STRUCTURE-ACTIVITY-RELATIONSHIPS OF 2-CHLORO-2'-ARABINO-FLUORO-2'-DEOXYADENOSINE AND RELATED ANALOGS - PROTEIN-BINDING, LIPOPHILICITY, AND RETENTION IN REVERSED-PHASE LC

Plasma protein binding of 2-chloro-2'-arabino-fluoro-2'-deoxyadenosine (CAFDA), 2-chloro-2'-deoxyadenosine (CdA), 2-fluoro-1-beta-D-arabinof uranosyladenine (F-araA) and structurally related analogues 2-chloro-a denosine (2-Cl-Ado), 5'-chloro-5'-deoxyadenosine (5'-Cl-5'-dAdo), as w ell as parent nucleosides 2'-deoxyadenosine (dAdo), 1-beta-D-arabinofu ranosyladenine (araA) and adenosine (Ado) was determined and correlate d with lipophilicity expressed as the logarithm of partition coefficie nt in n-octanol/water system (log P-o/w). Drug binding to human serum albumin (HSA) was utilized since it is considered to exemplify nonspec ific binding of small molecules to other macromolecules. Percentage of drugs bound to HSA increased from 3.5% to 27% following the order of increase in lipophilicity (log P-o/w increased from -0.970 to 0.498). A similar correlation was observed when protein binding was correlated with retention in reversed-phase liquid chromatography (RP-LC) (capac ity ratios, k', increased from 0.36 to 1.15), but the elution order of some compounds did not follow the parallel increase in either protein binding or lipophilicity. The introduction of a fluorine at the 2'-ar abino position of CdA not only increased the acid stability of CAFDA, but also resulted in a higher binding to HSA (27.0% for CAFDA versus 2 4.3% for CdA) and much higher lipophilicity (log P of 0.498 for CAFDA compared to 0.025 for CdA).