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

Abstract

Five novel nucleoside analogs with mono or bis-hydroxymethylated cyclopropane rings at the N 9 -position of the 2-chloroadenine moiety (2-chloro-carbocyclic oxetanocin A [COA-Cl] analog) were synthesized and evaluated using human umbilical vein endothelial cells. All the prepared compounds (2a-e) showed good to moderate activity with angiogenic potency. cis-2′-(Hydroxymethyl)cycloprop-1′-yl derivative (2b) at 100 µM had greater angiogenic activity than the other compounds did, with relative tube areas of 2.71 0.45 (mean standard deviation (S.D.)), which was superior to the potency of COA-Cl (2.30 0.59).

Drug/Lead Compound Hydroxymethylation as a Simple Approach to Enhance Pharmacodynamic and Pharmacokinetic Properties

“…Angiogenesis is a pathway for generating new capillaries from pre-existing vessels, which is important for physiological and pathological processes, such as wound healing, tumor growth, and metastasis ( Bobek et al, 2006 ; Collinson and Donnelly, 2004 ; O´Toole et al, 2001 ). Considering this effect, Tsukamoto et al, (2010a ) reported the first angiogenesis promoter of low molecular weight, a soluble and stable hydroxymethyl derivative, named 2-chloro-carbocyclic oxetanocin A (COA-Cl - 49 ) which induces the phosphorylation and activation of MAPK, responsible for inducing angiogenesis and tube formation ( Tsukamoto et al, 2010b ; Sakakibara et al, 2017 ). With the aim of designing more potent COACl analogs ( Sakakibara et al, 2015 ), synthesized dihydroxymethyl compounds conjugated to the cyclobutane ring in positions 2 and 3 or around the functional group in position 2 of the COA-Cl purine skeleton.…”

A substrate-dependent reaction of 1-aryl-2-alkyl-1,2-diketones with 2-aroyl-1-chlorocyclopropanecarboxylates: selective access to 2′,5′-dicyclopropoxy-1,1′:4′,1′′-teraryls and pentafulvenes

“…1,2 The most petite cyclopropane ring is particularly unique among various carbocycles due to its distinct reactivity and unusual bonding connectivity, making it a lucrative target for organic chemists. 3 Furthermore, cyclopropane derivatives are profoundly found in a wide range of bioactive natural products, 4 pharmaceuticals, 5 agrochemicals, 3 c , d ,5 drug molecules, 6 enzyme inhibitors, 7 etc . Owing to their extensive spectrum of utilization, organic chemists have put terrific efforts into establishing many hallmark techniques for synthesizing value-added substituted cyclopropanes, 1–8 including transition metal-catalyzed or catalyst-free carbene insertion into alkenes, 9 Simmons–Smith cyclopropanation reactions, 10 Kulinkovich–De Meijere reactions, 11 Corey–Chaykovsky reactions (Michael-initiated ring-closure reactions), 12 etc .…”

“…3 Furthermore, cyclopropane derivatives are profoundly found in a wide range of bioactive natural products, 4 pharmaceuticals, 5 agrochemicals, 3 c , d ,5 drug molecules, 6 enzyme inhibitors, 7 etc . Owing to their extensive spectrum of utilization, organic chemists have put terrific efforts into establishing many hallmark techniques for synthesizing value-added substituted cyclopropanes, 1–8 including transition metal-catalyzed or catalyst-free carbene insertion into alkenes, 9 Simmons–Smith cyclopropanation reactions, 10 Kulinkovich–De Meijere reactions, 11 Corey–Chaykovsky reactions (Michael-initiated ring-closure reactions), 12 etc . Though the described protocols are still in vogue today, they also have many notable shortcomings: requirement of heavy toxic metals, specific substrate scope, harsh reaction conditions, poor atom economy, etc .…”

2-Cl-C.OXT-A stimulates contraction through the suppression of phosphodiesterase activity in human induced pluripotent stem cell-derived cardiac organoids

“…COA-Cl has also been shown to facilitate the functional recovery by enhancing angiogenesis and synaptogenesis in vivo in a model of ischemia [6]. Focusing on the chemical structure of COA-Cl, we hypothesized that the structure would be similar to that of xanthine derivatives, which act as nonspecific inhibitors of PDE [7]. We predicted that COA-Cl would act as an inhibitor of PDE and exert a positive inotropic effect on the heart.…”