Synthesis and Antitumor Activity of Cyclopropane Derivatives of Betulinic and Betulonic Acids

Abstract

New cyclopropane derivatives of betulin were synthesized by attachment of dichlorocarbenes or dibromocarbenes to the double bond of betulin diacetate, followed by the deprotection of hydroxyl groups. The betulin cyclopropane derivative was obtained from 20,29-dihydro-20,29-dichloromethylenebetulin by treatment with lithium in tert-butanol. These compounds were converted into the corresponding derivatives of betulonic acid by oxidation with chromium trioxide. The reduction of oxo group with sodium borohydride led to the corresponding derivatives of betulinic acid. 20,29-Dihydro-20,29-dichloromethylenebetulinic acid proved to be the most cytotoxic toward human melanoma of the Colo 38 and Bro lines and human ovarian carcinoma of the CaOv line (IC50 10 microM). 20,29-Dihydro-20,29-dibromomethylenebetulinic acid inhibited the growth of the Bro melanoma cell line and the CaOv carcinoma cell line practically by 50% at a concentration of 10 microM. The other derivatives of betulinic and betulonic acids were active toward all of the three cancer cell lines at concentrations higher than 10 microM. The English version of the paper: Russian Journal of Bioorganic Chemistry, 2005, vol. 31, no. 3; see also http://www.maik.ru.

Synthesis and Anticancer Activity of Novel Betulinic acid and Betulin Derivatives

“…Compounds 3, 4, 8, 12-14 were synthesized by the procedures reported in the literature [17,[19][20][21][22][23][24]. The structures of the mentioned compounds were confirmed with 1 H-and 13 C-NMR spectroscopy.…”

The Potential of Triterpenoids in the Treatment of Melanoma

“…The very poor solubility of acid 1 in water based media (< 1 mol/L) (Cichewicz & Kouzi, 2004;Symon et al, 2005), high hydrophobicity (log P) (Srivastava et al, 2002) and unsuitable pK parameters (absorption, distribution, metabolism and elimination), along with strong antitumor potential (Pisha et al, 1995) and low acute toxicity (Cichewicz & Kouzi, 2004) motivated a number of scientific institutions to synthesize derivatives, pro-drugs and formulations of betulinic acid (1) that could retain the activity and low toxicity, but improve the afore mentioned properties. The following semi-synthetic derivatives might be divided into three groups: simple derivatives of natural triterpenes (2.2.1), derivatives obtained by biotransformation procedures of betulinic acid (1) (2.2.2) and triterpenoids with modification of lupane skeleton (2.2.3).…”

“…These data show that 20(29) dihydroderivatives are comparably active to their unsaturated analogs (Biedermann et al, 2010;Sarek et al, 2007). Among the other explored addition reaction to 20(29)-double bond, there is the addition of halogene (Mukherjee et al, 1997) or dihalocarbene (Symon et al, 2005). In the study of Mukherjee's et al, cytotoxic activity (except melanoma lines) of the products of addition of bromine to betulonic (5), betulinic (1), and acetylbetulinic (65) acids (e.g.…”

“…A Russian team tested the activity of formerly prepared addition adducts 88 and 89 of dichloro-and dibromocarbene to betulinic acid (1) against human melanoma cells Colo 38 and Bro.92. The best results were achieved with a dichloroderivative 88 with the activity on Bro line slightly better than the activity of acid 1, nevertheless the authors claimed that the high lipophilicity of synthesized derivatives complicated in vitro tests, therefore further tests of the derivatization of these non-polar compounds were suggested (Symon et al, 2005). Another option to modify the isopropenyl side chain is substitution, respectively allylic oxidation.…”

Solubility Study of Betulonic Acid in the Presence of Hydroxypropyl-γ-cyclodextrin by Capillary Electrophoresis

“…1А) относится к пентациклическим тритерпиноидам лупаново-го ряда и обладает рядом полезных свойств, таких как антибактериальная, противовирусная, противораковая и анти-ВИЧ-активность [1,2]. Однако, несмотря на широкий спектр действия, применение бетулоновой кислоты в фармацевтической промышленности весьма ограничено из-за низкой растворимости в воде [3].…”