Synthesis and biological activity of ribose-5'-carbamate derivatives of vitamin B(12).
Twelve biologically active derivatives of vitamin B(12) (cyanocobalamin) have been synthesized in which spacers were attached to the ribose-5'-hydroxyl group of vitamin B(12). Their potential to act as oral delivery agents for proteins, nanospheres, or immunogens using the vitamin B(12) uptake system was evaluated by determining their affinity for intrinsic factor (IF) and non-IF. The ribose-5'-hydroxyl group of vitamin B(12) was activated through the use of 1,1'-carbonyldiimidazole (CDI), 1,1'-carbonyldi(1,2, 4-triazole) (CDT), or di(1-benzotriazolyl) carbonate (DBTC). Subsequent addition of an aminoalkane, diaminoalkane, or alkane diacid dihydrazide gave rise to vitamin B(12) derivatives suitable for attachment to various proteins, peptides, or nanospheres to enable oral delivery utilizing the vitamin B(12) uptake system. The ribose-5'-carbamate derivatives were found to possess similar affinity for intrinsic factor as that of the e-monocarboxylic acid of vitamin B(12). The affinity for non-IF was similar to cyanocobalamin or even higher for some of the smaller derivatives. Polysciences nanoparticles derivatized with vitamin B(12) 5'-carbamate adipic dihydrazide into CaCo-2 cells showed significantly higher levels of transport of the particles, when compared to unmodified particles.
McEwan
J F
JF
Biotech Australia Pty Ltd., P.O. Box 20, Roseville, NSW 2069, Australia. john_mcewan@mail.bioaust.com.au
Veitch
H S
HS
Russell-Jones
G J
GJ
D000272:Adipates / Q000737:chemistry; D001667:Binding, Competitive; D001692:Biological Transport; D018938:Caco-2 Cells; D002219:Carbamates / Q000737:chemistry*; D004337:Drug Carriers; D006801:Humans; D006834:Hydrazines / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D007437:Intrinsic Factor / Q000378:metabolism; D015394:Molecular Structure; D011506:Proteins / Q000008:administration & dosage; D012266:Ribose / Q000737:chemistry*; D014805:Vitamin B 12 / Q000737:chemistry*
D000272:Adipates; D002219:Carbamates; D004337:Drug Carriers; D006834:Hydrazines; D011506:Proteins; D012266:Ribose; C029900:adipic acid; D007437:Intrinsic Factor; D014805:Vitamin B 12