DESIGN AND SYNTHESIS OF NEW POLYESTER DENDRIMERS, AND APPLICATION TO DRUG DELIVERY SYSTEM

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1. The scope and limitation of our new Michael addition reaction in a 5M aqueous KOH solution. We found that this simple Michel reaction was useful only for the reaction of 1,3-ketoesters or 1.3-diesters with acrvlates both carrying bulky or stable alkyl groups in a basic solution.2. Synthesis of "malonate dendrimer". The building block was prepared from the Michael addition of benzyl malonate to t-butyl acrylate, followed by the addition of ethylene glycol to the forcal carboxyl. The "malonate dendrimers" were synthesized up to [G3-32tBu] by repetition of [deprotection by HCOOH, then condensation by EDCI/DMAP] reactions.3. Characterizion of the "malonate dendrimer". The molecular weights of these dendrimers were confirmed by ESI-MS measurements. The assignments of Hi and C^<13> chemical shifts of NMR spectra were carried out using various kinds of measurements such as COSY, HMBC and HMQC, etc. The back-folded shape of G3 dendrimer in CDCl_3 with the peripheral tBu located in the void space deeply inside was suggested from the analysis of NOESY measurements. The'particle size measurements in MeOH for G0~G3 were carried out using the dynamic light scattering method. The particle sizes of these dendrimers are ca. 40% smaller than those calculated for the stretched conformation.4. Application of these dendrimers to drug delivery system. A polyester dendron with 16 mannose molecules (for targeting and increase of solubility in water) at the periphries and anthracene at the focal point was successfully synthesized. The bioassay using mouse peritoneal cells confirmed the efficient uptake of this dendron.