Synthesis of eudistomin D analogues and its effects on adenosine receptors

doi:10.1016/j.bmc.2008.01.041

Bioorganic & Medicinal Chemistry

Volume 16, Issue 7, 1 April 2008, Pages 3825-3830

https://doi.org/10.1016/j.bmc.2008.01.041 Get rights and content

Abstract

Six analogues (1–6) of eudistomin D, a β-carboline alkaloid from a marine tunicate Eudistoma olivaceum, were synthesized, and their affinity and selectivity for adenosine receptors A₁, A_2A, and A₃ were examined. All the synthetic compounds 1–6 did not show affinity to the adenosine A₁ receptor. δ-Carboline 3 exhibited the most potent affinity to the adenosine receptor A₃ among compounds 1–6. δ-Carbolines 3 and 4 showed better affinity than the corresponding β-carbolines 1 and 2, respectively, while N-methylation (2, 4, and 6, respectively) of the pyrrole ring in 1, 3, and 5 resulted in the reduced affinity to the adenosin A₃ receptor. On the other hand, an eudistomin D derivative, BED, exhibited modest affinity to all the receptors A₁, A_2A, and A₃ but no selectivity.

Graphical abstract

Introduction

During our continuing search for bioactive metabolites from marine organisms, we have found that eudistomin D, a β-carboline alkaloid from a marine tunicate Eudistoma olivaceum,¹ and its analogues such as 7-bromoeudistomin D (BED)² are potent inducers of Ca²⁺-release from sarcoplasmic reticulum (SR)³ as well as inhibitors of phosphodiesterase,⁴ and are more potent than caffeine. Caffeine exhibits a variety of physiological activities (or action) including regulation of the blood pressure, respiratory functioning, gastric and colonic activity, urine volume, and exercise performance.⁵ The mechanism of actions of caffeine is reported to be competitive antagonism to A₁ and A_2A adenosine receptors,⁶ induction of Ca²⁺-release from SR, inhibition of phosphodiesterase, and so on. Previously, our group has found that a hybrid molecule of caffeine and eudistomin D showed a potent affinity for adenosine receptor A₃ subtype.⁷ In the present study, the methylated analogues (1 and 2, respectively) of eudistomoin D and BED in place of the bromine atom were designed and synthesized. δ-Carboline analogues 3 and 4 were also synthesized. The 2-N-methyl derivatives (5 and 6, respectively) of 1 and 2 were also prepared to examine effects of the 2-N-methyl group on the activity of adenosine receptors.

Section snippets

Chemistry

The synthesis of β-carboline analogues 1 and 2 is summarized in Scheme 1. Coupling of 2,6-dimethyl-4-bromoanisole (7)⁸ and 3-aminopyridine (8) in DMF with Pd₂(dba)₃, Xphos,⁹ and NaO^tBu afforded 9 in 88% yield. Photocyclization of 9 in toluene gave 10 and 11 in 31% and 45% yield, respectively, and treatment of 10 with BBr₃ in CH₂Cl₂ furnished 1 in 78% yield. Methylation of 10 with MeI and NaH in DMF provided 12 in 57% yield, which was treated with BBr₃ in CH₂Cl₂ to afford 2 in 78% yield.

Instruments and analyses

The IR spectrum was recorded on a JASCO FT/IR-5300 spectrometer. UV spectra were recorded on a Shimadzu UV1600PC spectrophotometer. Proton and carbon NMR spectra were recorded on Bruker 500 and/or 600 MHz and JEOL 400 MHz spectrometers. EI mass spectra were obtained on a DX-303 mass spectrometer.

N-(4-Methoxy-3,5-dimethylphenyl)pyridin-3-amine (9)

DMF (1.5 mL) was added to an oven-dried Schlenk tube charged with 3-aminopyridine (8) (47.7 mg, 0.51 mmol), Pd₂(dba)₃ (23 mg, 25 μmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (21 mg, 43 μmol), and

Acknowledgments

We thank S. Oka, Center for Instrumental Analysis, Hokkaido University, for EI-MS measurements. This work was partly supported by a Grant-in-Aid from the Uehara Memorial Foundation and Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

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