115044-75-2Relevant academic research and scientific papers
The Chemoenzymatic Synthesis of 2-Chloro- and 2-Fluorocordycepins
Denisova, Alexandra O.,Tokunova, Yulia A.,Fateev, Ilja V.,Breslav, Alexandra A.,Leonov, Vladimir N.,Dorofeeva, Elena V.,Lutonina, Olga I.,Muzyka, Inessa S.,Esipov, Roman S.,Kayushin, Alexey L.,Konstantinova, Irina D.,Miroshnikov, Anatoly I.,Stepchenko, Vladimir A.,Mikhailopulo, Igor A.
, p. 4853 - 4860 (2017)
Two approaches to the chemoenzymatic synthesis of 2-fluorocordycepin and 2-chlorocordycepin were studied: (i) the use of 3′-deoxyadenosine (cordycepin) and 3′-deoxyinosine (3′dIno) as donors of 3-deoxy- d -ribofuranose in the transglycosylation of 2-fluoro- (2F Ade) and 2-chloroadenine (2Cl Ade) catalyzed by the recombinant E. coli purine nucleoside phosphorylase (PNP), and (ii) the use of 2-fluoroadenosine and 3′-deoxyinosine as substrates of the cross-glycosylation and PNP as a biocatalyst. An efficient method for 3′-deoxyinosine synthesis starting from inosine was developed. However, the very poor solubility of 2Cl Ade and 2F Ade is the limiting factor of the first approach. The second approach enables this problem to be overcome and it appears to be advantageous over the former approach from the viewpoint of practical synthesis of the title nucleosides. The 3-deoxy-α- d -ribofuranose-1-phosphate intermediary formed in the 3′dIno phosphorolysis by PNP was found to be the weak and marginal substrate of E. coli thymidine (TP) and uridine (UP) phosphorylases, respectively. Finally, one-pot cascade transformation of 3-deoxy- d -ribose in cordycepin in the presence of adenine and E. coli ribokinase, phosphopentomutase, and PNP was tested and cordycepin formation in ca. 3.4% yield was proved.
Synthesis of the 2-Chloro Analogues of 3'-Deoxyadenosine, 2',3'-Dideoxyadenosine, and 2',3'-Didehydro-2',3'-dideoxyadenosine as Potential Antiviral Agents
Rosowsky, Andre,Solan, Vishnu C.,Sodroski, Joseph G.,Ruprecht, Ruth M.
, p. 1135 - 1140 (2007/10/02)
2-Chloro-3'-deoxyadenosine (2-chlorocordycepin), 2-chloro-2',3'-dideoxyadenosine (2-ClddAdo), and 2-chloro-2',3'-didehydro-2',3'-dideoxyadenosine (2-ClddeAdo) were synthsized from 2-chloroadenosine (2-ClAdo) as candidate antiretroviral agents on the basis that 2-chloro substitution would prevent enzymatic deamination and increase efficacy relative to 2',3'-dideoxyadenosine (ddAdo).Reduction of 2-chloro-5'-(4,4'-dimethoxytrityl)-2',3'-O-thiocarbonyladenosine with n-Bu3SnH, followed by detritylation with AcOH, unexpectedly gave a mixture of 2-chlorocordycepin and 2-chloroadenine.Treatment of the crude n-Bu3SnH reduction product with 1,1'- thiocarbonyldiimidazole, followed by another cycle of n-Bu3SnH reduction and detritylation with silica gel afforded 2-ClddAdo and a byproduct identified as 2-chloro-2',3'-O-methyleneadenosine.Treatment of 2-chloro-5'-O-(4,4'-dimethoxytrityl)-2',3'-thiocarbonyladenosine with 1,3-dimethyl-2-phenyl-1,3,2-diazaphospholidine followed by silica gel detritylation afforded 2-ClddeAdo. 2-ClddAdo and 2-ClddeAdo were tested for activity against human immunodeficiency virus (HIV) in a cultured human T4+ lymphocyte cell line.At a concentration of 100 μM, 2-ClddAdo inhibited reverse transcriptase (RT) production by 97percent, while 2',3'-dideoxyadenosine (ddAdo) gave >99percent inhibition.In growth assays against uninfected T4+ cells, however, 100 μM 2-ClddAdo gave 23percent inhibition while 100 μM ddAdo was nontoxic.At a nontoxic concentration of 20 μM, RT production was 75percent inhibited by ddAdo but only 43percent inhibited by 2-ClddAdo.Thus, a 2-chloro substituent increased host cell toxicity but decreased antiretroviral activity.The unsaturated analogue 2-ClddeAdo was more cytotoxic than 2-ClddAdo, and antiviral effects could not be measured above 20 μM, where was only 75percent inhibition of RT production.Because of the decreased therapeutic index of 2-ClddeAdo relative to 2-ClddAdo and ddAdo, >90percent inhibition of viral protein synthesis at a nontoxic concentration could not be achieved.In growth assays with cultured human and B lymphocytes, 100 μM 2-chlorocordycepin gave 60-70percent growth inhibition, while the IC50 against mouse fibroblasts was only 30 μM.The high cytotoxicity of 2-chlorocordycepin precluded consideration of this compound as an antiviral agent.
