Synthesis and Evaluation of Novel Carbocyclic Oxetanocin A (COA-Cl) Derivatives as Potential Tube Formation Agents

Abstract

Six novel carbocyclic oxetanocin A analogs (2-chloro-C.OXT-A; COA-Cl) with various hydroxymethylated or spiro-conjugated cyclobutane rings at the N⁹-position of the 2-chloropurine moiety were synthesized and evaluated using human umbilical vein endothelial cells. All prepared compounds (2a–f) showed good to moderate activity with angiogenic potency. Among these compounds, 100 µM cis–trans-2′,3′-bis(hydroxymethyl)cyclobutyl derivative (2b), trans-3′-hydroxymethylcyclobutyl analog (2d), and 3′,3′-bis(hydroxymethyl)cyclobutyl derivative (2e) had greater angiogenic activity, with relative tube areas of 3.43±0.44, 3.32±0.53, and 3.59±0.83 (mean±standard deviation (S.D.)), respectively, which was comparable to COA-Cl (3.91±0.78). These data may be important for further development of this class of compounds as potential tube formation agents.

Graphical Abstract