NUCLEOTIDES .53. 6-AMINOHEXANOYL-LINKED CONJUGATES OF MONOMERIC AND TRIMERIC CORDYCEPIN

To improve cell permeability, monomeric 3'-deoxyadenosine (cordycepin) and antivirally active trimeric 3'-deoxyadenylyl-(2'-5')-3'-deoxyaden ylyl-(2'- 5')-3'-deoxyadenosine (2'-5')d(3')(A-A-A); cordycepin-trimer core) were modified at the 2'-O- or 5'-O-position by myristic, cholic , and folic acid = terradecanoic, 3 alpha,7 alpha,12 alpha-trihydroxy- 5 beta-cholan-24-oic, and -oxopteridin-6-yl)methyl]amino}benzoyl}-L-gl utamic acid, resp., linked by a 6-aminohexanoyl spacer. Syntheses of t he trimeric educts 21, 27, and 28 were performed by phosphoramidite ch emistry, using beta-eliminating 2-(4-nitrophenyl)ethyl (npe), 2-(4-nit rophenyl)ethoxycarbonyl (npeoc) and (9H-fluoren-9-yl)methoxycarbonyl ( fmoc) groups which allow a deprotection by DBU in an aprotic solvent w ithout harming the ester-bounded conjugates, to give the products 24-2 6 and 31-33. The metabollically stable (2'-5')A derivatives 26 and 33, covalently linked to folic acid either at the 2'-terminus or at the 5 '-terminus of (2'-5')d(3')(A-A-A), respectively, are a new class of th e anti-HIV-1 compounds. Inhibition of HIV-1 reverse transcriptase (RT) activity by 26 and 33 was 45 and 81%, respectively. Only 33 activated recombinant, human RNase L by 35%.