Format

Send to

Choose Destination
J Med Chem. 1994 Oct 14;37(21):3579-87.

Nucleic acid related compounds. 84. Synthesis of 6'-(E and Z)-halohomovinyl derivatives of adenosine, inactivation of S-adenosyl-L-homocysteine hydrolase, and correlation of anticancer and antiviral potencies with enzyme inhibition.

Author information

1
Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah 84602.

Abstract

Treatment of 9-[6-(E)-(tributylstannyl)-5,6-dideoxy-2,3-O-isopropylidene- beta-D-ribo-hex-5-enofuranosyl]adenine [2b(E)] or the 6-N-benzoyl derivative 2a(E) with iodine (or N-iodosuccinimide) or bromine (or N-bromosuccinimide) gave virtually quantitative and stereospecific conversions to the 6'-(E)-(halohomovinyl)nucleoside analogues. Analogous treatment of the 6'-(Z)-vinyl-stannanes gave the 6'-(Z)-halo compounds. Treatment of 2a or 2b with chlorine or xenon difluoride/silver triflate gave E and Z mixtures of the respective 6'-chloro- or 6'-fluorohomovinyl products. Deprotection gave the 9-[6-(E and Z)-halo-5,6-dideoxy-beta-D-ribo- hex-5-enofuranosyl]-adenines [(E and Z)-5',6'-didehydro-6'-deoxy-6'-halohomoadenosines, EDDHHAs and ZDDHHAs, 4c-7c(E and Z)]. The acetylenic 5',5',6',6'-tetradehydro-6'- deoxyhomoadenosine (3c) and the 5'-bromo-5'-deoxy-5'-methyleneadenosine (10c) regioisomer of EDDBHA [5c(E)] also were obtained from 2. Concentration- and time-dependent inactivations of S-adenosyl-L-homocysteine (AdoHcy) hydrolase were observed with 3c and the 6'-(halohomovinyl)adenosine analogues. The order of inhibitory potency was I > Br > Cl > F and E > Z for the geometric isomers. AdoHcy hydrolase effected "hydrolysis" of the 6'-halogen from the (halohomovinyl)Ado compounds (to give the putative 6'-carboxaldehyde which underwent spontaneous decomposition) independently of its oxidative activity. Partition ratios for these hydrolytic turnovers/lethal inhibitory events were in the order F > Cl > Br > I. Biological activities were evaluated with several viruses and cancer cell lines, and potencies were generally in the order I > Br > Cl > F and E > Z isomers. This represents the first observation of a direct correlation of cytostatic activity with inhibition of AdoHcy hydrolase and highlights the potential of this enzyme as a viable target for chemotherapeutic intervention in anticancer as well as antiviral drug design.

PMID:
7932585
DOI:
10.1021/jm00047a015
[Indexed for MEDLINE]

Supplemental Content

Loading ...
Support Center