5987-76-8Relevant academic research and scientific papers
A3 Adenosine Receptor Antagonists with Nucleoside Structures and Their Anticancer Activity
Buccioni, Michela,Dal Ben, Diego,Francucci, Beatrice,Lambertucci, Catia,Maggi, Federica,Marucci, Gabriella,Santoni, Giorgio,Spinaci, Andrea,Volpini, Rosaria
, (2022/02/10)
The overexpression of the A3 adenosine receptor (AR) in a number of cancer cell types makes it an attractive target for tumor diagnosis and therapy. Hence, in the search for new A3AR ligands, a series of novel 2,N6-disubstituted adenosines (Ados) was synthesized and tested in radioligand binding and functional assays at ARs. Derivatives bearing a 2-phenethylamino group in the N6-position were found to exert higher A3AR affinity and selectivity than the corresponding N6-(2,2-diphenylethyl) analogues. 2-Chloro-N6-phenylethylAdo (15) was found to be a potent full A3AR agonist with a Ki of 0.024 nM and an EC50 of 14 nM, in a cAMP accumulation assay. Unlike 15, the other ligands behaved as A3AR antagonists, which concentration-dependently reduced cell growth and exerted cytostatic activity on the prostate cancer cell line PC3, showing comparable and even more pronounced effects with respect to the ones elicited by the reference full agonist Cl-IB-MECA. In particular, the N6-(2,2-diphenylethyl)-2-phenylethynylAdo (12: GI50 = 14 μM, TGI = 29 μM, and LC50 = 59 μM) showed the highest activity proving to be a potential antitumor agent. The cytostatic effect of both A3AR agonist (Cl-IB-MECA) and antagonists (12 and other newly synthesized com-pounds) confirm previous observations according to which, in addition to the involvement of A3ARs, other cellular mechanisms are responsible for the anticancer effects of these ligands.
2-Substituted α,β-Methylene-ADP Derivatives: Potent Competitive Ecto-5′-nucleotidase (CD73) Inhibitors with Variable Binding Modes
Bhattarai, Sanjay,Pippel, Jan,Scaletti, Emma,Idris, Riham,Freundlieb, Marianne,Rolshoven, Georg,Renn, Christian,Lee, Sang-Yong,Abdelrahman, Aliaa,Zimmermann, Herbert,El-Tayeb, Ali,Müller, Christa E.,Str?ter, Norbert
supporting information, p. 2941 - 2957 (2020/04/10)
CD73 inhibitors are promising drugs for the (immuno)therapy of cancer. Here, we present the synthesis, structure-activity relationships, and cocrystal structures of novel derivatives of the competitive CD73 inhibitor α,β-methylene-ADP (AOPCP) substituted in the 2-position. Small polar or lipophilic residues increased potency, 2-iodo- and 2-chloro-adenosine-5′-O-[(phosphonomethyl)phosphonic acid] (15, 16) being the most potent inhibitors with Ki values toward human CD73 of 3-6 nM. Subject to the size and nature of the 2-substituent, variable binding modes were observed by X-ray crystallography. Depending on the binding mode, large species differences were found, e.g., 2-piperazinyl-AOPCP (21) was >12-fold less potent against rat CD73 compared to human CD73. This study shows that high CD73 inhibitory potency can be achieved by simply introducing a small substituent into the 2-position of AOPCP without the necessity of additional bulky N6-substituents. Moreover, it provides valuable insights into the binding modes of competitive CD73 inhibitors, representing an excellent basis for drug development.
Synthesis and biological evaluation of a novel C8-pyrrolobenzodiazepine (PBD) adenosine conjugate. A study on the role of the PBD ring in the biological activity of PBD-conjugates
Bhakta, Sanjib,Brucoli, Federico,Ferguson, Lindsay,Fox, Keith R.,Wells, Geoff
supporting information, (2020/03/19)
Here we sought to evaluate the contribution of the PBD unit to the biological activity of PBD-conjugates and, to this end, an adenosine nucleoside was attached to the PBD A-ring C8 position. A convergent approach was successfully adopted for the synthesis of a novel C8-linked pyrrolo(2,1-c)(1,4)benzodiazepine(PBD)-adenosine(ADN) hybrid. The PBD and adenosine (ADN) moieties were synthesized separately and then linked through a pentynyl linker. To our knowledge, this is the first report of a PBD connected to a nucleoside. Surprisingly, the compound showed no cytotoxicity against murine cells and was inactive against Mycobacterium aurum and M. bovis strains and did not bind to guanine-containing DNA sequences, as shown by DNase I footprinting experiments. Molecular dynamics simulations revealed that the PBD-ADN conjugate was poorly accommodated in the DNA minor groove of two DNA sequences containing the AGA-PBD binding motif, with the adenosine moiety of the ligand preventing the covalent binding of the PBD unit to the guanine amino group of the DNA duplex. These interesting findings shed further light on the ability of the substituents attached at the C8 position of PBDs to affect and modulate the biological and biophysical properties of PBD hybrids.
Synthesis, characterization and biological evaluation of purine nucleoside analogues
Malthum, Shankaraiah,Polkam, Naveen,Allaka, Tejeswara Rao,Chepuri, Kalyani,Anireddy, Jaya Shree
supporting information, p. 4166 - 4168 (2017/10/13)
We present a convenient route for the synthesis of C6-amino-C5′-N-cyclopropyl carboxamido-C2-alkynylated purine nucleoside analogues 11a–g via Sonogashira coupling reaction. The nine step synthesis is easy to perform, employing commercially available reagents. Compound 9 is used as key intermediate for the synthesis of analogues 11a–g. Synthetic intermediates and final products are appropriately characterized by IR, 1H NMR, 13C NMR and Mass. The modified nucleoside analogues 11a–g is evaluated for in vitro anticancer activity against MDA-MB-231 and Caco-2 cell lines. Screening data reveals that compounds 11b and 11e displayed potent IC50 value of 7.9, 6.8 μg/mL respectively against MDA-MB-231 and of 7.5, 8.3 μg/mL respectively against Caco-2 than the standard drug doxorubicin, thus establishing the potential anti-cancer properties of these newer derivatives.
A New Class of Fluorinated A2A Adenosine Receptor Agonist with Application to Last-Step Enzymatic [18F]Fluorination for PET Imaging
Lowe, Phillip T.,Dall'Angelo, Sergio,Mulder-Krieger, Thea,IJzerman, Adriaan P.,Zanda, Matteo,O'Hagan, David
, p. 2156 - 2164 (2017/10/07)
The A2A adenosine receptor belongs to a family of G-coupled protein receptors that have been subjected to extensive investigation over the last few decades. Due to their prominent role in the biological functions of the heart, lungs, CNS and brain, they have become a target for the treatment of illnesses ranging from cancer immunotherapy to Parkinson's disease. The imaging of such receptors by using positron emission tomography (PET) has also been of interest, potentially providing a valuable tool for analysing and diagnosing various myocardial and neurodegenerative disorders, as well as offering support to drug discovery trials. Reported herein are the design, synthesis and evaluation of two new 5′-fluorodeoxy-adenosine (FDA)-based receptor agonists (FDA-PP1 and FDA-PP2), each substituted at the C-2 position with a terminally functionalised ethynyl unit. The structures enable a synthesis of 18F-labelled analogues by direct, last-step radiosynthesis from chlorinated precursors using the fluorinase enzyme (5′-fluoro-5′-deoxyadenosine synthase), which catalyses a transhalogenation reaction. This delivers a new class of A2A adenosine receptor agonist that can be directly radiolabelled for exploration in PET studies.
Synthesis, characterization and biological evaluation of C5′-N-cyclopropylcarboxamido-C6-amino-C2-alkynylated purine nucleoside analogues
Ananda Mohan, Arasavelli,Veera Raghava Sharma, Ganapavarapu,Vidavalur, Siddaiah
, p. 637 - 651 (2017/12/06)
In an effort to develop potent antibacterial and anticancer agents, a series of C5′-N-cyclopropylcarboxamido-C6-amino-C2-alkynylated purine nucleoside analogues 11a-g were synthesized through a Sonogashira cross-coupling reaction. The nine-step synthesis is easy to perform, and employs commercially available reagents. 2-Iodo-5′-N-cyclopropylcarboxamidoadenosine (9) was used as the starting intermediate for the synthesis of title derivatives 11a-g. Synthetic intermediates (2–9) and final products (11a-g) were appropriately characterized by IR, 1H NMR, 13C NMR and mass spectroscopy. The synthesized purine nucleoside analogues (11a-g) were evaluated for their in vitro antibacterial activity against two gram-positive and two gram-negative bacteria. They were then tested for cytotoxicity against MDA-MB-231 and Caco-2 cancer cell lines to determine their anti-cancer activity. Among the tested compounds, compounds 11c and 11g showed most potent antibacterial activity against S.aureus and P.aeruginosa bacterial strains. Compounds 11b and 11e displayed considerable IC50s of 7.9 and 6.8 μg/mL, respectively, vs MDA-MB-231 cell lines of 7.5 and 8.3 μg/mL, respectively, against the Caco-2 cell lines.
Discovery of Leucyladenylate Sulfamates as Novel Leucyl-tRNA Synthetase (LRS)-Targeted Mammalian Target of Rapamycin Complex 1 (mTORC1) Inhibitors
Yoon, Suyoung,Kim, Jong Hyun,Kim, Sung-Eun,Kim, Changhoon,Tran, Phuong-Thao,Ann, Jihyae,Koh, Yura,Jang, Jayun,Kim, Sungmin,Moon, Hee-Sun,Kim, Won Kyung,Lee, Sangkook,Lee, Jiyoun,Kim, Sunghoon,Lee, Jeewoo
, p. 10322 - 10328 (2016/12/07)
Recent studies indicate that LRS may act as a leucine sensor for the mTORC1 pathway, potentially providing an alternative strategy to overcome rapamycin resistance in cancer treatments. In this study, we developed leucyladenylate sulfamate derivatives as LRS-targeted mTORC1 inhibitors. Compound 18 selectively inhibited LRS-mediated mTORC1 activation and exerted specific cytotoxicity against colon cancer cells with a hyperactive mTORC1, suggesting that 18 may offer a novel treatment option for human colorectal cancer.
Synthesis and evaluation of 2-ethynyl-adenosine-5′-triphosphate as a chemical reporter for protein AMPylation
Creech, Christa,Kanaujia, Mukul,Causey, Corey P.
, p. 8550 - 8555 (2015/08/06)
Protein AMPylation is a posttranslational modification (PTM) defined as the transfer of an adenosine monophosphate (AMP) from adenosine triphosphate (ATP) to a hydroxyl side-chain of a protein substrate. One recently reported AMPylator enzyme, Vibrio outer protein S (VopS), plays a role in pathogenesis by AMPylation of Rho GTPases, which disrupts crucial signaling pathways, leading to eventual cell death. Given the resurgent interest in this modification, there is a critical need for chemical tools that better facilitate the study of AMPylation and the enzymes responsible for this modification. Herein we report the synthesis of 2-ethynyl-adenosine-5′-triphosphate (2eATP) and its utilization as a non-radioactive chemical reporter for protein AMPylation.
A localized tolerance in the substrate specificity of the fluorinase enzyme enables "last-step" 18F fluorination of a RGD peptide under ambient aqueous conditions
Thompson, Stephen,Zhang, Qingzhi,Onega, Mayca,McMahon, Stephen,Fleming, Ian,Ashworth, Sharon,Naismith, James H.,Passchier, Jan,O'Hagan, David
supporting information, p. 8913 - 8918 (2014/10/15)
A strategy for last-step 18F fluorination of bioconjugated peptides is reported that exploits an "Achilles heel" in the substrate specificity of the fluorinase enzyme. An acetylene functionality at the C-2 position of the adenosine substrate projects from the active site into the solvent. The fluorinase catalyzes a transhalogenation of 5-chlorodeoxy-2- ethynyladenosine (ClDEA) to 5-fluorodeoxy-2-ethynyladenosine (FDEA). Extending a polyethylene glycol linker from the terminus of the acetylene allows the presentation of bioconjugation cargo to the enzyme for 18F labelling. The method uses an aqueous solution (H218O) of [ 18F]fluoride generated by the cyclotron and has the capacity to isotopically label peptides of choice for positron emission tomography (PET).
Pd-catalysed amidation of 2,6-dihalopurine nucleosides. Replacement of iodine at 0 °c
Bosch, Lluís,Cial?cu, Ionela,Caner, Joaquim,Ariza, Xavier,Costa, Anna M.,Terrazas, Montserrat,Vilarrasa, Jaume
body text, p. 1358 - 1362 (2012/04/10)
Pd-catalysed reactions of 2-Cl, 2-Br and 2-I derivatives of a 6-chloropurine nucleoside with benzamide have been compared, using Pd 2dba3, Xantphos and Cs2CO3 in toluene, between 20 and 80 °C. The reactivity order was 2-I > 2-Br > 6-Cl ? 2-Cl. The 2-I substituent could be replaced even at 0 °C, under conditions disclosed here for the first time. On the other hand, the replacement of the chlorine atom at position 2 (2-Cl) required 110 °C.
