The Synthesis Of Bone Targeting Potential Of Bisphosphonate-Statin Conjugates And Harmine Derivatives

This dissertation work includes two chapters:Synthesis and hydroxyapatite binding activity of statin-bisphosphonate conjugates as potential antiosteoporosis drugs were studied in chapter one. Osteoporosis is the most common bone disease, affecting millions of people worldwide and leading to high expenditure. Most of the current therapies available for its treatment are limited to the prevention or slowing down of bone loss rather than enhancing bone formation. Recently scientists found that statins (3-hydroxy -3-methylglutaryl coenzyme A reductase inhibitor), which were used to treat atherosclerosis and other cardiovascular events, could stimulate new bone formation in vitro and in vivo. However the systemic bioavailability to the bone was low with most statins due to substantial first pass metabolism to inactive compounds. Higher statin concentrations might be accomplished by targeted delivery to bone. To demonstrate the feasibility of this approach we prepared conjugates between a bone targeting bisphosphonate and the statins atorvastatin and fluvastatin. Tetraethyl 3-aminopropane-1,1-bisyldiphosphonate and tetraethyl amino-methylenebisphosphonate were synthesized using diethyl phosphonate as starting material. Then four statin-bisphosphonate conjugating compounds were obtained from atorvastatin lactone or fluvastatin lactone and tetraethyl 3-aminopropane-1,1-diylbisphosphonate or tetraethyl aminomethylenebisphosphonate via aminolysis and bromotnmethylsilane dealkylation.The statin-bisphosphonates conjugates displayed high binding activity to hydroxyapatite, a major constituent of bone. The corresponding values of absorption ratio were between 70% and 80% on HAP, implying these modified statins possess the potential of bone targeting property.The study on synthesis of harmine derivatives was investigated in chapter two.β-Carboline carbonyl azide was synthesized using 6-bromoindole as starting material by 10 steps via the nucleophilic substitution, Vilsmeier-Haack, Knoevenagel condensation, reduction and Pictet-Spengler as key steps. Then ten 1-alkylaminocarbonylamino-7-methoxy-β-carbolines were synthesized from Carbonyl azide with the corresponding amines via the Curtius rearrangement and nucleophile addition. All these alkyl(aryl)aminocarbonylamino-7-methoxy-β-carbolines were new and characterized by ¹H NMR, ¹³C NMR and MS spectrum. Further research work on antitumor activity in vitro is in progress.