Syntheses and calcium-mobilizing evaluations of N1-glycosyl-substituted stable mimics of cyclic ADP-ribose.
Cyclic ADP-ribose (cADPR) is not only a potent endogenous calcium modulator but also a second messenger. However, studies on the mechanism of cADPR action were limited due to its instability and lack of available structural modifications in the N1-glyosyl unit of cADPR. In the present work, a series of N1-glycosyl mimics with different configurational glycosyls or an ether strand were designed and synthesized mimicking the furanose ring. S(N)2 substitutions were carried out between the protected inosine and glycosyl triflates to form the N1-glycosylinosine derivatives, accompanied with some O6-glycosyl-substituted as side products. The intramolecular cyclization was followed the strategy described by Matsuda et al. It was found that the 8-unsubstituted substrate could also be used to construct the intramolecular cyclic pyrophosphate. The activities of N1-glycosyl-substituted cADPR mimics were evaluated by induced Ca2+ release in rat brain microsomes and HeLa cells. It was found that the configuration of the N1-glycosyl moiety in cADPR is not a critical structural factor for retaining the activity of mobilizing Ca2+ release. More interestingly, the N1-acyclic analogue 6 exhibited strong activity by inducing Ca2+ release in both rat brain microsomes and HeLa cells. It constitutes a useful tool for further studies.
Huang
Li-Jun
LJ
National Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, P. R. China, 100083.
Zhao
Yong-Yuan
YY
Yuan
Lan
L
Min
Ji-Mei
JM
Zhang
Li-He
LH
D000818:Animals; D001921:Brain / Q000378:metabolism / Q000648:ultrastructure; D002118:Calcium / Q000378:metabolism*; D018360:Crystallography, X-Ray; D036563:Cyclic ADP-Ribose / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003500:Cyclization; D006367:HeLa Cells; D006801:Humans; D066298:In Vitro Techniques; D007290:Inosine Diphosphate / Q000138:chemical synthesis / Q000737:chemistry; D007291:Inosine Monophosphate / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008861:Microsomes / Q000378:metabolism; D018716:Molecular Mimicry; D051381:Rats; D017207:Rats, Sprague-Dawley; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013329:Structure-Activity Relationship
C469565:N(1)-((2-O-phosphorylethoxy)methyl)-8-chloro-5'-O-phosphorylinosine 5',5''-cyclic pyrophosphate; D036563:Cyclic ADP-Ribose; D007291:Inosine Monophosphate; D007290:Inosine Diphosphate; D002118:Calcium