Synthesis of NO-Donor Bisphosphonates and Their in-Vitro Action on Bone Resorption

Lazzarato, Loretta; Rolando, Barbara; Lolli, Marco Lucio; Tron, Gian Cesare; Fruttero, Roberta; Gasco, Alberto; Deleide, G.; Guenther, Harald L.

doi:10.1021/jm040830d

Cited by 24 publications

(26 citation statements)

References 45 publications

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“…Then, compound 13 was reacted with the corresponding n-alkylamine via a 1,4-conjugated addition reaction to afford the respective Michael adducts ( 14 – 21 ). Once these synthetic precursors were available, they were hydrolyzed by treatment with bromotrimethylsilane in methylene chloride40 to afford the free bisphosphonic acids ( 22 – 29 ). The synthesis of this new 2-alkylaminoethyl gem -bisphosphonates is presented in Scheme 1.…”

Section: Resultsmentioning

confidence: 99%

Synthesis and biological evaluation of new 2-alkylaminoethyl-1,1-bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii targeting farnesyl diphosphate synthase

Rosso

Szajnman

Malayil

et al. 2011

Bioorganic & Medicinal Chemistry

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The effect of long chain 2-alkylaminoethyl-1,1-bisphosphonates against proliferation of the clinically more relevant form of Trypanosoma cruzi, the etiologic agent of American trypanosomiasis (Chagas' disease), and against tachyzoites of Toxoplasma gondii was investigated. Particularly, compound 26 proved to be an extremely potent inhibitor against the intracellular form of T. cruzi, exhibiting IC 50 values at the nanomolar range. This cellular activity was associated with a strong inhibition of the enzymatic activity of T. cruzi farnesyl diphosphate synthase (TcFPPS), which constitutes a valid target for Chagas' disease chemotherapy. Compound 26 was an effective agent against T. cruzi (amastigotes) exhibiting an IC 50 value of 0.67 μM, while this compound showed an IC 50 value of 0.81 μM against the target enzyme TcFPPS. This drug was less effective against the enzymatic activity of T. cruzi solanesyl diphosphate synthase TcSPPS showing an IC 50 value of 3.2 μM. Interestingly, compound 26 was also very effective against T. gondii (tachyzoites) exhibiting IC 50 values of 6.23 μM. This cellular activity was also related to the inhibition of the enzymatic activity towards the target enzyme TgFPPS (IC 50 = 0.29 μM) As bisphosphonate-containing compounds are FDA-approved drugs for the treatment of bone resorption disorders, their potential low toxicity makes them good candidates to control different tropical diseases.The hemoflagellated protozoan parasite Trypanosoma cruzi is the etiological agent of Chagas' disease or American trypanosomiasis, which is an endemic disease widespread from southern United States to southern Argentina. It has been estimated that close to 18 million people are infected and over 40 million are at risk of infection by T. cruzi. 1 The central nervous system is the most frequently affected site in AIDS patients, with meningoencephalitis occurring approximately in 75% of cases. The next normally affected organ is the heart with myocarditis.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptBioorg Med Chem. Author manuscript; available in PMC 2012 April 1. In addition, since people migrate from endemic areas, the possibility for cases in developed nations will also escalate. Chemotherapy for Chagas' disease still remains unsatisfactory due to limited efficacy and common side effects of the currently available drugs such as nifurtimox (1), now discontinued, and benznidazole (2), which present toxicity associated with their continued use. [2][3][4] The parasite has a complex life cycle involving blood-sucking Reduv...

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Section: Resultsmentioning

confidence: 99%

Synthesis and biological evaluation of new 2-alkylaminoethyl-1,1-bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii targeting farnesyl diphosphate synthase

Rosso

Szajnman

Malayil

et al. 2011

Bioorganic & Medicinal Chemistry

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“…The NO-bisphosphonate hybrids ( 58 , 59 ) [114,115] nicely illustrate this strategy. As mentioned above, these compounds can selectively deliver NO to bone tissue because of the high affinity of bisphosphonates for bone mineral content.…”

Section: Expert Opinionmentioning

confidence: 99%

“…The hybrid compounds accumulate preferentially in bone because of the high affinity of bisphosphonates for bone mineral content. Screened by an in vitro cell assay of osteoclasts, the hybrid compounds also showed a potent bone resorption-inhibitory activity through an NO-dependent mechanism [114,115] .…”

Section: No Hybrid Compounds For Other Therapeutic Applicationsmentioning

confidence: 99%

NO donor hybrid compounds as multifunctional therapeutic agents

Fang

Lehmann

2008

Expert Opinion on Therapeutic Patents

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Background : In the 1980s, nitric oxide (NO) was found to be a crucial signaling and regulating molecule with wide-ranging functions in the cardiovascular, nervous and immune systems, such as blood vessel relaxation, neurotransmission and pathogen suppression. Deficiency or dysfunction of NO, which may result from ageing and other etiological or pathological factors, is implicated in the initiation and progression of many diseases. Delivery of supplementary NO is thought to be an attractive therapeutic option to prevent disease progression; NO donor hybrid compounds are also suspected of being useful. Objectives : These bi-or multifunctional compounds contain an NO-releasing moiety linked to another well-established biologically active molecule mostly through some kind of spacer. Such hybrid compounds may perform as intact molecules or be metabolized, yielding two or even more parent pharmacophores in vivo and perhaps producing a synergic response. From the middle of the 1990s up to now, a considerable number of NO hybrid compounds have been synthesized and screened. The role of NO donor hybrid compounds has been extended from the initial inflammatory and cardiovascular diseases to gastrointestinal disorders, microbial infections, cancer, neurodegenerative diseases, sexual dysfunction, ocular hypertension and others. Method/conclusion : In this review, we introduce NO donor hybrid compounds, then focus on the corresponding relevant patents with regard to its various applications and, in conclusion, discuss the chances and drawbacks of this strategy in drug discovery.

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“…All the pKa values are in keeping with those found for similar compounds. 20,21 In the case of compounds 24, 24a, 25 and 25a the picture is complicated by the presence of a fifth pK a associated with the protonation of the basic nitrogen. These pentaprotic BPs have three dissociation constants (pK a1 , pK a2 , pK a5 ) corresponding to the first, second, and fourth ionization of the bisphosphonic group.…”

Section: Dissociation Constantsmentioning

confidence: 99%

Synthesis and preliminary pharmacological characterisation of a new class of nitrogen-containing bisphosphonates (N-BPs)

Lolli

Rolando

Tosco

et al. 2010

Bioorganic & Medicinal Chemistry

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a new series of bisphosphonates bearing either the nitrogen containing NO-donor furoxan (1,2,5-oxadiazole 2-oxide) system or the related furazan (1,2,5-oxadiazole) in lateral chain has been developed. pK a values and affinity for hydroxyapatite were determined for all the compounds. The products were able to inhibit osteoclastogenesis on RAW 246.7 cells at 10 M concentration. The most active compounds were further assayed on human PBMC cells and on rat microsomes. Unlike most nitrogen-containing bisphosphonates which target farnesyl pyrophosphate synthase, experimental and theoretical investigations suggest that the activity of our derivatives may be related to different mechanisms. The furoxan derivatives were also tested for their ability to relax rat aorta strips in view of their potential NO-dependent vasodilator properties.

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Synthesis of NO-Donor Bisphosphonates and Their in-Vitro Action on Bone Resorption

Cited by 24 publications

References 45 publications

Synthesis and biological evaluation of new 2-alkylaminoethyl-1,1-bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii targeting farnesyl diphosphate synthase

Synthesis and biological evaluation of new 2-alkylaminoethyl-1,1-bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii targeting farnesyl diphosphate synthase

NO donor hybrid compounds as multifunctional therapeutic agents

Synthesis and preliminary pharmacological characterisation of a new class of nitrogen-containing bisphosphonates (N-BPs)

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