Reactions of 2-acyloxyisobutyryl halides with nucleosides. 7. Synthesis and biological evaluation of some 2,2'-anhydro-1-(3',5'-di-O-acyl-.beta.-D-arabinofuranosyl)cytosine hydrochlorides

Abstract

The direct acylation of 2,2'-anhydro-1(beta-D-arabinofuranosyl)cytosine hydrochloride (cycloC) with a homologous series of saturated and unsaturated acyl chlorides in dimethylacetamide has been investigated. Such acylation reactions have made available a considerable number of 3',5'-diesters of cycloC that have been examined for biological activities. The compounds all show cytotoxicity against HeLa cells in tissue culture, and with the exception of the highly insoluble long-chain diesters (C16--C22), show pronounced activity against vaccinia and Herpes simplex viruses. Against L1210 leukemia in mice the compounds show varied activities, the C12--C14 saturated diesters and the C18--C22 unsaturated diesters being highly effective. Other diesters, varying by only a few methylene groups, show dramatically different results.

Antiviral Activities of Acyl Derivatives of 2,2′-Anhydro-1-β- d -Arabinofuranosylcytosine and 1-β- d -Arabinofuranosylcytosine in Cell Culture

“…3'--decanoyl Ara-C was the most active compound among those synthesized in our systematic study (12)(13)(14). The compounds had substantial activity against deoxyribonucleic acid viruses, but were inactive against ribonucleic acid viruses, including measles, Sendai virus, poliovirus, and influenza virus.…”

“…In fact, the addition of a 3'--acyl group of appropriate chain length (C6 to C02) to cyclo-C was accompanied by enhanced antiviral activity (Table 1). A further increase in chain length, however, led to reduced activity due to the insolubility of such compounds in the culture medium (12)(13)(14)17). The cytotoxicity of these derivatives was examined by two different methods.…”

“…1-f-D-Arabinofuranosyladenine (Ara-A) was synthesized by Yoshio Nosaki in our laboratory. The other nucleosides were synthesized at Syntex Research, Palo Alto, Calif. (12)(13)(14). Solutions of all chemicals were made in maintenance medium immediately prior to use, except for compounds insoluble in water, which were initially dissolved in methanol.…”

“…These studies covered various 5'-esters of Ara-C prepared by the Upjohn group (8,31), and a number of 2,2'-anhydro-1-3-D-arabinofuranosylcytosine (cyclo-C) derivatives (7,24,27) also were synthesized. We have been engaged in a systematic study on the synthesis of acylated derivatives of Ara-C and cyclo-C and have examined the relationship between antiviral activity as well as antileukemic activity in mice and chemical structure (12)(13)(14)17). From our study on activity, we concluded that the introduction of short-chain acyl groups results in somewhat diminished activity relative to the parent nucleosides.…”

Studies on biologically active nucleosides and nucleotides. 5. Synthesis and antitumor activity of some 2,2'-anhydro-1-(3',5'-di-O-acyl-.beta.-D-arabinofuranosyl)cytosine salts and 2,2'-anhydro-1-(3'-O-acyl-.beta.-D-arabinofuranosyl)cytosine 5'-phosphates

“…The solvent was evaporated. 3.8-4.1 (m, 2, C,-H,), 4.07 (m, 1, Cq-H), 5.60 (br s! The solvent was A solution of valeric anhydride (5.2 g, 27.8 mmol) in acetonitrile (20 mL) was added dropwise to a stirred refluxing solution of 5'-cytidylic acid (3 g, 9.3 mmol) and boron trifluoride etherate (3.6 mL, 27.8 mmol) over a period of 7 min.…”