Structure-Activity Relationships of 2-Chloro-2′-arabino-fluoro-2′-deoxyadenosine and Related Analogues: Protein Binding, Lipophilicity, and Retention in Reversed-Phase LC

Abstract

Abstract Plasma protein binding of 2-chloro-2′-arabino-fluoro-2′-deoxyadenosine (CAFDA), 2-chloro-2′-deoxyadenosine (CdA), 2-fluoro-1-β-D-arabinofuranosyladenine (F-araA) and structurally related analogues 2-chloro-adenosine (2-Cl-Ado), 5′-chloro-5′-deoxyadenosine (5′-Cl-5′-dAdo), as well as parent nucleosides 2′-deoxyadenosine (dAdo), 1-β-D-arabinofuranosyladenine (araA) and adenosine (Ado) was determined and correlated with lipophilicity expressed as the logarithm of partition coefficient in n-octanol/water system (log Po/w). Drug binding to human serum albumin (HSA) was utilized since it is considered to exemplify nonspecific 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 Po/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) (capacity 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′-arabino 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 24.3% for CdA) and much higher lipophilicity (log P of 0.498 for CAFDA compared to 0.025 for CdA).