ATP Synthesis-IN-1

ATP Synthesis-IN-1 (Compound 4), a quinoline derivative, potently inhibits PA ATP synthesis with an IC50 of 11.1μg mL and exhibits antibacterial properties. This compound is utilized in studying drug-resistant PA infections [1].

6-Hydroxypyridin-3-ylboronic acid is a heterocyclic building block.1,2It has been used in the synthesis of non-nucleoside inhibitors of hepatitis C virus (HCV) RNA-dependent RNA polymerase nonstructural protein 5B (NS5B).16-Hydroxypyridin-3-ylboronic acid has also been used in the synthesis of mammalian target of rapamycin (mTOR) inhibitors.2 1.Hendricks, R.T., Spencer, S.R., Blake, J.F., et al.3-Hydroxyisoquinolines as inhibitors of HCV NS5b RNA-dependent RNA polymeraseBioorg. Med. Chem. Lett.19(2)410-414(2009) 2.Verheijen, J.C., Richard, D.J., Curran, K., et al.Discovery of 4-morpholino-6-aryl-1H-pyrazolo[3,4-d]pyrimidines as highly potent and sselective ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR): Optimization of the 6-aryl substituentJ. Med. Chem.52(24)8010-8024(2009)

2,6-Dichloropurine-9-β-D-riboside is a building block.1,2It has been used in the synthesis of photoaffinity probes for nucleotide binding sites in proteins. 1.Wower, J., Hixson, S.S., Sylvers, L.A., et al.Synthesis of 2,6-diazido-9-(β-D-ribofuranosyl)purine 3',5'-bisphosphate: Incorporation into transfer RNA and photochemical labeling of Escherichia coli ribosomesBioconjug. Chem.5(2)158-161(1994) 2.Seiter, M.S., Bauer, M.P., Bogel, P.D., et al.Synthesis of novel spin-labeled photoaffinity derivatives of NAD+ and ATP and their characterization as coenzymes and substrates of several enzymesSynthesis2269-273(1996)

Pantothenate Kinase Inhibitor (PANKi) is a reversible inhibitor of pantothenate kinase (PanK; IC50s = 70, 92, and 25 nM for PanK1β, PanK2, and PanK3, respectively), the rate-limiting enzyme in the synthesis of coenzyme A .1It binds to the ATP-PanK3 complex with an apparent binding constant of 300 nM and exhibits mixed-type inhibition with respect to ATP and pantothenate. PANKi inhibits CoA biosynthesis in C3A cells (IC50= 0.9 μM) with no effect on cell viability when used at concentrations up to 8 μM. PANKi (5 μM) synergizes with BSO to induce ferroptosis in PANC-1 cells and sensitizes the cells to imidazole ketone erastin-induced ferroptosis.2 1.Sharma, L.K., Leonardi, R., Lin, W., et al.A high-throughput screen reveals new small-molecule activators and inhibitors of pantothenate kinasesJ. Med. Chem.58(3)1563-1568(2015) 2.Badgley, M.A., Kremer, D.M., Maurer, H.C., et al.Cysteine depletion induces pancreatic tumor ferroptosis in miceScience368(6486)85-89(2020)

Mtb ATP synthase-IN-1 (compound 6ab) is a potent inhibitor of Mycobacterium tuberculosis (Mtb) ATP synthase (MIC = 0.452-0.499 μg mL) [1] that can be used in anti-mycobacterium research, showing low cytotoxicity (Vero IC 50 > 64 μg mL) and acceptable oral bioavailability with good metabolic stability.

Thymidine 5′-diphosphate (dTDP), a crucial product of pyrimidine synthesis in organisms, is synthesized through the thymidylate kinase (TMPK)-catalyzed phosphorylation of 5′-thymidine monophosphate (dTMP), requiring ATP and Mg2+. It is further converted to thymidine 5′-triphosphate (dTTP) via TMPK catalysis. The activity of TMPK can be monitored by assessing the levels of dTDP [1] [2].

ATP Synthase Inhibitor 2 (Compound 22) TFA is a potent inhibitor of Pseudomonas aeruginosa ATP synthase with an IC50 value of 10 μg mL. It effectively halts ATP synthesis in Pseudomonas aeruginosa at a concentration of 128 μg mL [1].

Siderin, a Photosystem II inhibitor, effectively impedes ATP synthesis and chloroplast electron transport in photosynthesis within isolated spinach chloroplasts and is utilized in research on plant photosynthesis [1].

ATP Synthesis-IN-2 (Compound 5) is a potent inhibitor of ATP synthesis activity, exhibiting significant antibacterial properties with an IC50 value of 0.7 μg mL against Pseudomonas aeruginosa (PA) [1].

8-Chloroadenosine-5'-triphosphate (8-chloro ATP), a potent metabolite of the anticancer agent 8-chloro cyclic AMP (cAMP) and a nucleotide derivative, is produced through the biotransformation of 8-chloro cAMP into 8-chloroadenosine, followed by mono- and diphosphate intermediates. Accumulating for up to 12 hours after the administration of 8-chloro cAMP or 8-chloroadenosine, 8-chloro ATP inhibits cell growth, diminishes endogenous ATP levels, and reduces RNA synthesis without affecting DNA synthesis in multiple myeloma cells derived from patients. Moreover, it obstructs topoisomerase II-α-mediated relaxation of supercoiled pUC19 DNA at concentrations ranging from 1.5 to 8 mM and decreases topoisomerase II-α-enhanced ATP hydrolysis by 50% at a concentration of 1 mM in K562 human myelocytic leukemia cells.

Rp-Adenosine-5'-O-(1-thiotriphosphate) (Rp-ATP-α-S), a sulfur-containing nucleotide derivative isomer and a purinergic P2Y1 receptor agonist, promotes calcium mobilization in HEK293 cells expressing the human P2Y1 receptor (EC50 = 75 nM). This compound exhibits binding affinity to washed isolated human platelets (Ki = 156 nM) and attenuates ADP-induced aggregation in human platelet-rich plasma (PRP; pA2 = 4.74), as well as inhibits cAMP production triggered by prostaglandin E1 (PGE1) in human PRP (pA2 = 5.26). Furthermore, it triggers relaxation in carbamoylcholine-constricted guinea pig taenia coli strips (EC50 = 56 nM). Rp-ATP-α-S also contributes to the synthesis of cyclic dinucleotides, recognized by bacterial riboswitches.