Pyrimidine acyclic nucleosides. 5-Substituted 1-[(2-aminoethoxy)methyl]uracils as candidate antivirals

Abstract

Several 5-substituted analogues of the acyclic aminonucleoside 1-[2-aminoethoxy)methyl]uracil (5) were prepared for evaluation as antivirals. The uracil and thymine analogues were prepared in two steps from N-[2-(chloromethoxy)ethyl]phthalimide (1). The 5-chloro, 5-bromo, and 5-iodo analogues were prepared by halogenation of 5. These acyclic aminonucleosides exhibited neither cell toxicity nor antiviral activity. This is compatible with their lack of substrate properties toward herpes simplex virus thymidine kinase.

Acyclic Pyrimidine Nucleoside Analogues: Influence on Growth of L5178y Mouse Lymphoma Cells and Antiherpes Activity in KB Cells

“…Moreover, 1-(2'-hydroxyethoxymethyl)-5-aza-cytosine showed some antiviral activity in herpes virus infected KB cells. This compound appears to be more active than acyclic py rimidines previously evaluated [2,9,10,18]. Recently the corresponding cyclic cyt idine analogue, 5-aza-cytidine, has been reported to decrease the methylcytosine content of newly synthesized DNA [15].…”

“…Two new acyclic guanine derivatives have been de veloped which show marked antiherpesvi rus activity [1,12,21,22], As mentioned previously, no acyclic pyrimidines have shown great promise in this regard [2,9,10,18].…”

“…However, both acyclic pyrimidine nucleoside analogues are appreciably less active than acyclic guanine derivatives [2,9,10,17,18], f£>5-(2-bromovinyl)-2'-deoxyuridine [5] or the 2'-fluoroarabinosyl uracils or cytosines [11].…”

“…Acyclic pyrimidine nucleosides have al so been synthesized and evaluated for an tiviral activity [2,3,9,10,18]. Little or no antiherpesvirus activity has been found for several l-(2'-hydroxyethoxymethyl) derivatives of cytosine, or uracil [2,8,9,18] or for l-(2'-aminoethoxymethyl)-uracils [10], We have explored the activity of a number of uracil and cytosine derivatives with one of the following acyclic side chains: 2-hydroxyethoxymethyl, 2-aminoethoxymethyl, or 1,3-dihydroxypropoxymethyl.…”

“…Little or no antiherpesvirus activity has been found for several l-(2'-hydroxyethoxymethyl) derivatives of cytosine, or uracil [2,8,9,18] or for l-(2'-aminoethoxymethyl)-uracils [10], We have explored the activity of a number of uracil and cytosine derivatives with one of the following acyclic side chains: 2-hydroxyethoxymethyl, 2-aminoethoxymethyl, or 1,3-dihydroxypropoxymethyl. We primarily concentrated on 5-substitutions as have other investigators [2,9,24], Therefore, a number of ana logues of pyrimidine acyclic nucleosides have been synthesized and analyzed for cell growth inhibitor potency and for anti herpes activity.…”