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C2 ‐linked alkynyl poly‐ethylene glycol( PEG ) adenosine conjugates as water‐soluble adenosine receptor agonists
Author(s) -
Ferguson Lindsay,
Madieh Nasrin Shokrzadeh,
Vaideanu Alexandra,
Schatzlein Andreas,
Festa Joseph,
Singh Harprit,
Wells Geoffrey,
Bhakta Sanjib,
Brucoli Federico
Publication year - 2023
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.14128
Subject(s) - peg ratio , chemistry , polyethylene glycol , solubility , ethylene glycol , conjugate , adenosine , biochemistry , stereochemistry , combinatorial chemistry , organic chemistry , mathematical analysis , mathematics , finance , economics
A series of 12 novel polyethylene‐glycol(PEG)‐alkynyl C2‐adenosine(ADN) conjugates were synthesized using a robust Sonogashira coupling protocol and characterized by NMR spectroscopy and mass spectrometry analysis. The ADN‐PEG conjugates showed null to moderate toxicity in murine macrophages and 12c was active against Mycobacterium aurum growth (MIC = 62.5 mg/L). The conjugates were not active against Mycobacterium bovis BCG. Conjugates 10b and 11b exhibited high water solubility with solubility values of 1.22 and 1.18 mg/ml, respectively, in phosphate buffer solutions at pH 6.8. Further, 10b and 11b induced a significant increase in cAMP accumulation in RAW264.7 cells comparable with that induced by adenosine. Analogues 10c , 11c and 12c were docked to the A 1 , A 2A , A 2B and A 3 adenosine receptors (ARs) using crystal‐structures and homology models. ADN‐PEG‐conjugates bearing chains with up to five ethyleneoxy units could be well accommodated within the binding sites of A 1 , A 2A and A 3 ARs. Docking studies showed that compound 10b and 11b were the best A 2A receptor binders of the series, whereas 12c was the best binder for A 1 AR. In summary, introduction of hydrophilic PEG substituents at the C2 of adenine ring significantly improved water solubility and did not affect AR binding properties of the ADN‐PEG conjugates.