Low toxicity and unprecedented anti-osteoclast activity of a simple sulfur-containing gem-bisphosphonate: A comparative study

Granchi, Donatella; Scarso, Alessandro; Bianchini, Giulio; Chiminazzo, Andrea; Minto, Alberto; Sgarbossa, Paolo; Michelin, Rino A.; Pompo, Gemma Di; Avnet, Sofia; Strukul, Giorgio

doi:10.1016/j.ejmech.2013.04.032

Cited by 19 publications

(9 citation statements)

References 46 publications

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“…As previously mentioned, K citrate inhibited osteoclastogenesis as much as Ale 10–5 , which is routinely used as a positive control for the in vitro screening of anti-resorptive compounds [25]. Nitrogen-containing bisphosphonates, including alendronate, inhibit a key enzyme in the post-translational events regulating the intracellular signaling of OC [55].…”

Section: Discussionmentioning

confidence: 99%

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Potassium citrate prevents increased osteoclastogenesis resulting from acidic conditions: Implication for the treatment of postmenopausal bone loss

et al. 2017

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The extracellular acidic milieu in bones results in activation of osteoclasts (OC) and inhibition of osteoblasts (OB) causing a net loss of calcium from the skeleton and the deterioration of bone microarchitecture. Alkalinization through supplementation with potassium citrate (K citrate) has been proposed to limit the osteopenia progression, even though its pharmacological activity in bone microenvironment is not well defined. We evaluated if K citrate was able to prevent the adverse effects that acidic milieu induces on bone cells. OC and OB were maintained in neutral (pH 7.4) versus acidic (pH 6.9) culture medium, and treated with different K citrate concentrations. We evaluated the OC differentiation at seven days, by counting of multinucleated cells expressing tartrate-resistant acid phosphatase, and the activity of mature OC at 14 days, by quantifying of collagen degradation. To evaluate the effects on OB, we analyzed proliferation, mineralization, and expression of bone-related genes. We found that the low pH increased OC differentiation and activity and decreased OB function. The osteoclastogenesis was also promoted by RANKL concentrations ineffective at pH 7.4. Non-cytotoxic K citrate concentrations were not sufficient to steadily neutralize the acidic medium, but a) inhibited the osteoclastogenesis, the collagen degradation, and the expression of genes involved in RANKL-mediated OC differentiation, b) enhanced OB proliferation and alkaline phosphatase expression, whereas it did not affect the in vitro mineralization, and c) were effective also in OC cultures resistant to alendronate, i.e. the positive control of osteoclastogenesis inhibition. In conclusion, K citrate prevents the increase in OC activity induced by the acidic microenvironment, and the effect does not depend exclusively on its alkalizing capacity. These data provide the biological basis for the use of K citrate in preventing the osteopenia progression resulting from low-grade acidosis.

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Section: Discussionmentioning

confidence: 99%

“…OC cultures were derived from peripheral blood mononuclear cells (PBMC), as previously described [25]. PBMC were obtained from buffy-coats discarded from blood donations of eight volunteers (AVIS, Bologna, Italy).…”

Section: Methodsmentioning

confidence: 99%

Potassium citrate prevents increased osteoclastogenesis resulting from acidic conditions: Implication for the treatment of postmenopausal bone loss

et al. 2017

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“…[11,12] Conversely, BPs with R 1 = Ha re generally prepared by conjugate addition of nucleophiles to vinylidenebisphosphonate tetraethylester (VBP) [13] as at ypical building block. Through this method, BPs with heterocycles, [14] steroidc onjugates, [15] or other functional groups at the b position, such as thiols, [16] have been reported in the literature. General classes of BPs have also been prepared by metal-catalyzed addition of boronic acids and indoles to VBP,asrecently disclosed by our group.…”

Section: Introductionmentioning

confidence: 99%

Pyrrolidine‐Containing Bisphosphonates as Potential Anti‐Resorption Bone Drugs

Luca

Chiminazzo

Sperni

et al. 2017

Chemistry A European J

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Bisphosphonates, particularly those with N-substituted groups, are currently the most popular drugs for the treatment of osteoporosis. However, their chemical structures are still rather simple and new synthetic methods are needed to expand their molecular complexity and also improve their specificity of action towards other targets as anticancer, antibacterial, and antimalarial drugs. Herein, we report a new class of potential antiresorption bisphosphonate drugs that have a pyrrolidine unit with different substituents, obtained through a simple dipolar cycloaddition reaction between azomethine ylides and vinylidenebisphosphonate derivatives as precursors. The methodology led to the efficient preparation of a wide range of (1-methylpyrrolidine-3,3-diyl)bis(phosphonic esters) derivatives with different substituents in position 4.

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“…BPs with R 1 =OH are usually prepared from a carboxylic acid or an acyl chloride while BPs with R 1 =H are more commonly prepared by Michael addition of nucleophiles to vinylidenebisphosphonate tetraethylester (VBP) as a typical building block. The latter approach enabled the preparation of several classes of BPs bearing steroid conjugates, heterocycles or thiols . General classes of BPs have been prepared also by metal catalyzed addition of boronic acids and indoles to VBP as recently disclosed by our group .…”

Section: Introductionmentioning

confidence: 99%

Stereoselective Synthesis of Chiral Isatin Containing Bisphosphonates as Potential Anti‐Resorption Bone Drugs

et al. 2017

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Bisphosphonates are currently the major class of drugs used for the treatment of osteoporosis, a disease that leads to bone fragility and increase in fracture risk that affects hundreds of million elderly individual worldwide. All commercially available bisphosphonates are achiral albeit their activity is demonstrated to be related to inactivation of specific enzymes. Cinchona alkaloid urea derivatives are efficient organocatalysts for the asymmetric aldol reaction of ketones to an isatin containing bisphosphonate precursor to provide a class of new chiral enantioenriched potentially anti‐resorption bone drugs. High chemical yields were generally achieved in a wide array of substrates tested and in several cases ee′s in the 60–96 % range could be observed.

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Low toxicity and unprecedented anti-osteoclast activity of a simple sulfur-containing gem-bisphosphonate: A comparative study

Cited by 19 publications

References 46 publications

Potassium citrate prevents increased osteoclastogenesis resulting from acidic conditions: Implication for the treatment of postmenopausal bone loss

Potassium citrate prevents increased osteoclastogenesis resulting from acidic conditions: Implication for the treatment of postmenopausal bone loss

Pyrrolidine‐Containing Bisphosphonates as Potential Anti‐Resorption Bone Drugs

Stereoselective Synthesis of Chiral Isatin Containing Bisphosphonates as Potential Anti‐Resorption Bone Drugs

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