Methylenediphosphonotetrathioate: Synthesis, Characterization, and Chemical Properties

Amir, Aviran; Sayer, Alon Haim; Ezra, Alon; Fischer, Bilha

doi:10.1021/ic3026057

Cited by 6 publications

(13 citation statements)

References 33 publications

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“…A molecular weight of 239 m / z and 31 P NMR shift at 92.3 ppm revealed the presence of MDPT 17 . In addition, the 31 P NMR signal at 86.1 ppm can be correlated with the formation of oxidized MDPT product 18 (237 m / z ), in accordance with our previous findings . The singlet at 89.2 ppm corresponds to compound 19 , formed by an intramolecular nucleophilic attack and the loss of a water molecule.…”

Section: Resultssupporting

confidence: 90%

Nucleoside-(5′→P) Methylenebisphosphonodithioate Analogues: Synthesis and Chemical Properties

et al. 2013

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Nucleoside-(5'→P) methylenebisphosphonodithioate analogues are bioisosteres of natural nucleotides. The potential therapeutic applications of these analogues are limited by their relative instability. With a view toward improving their chemical and metabolic stability as well as their affinity toward zinc ions, we developed a novel nucleotide scaffold, nucleoside-5'-tetrathiobisphosphonate. We synthesized P1-(uridine/adenosine-5')-methylenebisphosphonodithioate, 2 and 3, and P1,P2-di(uridine/adenosine-5')-methylenebisphosphonodithioate, 4 and 5. Using (1)H and (31)P NMR-monitored Zn(2+)/Mg(2+) titrations, we found that 5 coordinated Zn(2+) by both N7 nitrogen atoms and both dithiophosphonate moieties, whereas 3 coordinated Zn(2+) by an N7 nitrogen atom and Pβ. Both 3 and 5 did not coordinate Mg(2+) ions. (31)P NMR-monitored kinetic studies showed that 3 was more stable at pD 1.5 than 5, with t(1/2) of 44 versus 9 h, respectively, and at pD 11 both showed no degradation for at least 2 weeks. However, 5 was more stable than 3 under an air-oxidizing atmosphere, with t1/2 of at least 3 days versus 14 h, respectively. Analogues 3 and 5 were highly stable to NPP1,3 and NTPDase1,2,3,8 hydrolysis (0-7%). However, they were found to be poor ectonucleotidase inhibitors. Although 3 and 5 did not prove to be effective inhibitors of zinc-containing NPP1/3, which is involved in the pathology of osteoarthritis and diabetes, they may be promising zinc chelators for the treatment of other health disorders involving an excess of zinc ions.

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Section: Resultssupporting

confidence: 90%

Nucleoside-(5′→P) Methylenebisphosphonodithioate Analogues: Synthesis and Chemical Properties

et al. 2013

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“…23 Nucleoside 5a underwent spontaneous air-oxidation in water (t 1/2 14 h). 19 Likewise, MDPT underwent 33% oxidation after 27 h. 17 However, dinucleotide, 4a, resisted air-oxidation for at least 3 d.…”

Section: Stability Assaysmentioning

confidence: 99%

“…Therefore, we recently developed methylenediphosphonotetrathioate (MDPT), 17 2, its O,O′-diester-MDPT derivatives, 18 3, and nucleoside-5′-MDPT analogues 4 and 5 (Fig. 1), as selective Zn(II) chelators.…”

Section: Introductionmentioning

confidence: 99%

“…[20][21][22] Specifically, MDPT, 2, exhibited high affinity to Zn(II) (log K 10.84), and was 10 7 -times more selective to Zn(II) vs. Ca(II)ions, however its relative sensitivity to air-oxidation limited its use. 17 O,O′-Diester-MDPT derivatives, 3, selectively chelate soft/ borderline metal-ions (Zn(II), Ni(II), Cu(I), and Fe(II)). However, M(II)-complexes of 3 are water insoluble and dissolve only in organic solvents such as DMSO and EtOH.…”

Section: Introductionmentioning

confidence: 99%

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Novel crown-ether–methylenediphosphonotetrathioate hybrids as Zn(ii) chelators

et al. 2015

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Hybrids of methylenediphosphonotetrathioate and crown-ether (MDPT-CE) were synthesized forming 7-,8-,9-,10- and 13-membered rings. Both 7- and 13-membered ring-containing compounds were found to be highly stable to air-oxidation for at least four weeks. These hybrids bind Zn(II) by both MDPT and CE moieties, forming a 2 : 1 L : Zn(II) complex. Interestingly, the 13-membered ring MDPT-CE showing a high affinity to Zn(II) (Ka 3 ± 0.5 × 10(6) mol(-2) L(2)) does not bind Li(I) or Na(I). The 13-Membered MDPT-CE hybrid is a promising water-soluble, air-stable, high-affinity Zn(II)-chelator, exhibiting selectivity to Zn(II) vs. Mg(II), Na(I), and Li(I).

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“…Furthermore, 2 was 8 and 2.5 times more potent than glutathione (GSH) and EDTA in the Cu(I)/H 2 O 2 system, respectively. 8 Analogue 1, R = benzyl, proved to be a potent antioxidant (IC 50 53 μM), inhibiting, via chelation, the Cu(I)-catalyzed Fenton reaction at a 4-fold lower concentration than GSH. Analogue 1, R = CH 3 (CH 2 ) 7 , inhibited the Fe(II)-catalyzed Fenton reaction at about the same concentration as ascorbic acid (IC 50 83 vs 93 μM).…”

Section: ■ Introductionmentioning

confidence: 99%

Novel Cu(I)-Selective Chelators Based on a Bis(phosphorothioyl)amide Scaffold

et al. 2014

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Bis(dialkyl/aryl-phosphorothioyl)amide (BPA) derivatives are versatile ligands known by their high metal-ion affinity and selectivity. Here, we synthesized related chelators based on bis(1,3,2-dithia/dioxaphospholane-2-sulfide)amide (BTPA/BOPA) scaffolds targeting the chelation of soft metal ions. Crystal structures of BTPA compounds 6 (N(-)R3NH(+)) and 8 (NEt) revealed a gauche geometry, while BOPA compound 7 (N(-)R3NH(+)) exhibited an anti-geometry. Solid-state (31)P magic-angle spinning NMR spectra of BTPA 6-Hg(II) and 6-Zn(II) complexes imply a square planar or tetrahedral geometry of the former and a distorted tetrahedral geometry of the latter, while both BTPA 6-Ni(II) and BOPA 7-Ni(II) complexes possibly form a polymeric structure. In Cu(I)-H2O2 system (Fenton reaction conditions) BTPA compounds 6, 8, and 10 (NCH2Ph) were identified as most potent antioxidants (IC50 32, 56, and 29 μM, respectively), whereas BOPA analogues 7, 9 (NEt), and 11 (NCH2Ph) were found to be poor antioxidants. In Fe(II)-H2O2 system, IC50 values for both BTPA and BOPA compounds exceeded 500 μM indicating high selectivity to Cu(I) versus the borderline Fe(II)-ion. Neither BTPA nor BOPA derivatives showed radical scavenging properties in H2O2 photolysis, implying that inhibition of the Cu(I)-induced Fenton reaction by both BTPA and BOPA analogues occurred predominantly through Cu(I)-chelation. In addition, NMR-monitored Cu(I)- and Zn(II)-titration of BTPA compounds 8 and 10 showed their high selectivity to a soft metal ion, Cu(I), as compared to a borderline metal ion, Zn(II). In summary, lipophilic BTPA analogues are promising highly selective Cu(I) ion chelators.

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Methylenediphosphonotetrathioate: Synthesis, Characterization, and Chemical Properties

Cited by 6 publications

References 33 publications

Nucleoside-(5′→P) Methylenebisphosphonodithioate Analogues: Synthesis and Chemical Properties

Nucleoside-(5′→P) Methylenebisphosphonodithioate Analogues: Synthesis and Chemical Properties

Novel crown-ether–methylenediphosphonotetrathioate hybrids as Zn(ii) chelators

Novel Cu(I)-Selective Chelators Based on a Bis(phosphorothioyl)amide Scaffold

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