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 N 9 -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 cistrans-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.

Synthesis and Evaluation of Novel Cyclopropane Nucleoside as Potential Tube Formation Agents

“…[6][7][8]15) Secondary alcohols 3a-d were treated with 2,6-dichloropurine and underwent the Mitsunobu reaction [15][16][17][18] in the presence of PPh 3 and diisopropyl azodicarboxylate (DIAD) to give 9-cyclopropylmethyl-2,6-dichloropurine congeners 4a-d in 29-49% yield. Then, 4c was subsequently treated with methanolic ammonia to obtain the desired product 2c in 67% yield.…”

“…4) In a single exceptional case, a COA-Cl analog (1e), regioisomer of the two hydroxymethyl groups at the cyclobutane ring of 1a, exhibited angiogenic activity that was comparable to that of COA-Cl 1a. 7) Collectively, these studies indicated that the structure of not only the cyclobutane ring moiety but also the 2-substituted purine skeleton in COA-Cl 1a is essential for angiogenic activity.…”

“…[1][2][3] Therefore, we synthesized the first low-molecularweight angiogenesis promoter, 2-chloro-carbocyclic oxetanocin A (2-Chloro-C.OXT-A; COA-Cl, 1a, racemate, Fig. 1), [4][5][6][7][8] with a molecular weight (MW) of 284 that is suitable for pharmaceutical use via percutaneous and transmucosal absorption. Furthermore, it is expected to have practical applications as a therapeutic agent for wound healing, Buerger's disease, or peripheral arterial obliterative disease, and could be developed as an adhesive skin patch, lotion, or oral agent.…”

“…4,10,11) The need to understand the utility and unique mechanism of action of COA-Cl 1a has triggered intensive efforts to discover novel COA-Cl analogs with enhanced angiogenic activity and reduced cytotoxicity. 4,[6][7][8] However, our previous work resulted in analogs that were almost similar as or less potent than COA-Cl 1a. For example, Fig.…”

COA-Cl prevented TGF-β1-induced CTGF expression by Akt dephosphorylation in normal human dermal fibroblasts, and it attenuated skin fibrosis in mice models of systemic sclerosis

“…COA-Cl (6-amino-2-chloro-9-[trans-trans-2,3-bis(hydroxymethyl)cyclobutyl]purine) is a recently synthesized novel nucleic acid analog, which has adenosine-like structure [6]. There are some reports showing beneficial effects of COA-Cl in in vitro and in vivo experiments.…”