K. S. Bekker, N. Chukanov, S. Popov
Jul 1, 2013
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Chemistry of Natural Compounds
Abstract
1-Amino-1,1-bisphosphonates are attracting more and more attention in various areas of chemistry and medicine owing to a combination of unique chemical, physical, and biological properties that enable various biologically active compounds used as immunomodulators, calcium-exchange regulators, antitumor drugs, etc. to be synthesized [1]. Conjugation of natural biologically active compounds and bisphosphonates in order to enhance the binding or accumulation of the biologically active compounds in certain organs in vivo, e.g., bone, is a separate focus area that will, in turn, facilitate targeted delivery of the pharmaceutical. In particular, we reported earlier on modification of folic acid [2]. We decided to synthesize conjugates of bisphosphonic acids with derivatives of betulinic, betulonic, and ursolic acids because they exhibit antimalarial, anticancer, anti-inflammatory, and antiviral activity. Acetylursolic acid was modified by synthesizing its chloride 1 according to the literature method [3]. Then, 1 (0.30 g, 0.6 mmol) was treated with a 10-fold excess of ethylenediamine to give the corresponding amide that was next acylated by acetic anhydride (0.7-mmolar amount) in Py at the free amine group to form the 8a-(2-acetylaminoethylcarbamoyl)4,4,6a,6b,11,12,14b-heptamethyl-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-eicosahydropicen-3-yl ester of acetic acid (2) in 85% yield. Further reaction of 2 (0.35 g, 0.6 mmol) and P(OEt)3 (1.5 mL, 8.8 mmol) in the presence of POCl3 (0.15 mL, 1.6 mmol), analogously to the literature method [4], formed 8a-{2-[1,1-bis-(diethylphosphoryl)ethylamino]ethylcarbamoyl}4,4,6a,6b,11,12,14b-heptamethyl-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-eicosahydropicen-3-yl ester of acetic acid (3) in 70% yield. Apparently, the second amide group was less reactive because of steric hindrance.