Nucleic acid base grafted poly(ethylenimine): Polynucleotide analog and therapeutic agent

Abstract

U n i v e r s i t y o f Michigan, Ann Arbor, M I USA 48109 V i c t o r P. Chu, present address Abbott Laboratories, D-gOU, AP3B, North Chicago, I L 60064 A b s t r a c t -Poly(N-acyl ethylenimine) o f v a r i o u s molecular weights was synthesized by t h e c a t i o n i c ring-opening p o l y m e r i z a t i o n o f 2-H-2-oxazoline and 2-methyl-2-oxazoline. a f f o r d e d t h e l i n e a r poly(ethy1enimine) which was used i n t h e f o l l o w i n g g r a f t i n g r e a c t i o n s . Vapor pressure osmometry, g e l permeation chromatography and v i s c o s i t y measurements were used t o c h a r a c t e r i z e t h e polymers synthesized. Potassium 2-(cytos-1 -yl )propanoate and potassium 3-(cytos-1 -yl )butanoate were synthesized i n good y i e l d from t h e n u c l e i c a c i d base. These c y t o s y l pendant groups were g r a f t e d onto t h e p o l y ( e t h y 1 -enimi ne) u s i n g 4-chl oro-1-(4-chlorobenzenesul f o n y l ) b e n z o t r i azole, 90% g r a f t , and norborn-5-ene-2.3-carboximido diphenyl phosphate, 70% g r a f t . G r a f t i n g o f t h e 2-butoxycarbonyl and -n-butoxycarbonyl p r o t e c t e d c y t o s y l pendant groups r e s u l t e d i n a 47% g r a f t . Hypochromicity s t u d i e s i n d i c a t e d an ordered s t r u c t u r e a t t h e l o c a l l e v e l . The secondary s t r u c t u r e i s a base-stacked conformation. L i g h t s c a t t e r i n g r e s u l t s gave i n s i g h t i n t o t h e t e r t i a r y s t r u c t u r e o f t h e macromolecule. polymer e x i s t s i n s o l u t i o n as s t i f f chains, r o d -l i k e i n nature. Continuous m i x i n g experiments were c a r r i e d o u t w i t h p o l y r i b onucleotides. The Job p l o t s i n d i c a t e d increased l e v e l o f ordered conformation w i t h e i t h e r an increase i n t h e molecular weight o r an increase o f t h e base t o base d i s t a n c e i n t h e analog.