Aminoalkylcarbamoylphosphonates reduce TNFα release from activated immune cells

Harel, Efrat; Rubinstein, Abraham; Chen, Weibin; Breuer, Eli; Tirosh, Boaz

doi:10.1016/j.bmcl.2010.09.048

Cited by 7 publications

(2 citation statements)

References 30 publications

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“…Earlier, we reported that the two acyclic aminoalkylCPOs 12 and 13 , as well as the alicyclic cis-ACCP ( 15 ), were able to reduce TNFα secretion to a level equivalent to the reduction caused by the steroid drug, budesonide. The reduction in TNFα levels was not accompanied by cytotoxicity, nor did it inhibit cell proliferation . Among the compounds in this table, we singled out 15 (cis-ACCP) for an in-depth examination, which included two in vivo models and a pharmacokinetic study .…”

Section: Resultsmentioning

confidence: 99%

“…The reduction in TNFα levels was not accompanied by cytotoxicity, nor did it inhibit cell proliferation. 35 Among the compounds in this table, we singled out 15 (cis-ACCP) for an in-depth examination, which included two in vivo models and a pharmacokinetic study. 25 Compound 15 (cis-ACCP) was evaluated in vitro and in two in vivo cancer metastasis models.…”

Section: ■ Resultsmentioning

confidence: 99%

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Carbamoylphosphonates Control Tumor Cell Proliferation and Dissemination by Simultaneously Inhibiting Carbonic Anhydrase IX and Matrix Metalloproteinase-2. Toward Nontoxic Chemotherapy Targeting Tumor Microenvironment

et al. 2012

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Carbamoylphosphonates (CPOs) have been identified as inhibitors of matrix metalloproteinases (MMPs) and as orally active, bioavailable, and safe antimetastatic agents. In this article, we focus on the direct antitumor activity of the CPOs. We discovered that CPOs also inhibit carbonic anhydrases (CAs), especially the IX and XII isoforms identified as cancer promoting factors. Thus, CPOs can be regarded as novel nontoxic drug candidates for tumor microenvironment targeted chemotherapy acting by two synergistic mechanisms, namely, inhibiting CAs and MMPs simultaneously. We have also demonstrated that the ionized CPO acid is unable to cross the cell membrane and thus limited to interact with the extracellular domains of isozymes CAIX and CAXII. Finally, applying CPOs against cancer cells in hypoxic conditions resulted in the dose dependent release of lactate dehydrogenase, confirming the direct interaction of the CPOs with the cancer related isozymes CAIX and XII and thereby promoting cellular damage.

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Section: Resultsmentioning

confidence: 99%

Section: ■ Resultsmentioning

confidence: 99%

Carbamoylphosphonates Control Tumor Cell Proliferation and Dissemination by Simultaneously Inhibiting Carbonic Anhydrase IX and Matrix Metalloproteinase-2. Toward Nontoxic Chemotherapy Targeting Tumor Microenvironment

et al. 2012

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Iodine‐Promoted Rapid Construction of Carbamoylphosphonates from Phosphinecarboxamides

Wu¹,

Wu²,

Wang³

et al. 2018

Adv Synth Catal

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A one-step, I 2 -promoted PÀH phosphorylation and oxygenation of phosphinecarboxamides to give carbamoylphosphonates was achieved. This transformation exhibits exceptional substrate generality and functional group compatibility and affords good to excellent yields of the desired phosphonates. Notably, cyclic carbamoylphosphonates can be obtained from diols. The mechanism was investigated using IR, 1 H and 31 P NMR spectroscopy.

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Orally Active, Antimetastatic, Nontoxic Diphenyl Ether‐Derived Carbamoylphosphonate Matrix Metalloproteinase Inhibitors

et al. 2011

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Seven 4-phenoxybenzenesulfonamidopolymethylene carbamoylphosphonates (CPOs) bearing two to eight methylene units in the polymethylene chain were synthesized and evaluated as matrix metalloproteinase (MMP) inhibitors. The five lowest homologues [(CH₂)₂-₆] are selective MMP-2 inhibitors, whereas the two with the longest linkers [(CH₂)₇,₈] lack inhibitory activity. The most potent homologues are those with (CH₂)₅,₆; these two were evaluated for antimetastatic activity in a murine melanoma model and showed good potency both by oral and intraperitoneal administration without any toxic--including musculoskeletal--side effects. In contrast to the previously reported cis-ACCP, which was shown to inhibit MMP-2 for ∼30 min, the new compounds inhibit MMP activity for the duration of measurement, lasting several hours. Pharmacokinetic evaluation revealed, on the one hand, low oral bioavailability; on the other hand, a relatively large calculated volume of distribution, consistent with the observed reversible absorption of CPO 5 to hydroxyapatite, as a model for bone.

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Aminoalkylcarbamoylphosphonates reduce TNFα release from activated immune cells

Cited by 7 publications

References 30 publications

Carbamoylphosphonates Control Tumor Cell Proliferation and Dissemination by Simultaneously Inhibiting Carbonic Anhydrase IX and Matrix Metalloproteinase-2. Toward Nontoxic Chemotherapy Targeting Tumor Microenvironment

Carbamoylphosphonates Control Tumor Cell Proliferation and Dissemination by Simultaneously Inhibiting Carbonic Anhydrase IX and Matrix Metalloproteinase-2. Toward Nontoxic Chemotherapy Targeting Tumor Microenvironment

Iodine‐Promoted Rapid Construction of Carbamoylphosphonates from Phosphinecarboxamides

Orally Active, Antimetastatic, Nontoxic Diphenyl Ether‐Derived Carbamoylphosphonate Matrix Metalloproteinase Inhibitors

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