine L-phenylalanine L-tyrptophan) conjugates of betulonic acid at C-28 carboxylic acid position, as well as three C-3 position modified derivatives of betulonic acid (3-oxime-betulinic acid 3-amino-betulinicacid 3-hydrazone-betulinic acid) were synthesized in efforts to develop potential antitumor agents. All the derivatives are new compounds except L-alanine conjugate of betulinic acid 3-oxime-betulinic acid and 3-amino- betulinic acid.Fourth, MTT [3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide] assay showed that betulinic acid could inhibit the proliferation of ten tomor cell lines, in which the IC50 of KB (human oral epidermoid cancinoma) cells was the least. Besides, the inhibitory rates (IR%) of all derivatives were calculated against KB cell lines.