Bone targeted drugs 2. synthesis of estrogens with hydroxyapatite affinity

Willson, Timothy M.; Henke, Brad R.; Momtahen, Tanya M.; Garrison, Deanna T.; Moore, Linda B.; Geddie, Nora G.; Baer, Philip G.

doi:10.1016/0960-894x(96)00165-5

Cited by 15 publications

(2 citation statements)

References 7 publications

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“…In any event, if metallofullerols eventually prove to be microcolloidal suspensions, they may improve on the properties of the colloids being examined as bone-targeting chemotherapy agents to treat leukemia, bone cancer and bone pain (56,57). In fact, metallofullerols may have a special utility for this purpose, because empty fullerols (60) and other polyhydroxylated compounds (61,62) have also demonstrated a high affinity for cortical bone.…”

Section: Resultsmentioning

confidence: 99%

In vivo studies of fullerene-based materials using endohedral metallofullerene radiotracers

Cagle

Kennel²,

Mirzadeh³

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

290

156

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Biodistribution studies of a water-soluble radioactive metallofullerene compound have been conducted using BALB͞c mice. To this end, a sample containing Ho x @C 82 (x ‫؍‬ 1, 2) was purified and derivatized to prepare the watersoluble metallofullerol, Ho x @C 82 Since the discovery of fullerenes in 1985 (1) and the subsequent incorporation of metal atoms within their carbon cage (2), intense interest has focused on these unique molecules. Research efforts have greatly extended our knowledge of the chemical and biological properties of empty fullerenes (3; for review, see ref. 4), but comparatively little is known about endohedral metallofullerenes because of their low production yields, low solution solubilities, difficult purification, and air sensitivity (5-9). However, advances in HPLC purification procedures (5-9) and chemical derivatization (10-15) of fullerenes have recently expanded research possibilities into applications for metallofullerenes when relatively small amounts of material are required.One potential application for metallofullerenes is in the field of nuclear medicine. Current radiopharmaceuticals employ small quantities (nanograms to milligrams) of drugs containing specially chelated radioisotopes of metals for imaging or therapeutic applications. The chelating ligands prevent direct binding of the toxic metal ions with serum components and tissue by providing a thermodynamically stable molecular environment. A major concern with these drugs, however, is their in vivo kinetic instability, which can allow the release of small amounts of toxic radiometals (16). It is envisioned, therefore, that metallofullerenes could provide a unique alternative to chelating compounds because of their resistance to metabolism and their high kinetic stability. Additionally, the large carbon-based surface area of fullerenes and metallofullerenes (Ϸ200 Å 2 ) facilitates the development of tissue-targeting compounds by using established metallofullerene derivative chemistry (10-15). Thus, the metallofullerenes may be useful as a new, more stable alternative for transporting radiometals in vivo.Empty fullerenes have low cytotoxicity both in vitro (17-22) and in vivo (17,(23)(24)(25)(26), despite one report of a photosensitizing C 60 derivative (24). In addition, empty fullerenes and their derivatives have been tested for their biodistribution, and some C 60 derivatives have shown promise as anti-HIV (27-34) and anticancer (35-37) agents and as an agent to reduce reactive oxygen species (20,21). Dugan et al. (17,38) have also demonstrated the usefulness of fullerene derivatives as biological freeradical scavengers in vivo. Research involving the biodistribution of fullerenes in vivo is limited to studies on C 60 and La@C 82 suspensions (23, 25), and to three water-soluble C 60 derivatives (26,30,39). All of these studies indicate rapid localization and long-term residency in the liver (Ͻ1% clearance), and one of the studies demonstrated that fullerenes are not metabolized rapidly in vivo (39). To help opti...

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Section: Resultsmentioning

confidence: 99%

In vivo studies of fullerene-based materials using endohedral metallofullerene radiotracers

Cagle

Kennel²,

Mirzadeh³

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

290

156

View full text Add to dashboard Cite

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“…For example, in the resorption lacuna beneath osteoclasts, it has been estimated that concentrations of alendronate (the prototypical bisphosphonate) can be as high as 0.5 m m (13). Not surprisingly, a number of groups have attempted to explore novel bone‐targeting moieties beyond classical bisphosphonates for use in other chemical classes, affecting alternate biological pathways known to influence the bone remodeling process (14–16).…”

mentioning

confidence: 99%

SAR of Carbon‐Linked, 2‐Substituted Purines: Synthesis and Characterization of AP23451 as a novel Bone‐Targeted Inhibitor of Src Tyrosine Kinase With In Vivo Anti‐Resorptive Activity

Shakespeare¹,

Wang²,

Bohacek³

et al. 2008

Chem Biol Drug Des

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Targeted disruption of the pp60(src) (Src) gene has implicated this tyrosine kinase in osteoclast-mediated bone resorption and as a therapeutic target for the treatment of osteoporosis and other bone-related diseases. Here, we describe structure activity relationships of a novel series of carbon-linked, 2-substituted purines that led to the identification of AP23451 as a potent inhibitor of Src tyrosine kinase with antiresorptive activity in vivo. AP23451 features the use of an arylphosphinylmethylphosphinic acid moiety which confers bone-targeting properties to the molecule, thereby increasing local concentrations of the inhibitor to actively resorbing osteoclasts at the bone interface. AP23451 exhibited an IC50 = 68 nm against Src kinase; an X-ray crystal structure of the molecule complexed with Src detailed the molecular interactions responsible for its Src inhibition. In vivo, AP23451 demonstrated a dose-dependent decrease in PTH-induced hypercalcemia. Moreover, AP23517, a structurally and biochemically similar molecule with comparable activity (IC50 = 73 nm) except devoid of the bone-targeting element, demonstrated significantly reduced in vivo efficacy, suggesting that Src activity was necessary but not sufficient for in vivo activity in this series of compounds.

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5‐Iodo‐3‐Ethoxypyrazoles: An Entry Point to New Chemical Entities

Guillou

Janin

2010

Chemistry A European J

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Our program, which has focused on the preparation of new pyrazole derivatives, has led us to report here an original and simplified preparation of ethyl 3-ethoxy-1H-pyrazole-4-carboxylate. This is based on the reaction of hydrazine monohydrochloride and diethyl 2-(ethoxymethylene)malonate. Further transformations of this key compound allowed the preparation of the two possible iodinated isomers, namely, 3-ethoxy-4-iodo- and 3-ethoxy-5-iodo-1H-pyrazole. These compounds have opened the way to a quick access to many original pyrazole series. As an illustration, we report here on the selectivity of N-arylation, by using the Lam and Cham method, the C4- and C5-arylation of some of these 3-ethoxypyrazole derivatives by using the Suzuki-Miyaura reaction, and C5-benzylation reactions by means of the Negishi reaction. This was followed by hydrolysis of the ethoxy group, which led to the corresponding pyrazol-3-one derivatives. As a conclusion of this work, we conducted an investigation into the regiochemistry of the condensation between diethyl 2-(ethoxymethylene)malonate and the hydrochloride salts of methyl, benzyl, or phenyl hydrazine.

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Bone targeted drugs 2. synthesis of estrogens with hydroxyapatite affinity

Cited by 15 publications

References 7 publications

In vivo studies of fullerene-based materials using endohedral metallofullerene radiotracers

In vivo studies of fullerene-based materials using endohedral metallofullerene radiotracers

SAR of Carbon‐Linked, 2‐Substituted Purines: Synthesis and Characterization of AP23451 as a novel Bone‐Targeted Inhibitor of Src Tyrosine Kinase With In Vivo Anti‐Resorptive Activity

5‐Iodo‐3‐Ethoxypyrazoles: An Entry Point to New Chemical Entities

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