Synthesis and Antiviral Activity of (Z)- and (E)-2,2-[Bis(hydroxymethyl)cyclopropylidene]methylpurines and -pyrimidines: Second-Generation Methylenecyclopropane Analogues of Nucleosides

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Abstract
The second generation of methylenecyclopropane analogues of nucleosides 5a − 5i and 6a − 6i was synthesized and evaluated for antiviral activity. The 2,2-bis(hydroxymethyl)methylenecyclopropane (11) was converted to dibromo derivative 7 via acetate 12. Alkylation−elimination of adenine (16) with 7 afforded the Z/E mixture of acetates 17 + 18, which was deacetylated to give analogues 5a and 6a separated by chromatography. A similar reaction with 2-amino-6-chloropurine (19) afforded acetates 20 + 21 and, after deprotection and separation, isomers 5f and 6f. The latter served as starting materials for synthesis of analogues 5b, 5e, 5g−5i and 6b, 6e, 6g−6i. Alkylation−elimination of N4-acetylcytosine (22) with 7 afforded a mixture of isomers 5c + 6c which were separated via N4-benzoyl derivatives 23 and 24. Deprotection furnished analogues 5c and 6c. Alkylation of 2,4-bis(trimethylsilyloxy)-5-methylpyrimidine (25) with 7 led to bromo derivative 26. Elimination of HBr followed by deacetylation and separation gave thymine analogues 5d and 6d. The guanine Z-isomer 5b was the most effective against human and murine cytomegalovirus (HCMV and MCMV) with EC50 = 0.27−0.49 μM and no cytotoxicity. The 6-methoxy analogue 5g was also active (EC50 = 2.0−3.5 μM) whereas adenine Z-isomer 5a was less potent (EC50 = 3.6−11.7 μM). Cytosine analogue 5c was moderately effective, but 2-amino-6-cyclopropylamino derivative 5e was inactive. All E-isomers were devoid of anti-CMV activity, and none of the analogues was significantly active against herpes simplex viruses (HSV-1 or HSV-2). The potency against Epstein−Barr virus (EBV) was assay-dependent. In Daudi cells, the E-isomers of 2-amino-6-cyclopropylamino- and 2,6-diaminopurine derivatives 6e and 6h were the most potent (EC50 ≈ 0.3 μM), whereas only the thymine Z-isomer 5d was active (EC50 = 4.6 μM). Guanine Z-derivative 5b was the most effective compound in H-1 cells (EC50 = 7 μM). In the Z-series, the 2-amino-6-methoxypurine analogue 5g was the most effective against varicella zoster virus (VZV, EC50 = 3.3 μM) and 2,6-diaminopurine 5h against hepatitis B virus (HBV, EC50 = 4 μM). Adenine analogues 5a and 6a were moderately active as substrates for adenosine deaminase.

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