Betulin-3,28-diphosphate. Physico-Chemical Properties and In Vitro Biological Activity Experiments

Abstract

Betulin-3,28-diphosphate (BDP) obtained by phosphorylation of betulin using POCl3 has two main structural forms—BDP-1 and BDP-2—which differ in ethanol solubility, melting point, FTIR spectra, thermoanalytical characteristics and biological activity. Betulin-3,28-diphosphate and its sodium salt (Na-BDP) were characterized using 13C and 31P-NMR spectra, powder XRD experiments, as well as differential scanning calorimetry (DSC) and thermogravimetric analysis (TG) methods. The exo-effects at 193 ± 8 °C for ethanol soluble BDP-1 samples (−19.7 ± 0.2 kJ∙mol−1) were about three times less than for ethanol insoluble BDP-2 samples f (−70.5 ± 0.7 kJ∙mol−1). The DSC curves of Na-BDP-1 and Na-BDP-2 characterized the endo-effects having a maximum at 95–112 °C. Water-soluble Na-BDP-1 was obtained as needle-like crystals, unlike poorly crystalline Na-BDP-2, whereas BDP-1 and BDP-2 aged with time and were isolated as amorphous substances. In vitro experiments on rats showed that compared to the control, Na-BDP-1 increased catalase and SOD activity and improved energy metabolism more effectively than Na-BDP-2.

The Improvement of Betulin-3, 28-Diphosphate Water-Solubility by Complexation With Amines–meglumine and Xymedon

“…In addition to improved solubility, betulin phosphates and phosphonates showed high activity as potential drugs [18][19][20][21][22][23]. In vitro and in vivo experiments demonstrated antimicrobial [19], antifungal [20], anti-inflammatory, antiviral [21] activities and an antitumor effect in the treatment of ductal carcinoma, glioblastoma, melanoma [22], Ehrlich ascites carcinoma [23] and other diseases.…”

“…The aging of samples leads to the formation of a different structural modification characterized by more close packing of solid layers. The crystallization water of the hydrate Na-BDP • 8H2O was removed from molecules with time [18]. In this regard, it is very important to find methods to increase and stabilize BDP solubility.…”

“…[14,15]. The suitable techniques to modify and graft additional polar groups are the formation of sulfates, phosphonate and phosphate groups [16][17][18][19][20][21][22]. Moreover, the phospholipid derivatives of betulin with improved solubility were synthesized [17].…”

“…The betulin sulphates have been demonstrated to be selective potent inhibitors of C1q interaction of with immunoglobulins and the classical pathway of complement activation [16]. The most favorable modification is the grafting of phosphate derivatives by 3-or 28-OH groups of betulin resulting in solubility improvement in comparison with the extremely low solubility of natural betulin (about 1.0•10 -4 -1.9·10 -3 g·l -1 depending on conditions) [17][18][19][20][21][22]. Fig.…”

“…Fig. 1a shows betulin-3,28-diphosphate (BDP) obtained by betulin phosphorylation with phosphorus oxychloride, BDP solubility in water is 50-1000 times higher than that of betulin, and its sodium salt (Na-BDP) solubility in water is up to 10 g·l -1 [18].…”