29279-66-1Relevant articles and documents
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Nashimura,A.,Ohta,M.
, p. 1530 - 1534 (1970)
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Fluorinated methylenecyclopropane analogues of nucleosides. Synthesis and antiviral activity of (Z)- and (E)-9-{[(2-fluoromethyl-2-hydroxymethyl)-cyclopropylidene]methyl}adenine and -guanine
Li, Chengwei,Prichard, Mark N.,Korba, Brent E.,Drach, John C.,Zemlicka, Jiri
, p. 2148 - 2155 (2008/09/21)
Synthesis and antiviral activity of the title fluoromethylenecyclopropane analogues 15a, 15b, 16a, and 16b is described. Methylenecyclopropane carboxylate was first transformed to 2,2-bis-hydroxymethylmethylenecyclopropane. Selective monoacetylation followed by introduction of fluorine gave 2-acetoxymethyl-2-fluoromethylmethylenecyclopropane as the key intermediate. The synthesis of analogues 15a, 15b, 16a, and 16b then followed alkylation-elimination procedure as described previously for other methylenecyclopropane analogues. The adenine Z-isomer 15a was found to be a potent inhibitor of Epstein-Barr virus (EBV) in vitro with EC50/CC50 (μM) 0.5/55.7. Compounds 15b, 16a, and 16b were also active but at higher concentrations, EC50/CC50 (μM) 3.2-7.5/53.6-64.1. Analogue 15a inhibited hepatitis C virus by virtue of its cytotoxicity and it moderately inhibited replication of the Towne strain of human cytomegalovirus (HCMV). The E-isomer 16a was a substrate for adenosine deaminase, whereas the Z-isomer 15a was not deaminated.
Spiropentane Mimics of Nucleosides: Analogues of 2′-Deoxyadenosine and 2′-Deoxyguanosine. Synthesis of All Stereoisomers, Isomeric Assignment, and Biological Activity
Guan, Hui-Ping,Ksebati, Mohamad B.,Cheng, Yung-Chi,Drach, John C.,Kern, Earl R.,Zemlicka, Jiri
, p. 1280 - 1290 (2007/10/03)
Synthesis of spirocyclic analogues of 2′-deoxyadenosine and 2′-deoxyguanosine (12a-15a and 12b-15b) is described. Rhodium-catalyzed reaction of ethyl diazoacetate with methylenecyclopropane 19, obtained from 2-bromo-2-bromomethylcyclopropane 17 via debromination (16), reduction (18), and acetylation (19), gave a mixture of all four isomeric spiropentanes 20a-20d. Hydrolysis afforded hydroxy carboxylic acids 21a-21d. Acetylation of separated proximal + medial-syn isomers 21a + 21b and medial anti + distal isomers 21c + 21d furnished acetates 22a + 22b and 22c + 22d. Curtius rearrangement effected by diphenylphosphoryl azide in tert-butyl alcohol performed separately with mixtures 22a + 22b and 22c + 22d led to BOC-amino spiropentanes 23a + 23b and 23c + 23d. After deacetylation all isomers 24a-24d were separated and deprotected to give aminospiropentane hydrochlorides 25a-25d. Free bases were of limited stability. The heterocyclic moieties were introduced into individual isomers 25a-25d via 6-chloropurine derivatives 26a-26d or 30a-30d. Ammonolysis of 26a-26d furnished the adenine isomeric series 12a-15a, whereas guanine derivatives 12b-15b were obtained by hydrolysis of 30a-30d with formic acid. The isomeric assignments followed from IR spectra of BOC-aminospiropentanes 24a-24d and NMR spectra of 12a-15a including NOE and (H,H) COSY. The proximal and medial-syn isomers 12a and 12b were modest inhibitors of human cytomegalovirus (HCMV) and Epstein-Barr virus (EBV) in culture, whereas the medial-anti isomer 12c was a substrate for adenosine deaminase. The distal isomer 15b was an anti-EBV agent. The medial-syn phosphoralaninate 34 was an effective inhibitor of HCMV replication in vitro. It was also active against herpes simplex virus type 1 (HSV-1), varicella zoster virus (VZV), human immunodeficiency virus (HIV-1), hepatitis B virus (HBV), and EBV with a varying degree of cytotoxicity.
