Synthesis of Sulfobetaines Based on Betulinic Acid and its Esters

Abstract

Methods for preparing sulfobetaines of betulinic acid that contained N,N-(dimethylammonium)butane-1-sulfonate, a new type of Zwitter-ion in a series of lupane-type pentacyclic triterpenoids, were developed in order to prepare new betulinic acid derivatives and to study the structure-biological-activity relationship.Keywords: betulinic acid, 1,4-butane sultone, sulfobetaine.Betulinic acid is the lead compound among lupane-type pentacyclic triterpenoids and is interesting as a platform for developing drugs with antitumor, antiviral, antimicrobial, and other types of pharmacological activity [1][2][3][4][5]. 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].New derivatives of betulinic acid (1) were prepared and their structure-biological-activity relationship was studied using the synthetic method developed by us for betulinic-acid sulfobetaines 2-4, a new class of lupane-type pentacyclic triterpenoids containing N,N-(dimethylammonium)butane-1-sulfonate bonded to the C-3 or C-28 position of the triterpene backbone.Sulfobetaines 2-4 were prepared by treating the corresponding triterpene C-3 or C-28 tertiary amine of 5-7 with commercially available 1,4-butane sultone [22,23]. Betulinic acid C-3 tertiary amine 5 was synthesized by acylating the C-3-OH of betulin 28-O-vinyl ether with chloroacetic acid (DCC, DMAP) and oxidizing in two steps the resulting betulin 3E-chloroacetate (9) with pyridinium chlorochromate (PCC) to give the corresponding aldehyde, which was reacted immediately after flash chromatography with NaClO 2 to obtain the 3E-chloroacetate of acid 10. Amination of 10 with an excess of N,N-dimethylamine (40% aqueous) gave tertiary amine 5 in 93% yield. C-28-O-Vinyl ether 8, which was prepared by us earlier via vinylation of betulin with acetylene in KOH-DMSO superbase [24], turned out to be a convenient intermediate for synthesizing betulinic acid 3E-chloroacetate 10. O OR 2 O 1 -4 N O SO 3 X = + _ N SO 3 _ + Y = 1: R 1 = R 2 = H; 2: R 1 = X, R 2 = H 3: R 1 = X, R 2 = Me; 4: R 1 = H, R 2 = Y

Recent Developments in the Functionalization of Betulinic Acid and Its Natural Analogues: A Route to New Bioactive Compounds

“…Positions 3 and 28 of BA skeleton are easily functionalized through esterification reactions and, consequently, many studies involving this transformation have been reported [17,22,27,31,34,35,36,37,38,39,40,41,42,43,44,45,46,47]. The used methodologies involve: (i) The reaction of 17-COOH group of BA 1 with alkyl halides in the presence of a base (mainly, K 2 CO 3 ), or (ii) the reaction of BA-based acyl chloride intermediate with alcohols, or even (iii) the reaction of 3-OH group of BA 1 with acid anhydrides in the presence of a catalyst [usually, 4-(dimethylamino)pyridine (DMAP)] (Scheme 11).…”