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Synthesis of BODIPY Derivatives Substituted with Various Bioconjugatable Linker Groups: A Construction Kit for Fluorescent Labeling of Receptor Ligands

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Abstract

The goal of the present study was to design small, functionalized green-emitting BODIPY dyes, which can readily be coupled to target molecules such as receptor ligands, or even be integrated into their pharmacophores. A simple two-step one-pot procedure starting from 2,4-dimethylpyrrole and ω-bromoalkylcarboxylic acid chlorides was used to obtain new ω-bromoalkyl-substituted BODIPY fluorophores (1a–1f) connected via alkyl spacers of different length to the 8-position of the fluorescent dye. The addition of radical inhibitors reduced the amount of side products. The ω-bromoalkyl-substituted BODIPYs were further converted to introduce various functional groups: iodo-substituted dyes were obtained by Finkelstein reaction in excellent yields; microwave-assisted reaction with methanolic ammonia led to fast and clean conversion to the amino-substituted dyes; a hydroxyl-substituted derivative was prepared by reaction with sodium ethylate, and thiol-substituted BODIPYs were obtained by reaction of 1a–1f with potassium thioacetate followed by alkaline cleavage of the thioesters. Water-soluble derivatives were prepared by introducing sulfonate groups into the 2- and 6-position of the BODIPY core. The synthesized BODIPY derivatives showed high fluorescent yields and appeared to be stable under basic, reducing and oxidative conditions. As a proof of concept, 2-thioadenosine was alkylated with bromoethyl-BODIPY 1b. The resulting fluorescent 2-substituted adenosine derivative 15 displayed selectivity for the A3 adenosine receptor (ARs) over the other AR subtypes, showed agonistic activity, and may thus become a useful tool for studying A3ARs, or a lead structure for further optimization. The new functionalized dyes may be widely used for fluorescent labeling allowing the investigation of biological targets and processes.

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Abbreviations

AR:

adenosine receptor

A1AR:

A1 adenosine receptor

A2AAR:

A2A adenosine receptor

A2BAR:

A2B adenosine receptor

A3AR:

A3 adenosine receptor

BHT:

3,5-di-tert-butyl-4-hydroxytoluene

BODIPY:

4,4-difluoro-1,3,5,7-tetramethyl-4-bora-3a,4a-diaza-s-indacene

BSA:

bovine serum albumin

CADO:

2-chloroadenosine

CCPA:

2-chloro-N6-cyclopentyladenosine

CGS21680:

4-[2-[[6-amino-9-(N-ethyl-β-d-ribofuranuronamidosyl)-9H-purin-2-yl]amino]ethyl]benzenepropanoic acid

CHO-cells:

Chinese hamster ovary cells

DCM:

dichloromethane

DMF:

dimethylformamide

DMSO:

dimethyl sulfoxide

DPCPX:

8-cyclopentyl-1,3-dipropylxanthine

FCS:

fetal bovine serum

FWHMabs :

full width at half maximum at the absorption

FWHMem :

full width at half maximum at the emission

h:

human

HBSS:

Hank’s balanced salt solution

HEK:

human embryonic kidney cells

HEPES:

(4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid

MW:

microwave

NECA:

5’-(N-ethylcarboxamido)adenosine

PBS:

phosphate buffer saline

r:

rat

RO-20-1724:

4-(3-butoxy-4-methoxyphenyl)methyl-2-imidazolidone

R-PIA:

(R)-N6-(1-methyl-2-phenylethyl)adenosine

TRIS:

tris(hydroxymethyl)aminomethan

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Acknowledgments

We are grateful to Prof. Dr. Markus Sauer and Dr. Ralf Brune for providing the infrastructure and guidance to determine fluorescent quantum yields. The Deutsche Forschungsgemeinschaft (DFG) is gratefully acknowledged for financial support (GRK 804).

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  1. PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University Bonn, 53121, Bonn, Germany

    Fabian Heisig, Sabrina Gollos & Christa E. Müller

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  1. Fabian Heisig
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  2. Sabrina Gollos
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  3. Sven J. Freudenthal
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  4. Ali El-Tayeb
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  5. Jamshed Iqbal
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Correspondence to Christa E. Müller.

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Fabian Heisig and Sabrina Gollos are contributed equally.

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ESM 1

NMR spectra and HRMS spectra of all new compounds, CE-UV data of compound 3e, absorption and emission spectra of compounds 1a-1 f. This material is available free of charge via the Internet at http://springer.com. (DOCX 21364 kb)

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Heisig, F., Gollos, S., Freudenthal, S.J. et al. Synthesis of BODIPY Derivatives Substituted with Various Bioconjugatable Linker Groups: A Construction Kit for Fluorescent Labeling of Receptor Ligands. J Fluoresc 24, 213–230 (2014). https://doi.org/10.1007/s10895-013-1289-4

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