Synthesis and antiviral activity of N9-[3-fluoro-2-(phosphonomethoxy)propyl] analogues derived from N6-substituted adenines and 2,6-diaminopurines

Abstract

An efficient method for the synthesis of N(9)-[3-fluoro-2-(phosphonomethoxy)propyl] (FPMP) derivatives of purine bases has been developed. Both (R)- and (S)-enantiomers of the N(6)-substituted FPMP derivatives of adenine and 2,6-diaminopurine were prepared and their anti-human immunodeficiency virus (HIV) and anti-Moloney murine sarcoma virus (MSV) activity was evaluated. Whereas none of the 6-substituted FPMPA derivatives showed any antiviral activity, several FPMPDAP derivatives had a moderate antiretroviral activity. Moreover, the data obtained from the study of the substrate activity of the active derivatives towards N(6)-methyl-AMP aminohydrolase support the notion that the studied N(6)-substituted FPMPDAP derivatives act as prodrugs of the antiretroviral FPMPG analogues.

Synthesis and applications of fluorinated nucleoside analogues

“…Compared to the original laborious procedure, an efficient method for the synthesis of N 9 -[3-fluoro-2-(phosphonomethoxy)propyl] (FPMP) derivatives of purine bases was developed in 2011 by Janeba and coworkers [116]. Both (R)-and (S)-enantiomers of the N-6 substituted FPMP derivatives of adenine and 2,6-diaminopurine were prepared and their anti-HIV and antiMoloney murine sarcoma virus (MSV) activity was evaluated.…”

Synthesis and Anti‐HIV Activity of Guanine Modified Fluorinated Acyclic Nucleoside Phosphonate Derivatives

“…Recently, we and others have employed phosphonate esters of fluorohydrin precursors 2a/b (Scheme 1) as convenient chiral starting materials in the synthesis of enantiomerically pure FPMPs bearing natural nucleobases. [15,16] Likewise, 6-chloropurine (1) was reacted under Mitsunobu conditions (Ph 3 P, DIAD) with precursors 2a/b to provide compounds 3a/b along with the concomitant formation of the corresponding triphenylphosphine adducts. However, by refluxing the crude reaction mixtures for 24 h in water, the undesired adducts were successfully hydrolyzed leading to the isolation of compounds 3a/b in excellent yields over two steps.…”

Medicinal Chemistry of Fluorinated Cyclic and Acyclic Nucleoside Phosphonates

“…Recently, Baszczyňski et al prepared series of both ( R )‐ and ( S )‐enantiomers of the N 6 ‐substituted FPMP derivatives of adenine (FPMPA, 120 , Fig. ) and 2,6‐diaminopurine (FPMPDAP, 121 ) for their subsequent biological evaluation.…”

“…The N 6 ‐substituted FPMPA analogues 120 displayed no activity against the viruses tested. On the other hand, several N 6 ‐substituted FPMPDAP derivatives 121 showed moderate anti‐HIV/MSV activity at subtoxic concentrations, although even the best analogues (i.e., N 6 ‐cyclopropyl and N 6 ‐allyl derivatives with EC 50 = 14.2 μM and EC 50 = 18.0 μM, respectively, against HIV‐1) proved three to four times less active than the parent ( R )‐FPMPDAP . They were also shown to act as prodrugs of the antiretroviral FPMPG analogues.…”

“…127, 128 N 6 -Methyl-AMP aminohydrolase 129 catalyzes deamination of N 6 -substituted 2,6-diaminopurine analogues to the corresponding guanine derivatives, and thus, the N 6 -substituted 2,6-diaminopurines can be considered to be prodrugs of the guanine analogues. 130 Recently, Baszczyňski et al 131 prepared series of both (R)-and (S)-enantiomers of the N 6 -substituted FPMP derivatives of adenine (FPMPA, 120, Fig. 31) and 2,6-diaminopurine (FPMPDAP, 121) for their subsequent biological evaluation.…”