Design And Synthesis Of Aqueous Betulinic Acid Derivatives With Pyrazole Rings On C-2 And C-3 Positions And Their Inhibitory Effect On The Differentiation And Maturation Of Osteoclasts

With the world’s population aging seriously, osteoporosis has become one of the most threatening diseases that endangered the health and life quality of individuals. The increasing demand of searching safe and effective agents for osteoporosis treatment has become one of the important issues for pharmaceutical companies and scietific researchers.In our previous study, a betulinic acid derivative with fused pyrazolyl ring, XJ13, was successfully screened as potent inhibitor on the osteoclastogenesis of RAW264.7, with IC50=0.1μM. However, the bioavailability of XJ13 was merely 2%, suggesting the poor aqueous solubility of the compound.Since improving the aqueous solubility is one of the most effective approaches to optimize the bioavailability of a compound, the current study designed and synthesized a series of derivatives by introducing safe and soluble groups including amino acid, amide, glycosyl, and oligomeric glycol at position C-28 of XJ13.According to analytical testing, most synthesized derivatives have demonstrated much better solubility compared with XJ13. In addition, the inhibitory effect on the differentiation and maturation of osteoclasts precursor RAW264.7 also improved remarkably. Compound 12,14,22, and 46 are the four most potent derivatives, with the aqueous solubility improved 6,27.5,11.5 and 7.5 fold respectively compared with XJ13, and the inhibitory effect on RAW264.7 improved more than 10 folds, while the IC50 value remained less than 0.01mM. Although still under investigation, the bioavailabilities of these betulinic acid derivatives are expected to be optimized.