New ionic derivatives of betulinic acid as highly potent anti-cancer agents

Abstract

Betulinic acid is a natural compound with high in vitro cytotoxicity toward many cancer cells. However, the poor water solubility of this compound hampers an effective in vivo cancer study. We prepared new ionic derivatives of betulinic acid with higher water solubilities, without losing the structural integrity and functionality of this compound. As a result, these new ionic derivatives have shown much higher inhibitory effects against different cancer cell lines such as melanoma A375, neuroblastoma SH-SY5Y and breast adenocarcinoma MCF7. For A375 cell lines, the derivative 5 exhibited a low IC50 value of 36 μM (vs 154 μM for betulinic acid); for MCF7 cell lines, the derivative 5 also exhibited a low IC50 value of 25 μM (vs 112 μM for betulinic acid). The high cytotoxicity of these new derivatives can be linked to their greatly improved water solubility. Our assay method used little DMSO in aiding the dissolution of these derivatives to demonstrate the advantage of improved water solubility and to mimic the in vivo study conditions. The cell viability studies based on both MTT and LDH assay methods have confirmed the high inhibitory effect of our ionic derivatives of betulinic acid (particularly 4 and 5) against different cancer cells.

Betulinic Acid: Recent Advances in Chemical Modifications, Effective Delivery, and Molecular Mechanisms of a Promising Anticancer Therapy

“…These compounds maintain the structure of BetA but have better water solubility. BetA and its derivatives inhibit melanoma cells and a variety of other cancer cells .

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Synthesis of Sulfobetaines Based on Betulinic Acid and its Esters

“…3E-(2-Chloroacetoxy)-28-hydroxylup-20(29)-ene (9). A solution of vinyl ether 8 (0.78 g, 1.667 mmol) and chloroacetic acid (0.32 g, 3.333 mmol) in anhydrous CH 2 Cl 2 (30 mL) was treated under Ar with DMAP (0.41 g, 3.333 mmol), stirred for 5 min, treated in one portion with DCC (0.69 g, 3.333 mmol), and stirred for 30 min.…”

“…Recently, a series of ionic betulinic-acid derivatives such as ammonium and triphenylphosphonium salts were synthesized. They exhibited significantly higher antitumor and antimicrobial activity than the acid itself [6][7][8][9][10][11][12][13]. Sulfobetaine derivatives of betulinic acid and other lupane-type pentacyclic triterpenoids have not been reported despite the frequent use of the biomimetic sulfobetaine group to design biologically active compounds with antibacterial, antiviral, and antiproliferative properties; to increase the solubility of hydrophobic compounds; and also to construct nanocarriers for targeted drug delivery [14][15][16][17][18][19][20][21].…”

Design, synthesis and biological evaluation of novel betulinic acid derivatives

“…In 1995, BA was reported as a highly selective growth inhibitor [18] of human melanoma, neuroectodermal and malignant tumor cells and was reported to induce apoptosis in these cells [19]. At the same time, a large number of BA derivatives have been synthesized to improve anti-HIV activity [20,21], to reduce the organ toxic effect of antitumor drugs [22] and to be evaluated as new anticancer agents [23]. Researchers have demonstrated that the presence of a polar substituent at the C-3 position was essential for the pharmacological activities of pentacyclic triterpenes [24].…”