Synthesis and Biological Activity of Ribose-5‘-Carbamate Derivatives of Vitamin B12

Twelve biologically active derivatives of vitamin B12 (cyanocobalamin) have been synthesized in which spacers were attached to the ribose-5‘-hydroxyl group of vitamin B12. Their potential to act as oral delivery agents for proteins, nanospheres, or immunogens using the vitamin B12 uptake system was evaluated by determining their affinity for intrinsic factor (IF) and non-IF. The ribose-5‘-hydroxyl group of vitamin B12 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 B12 derivatives suitable for attachment to various proteins, peptides, or nanospheres to enable oral delivery utilizing the vitamin B12 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 B12. The affinity for non-IF was similar to cyanocobalamin or even higher for some of the smaller derivatives. Polysciences nanoparticles derivatized with vitamin B12 5‘-carbamate adipic dihydrazide into CaCo-2 cells showed significantly higher levels of transport of the particles, when compared to unmodified particles.