A mouse model involving the human papillomavirus type-16 oncogenes develops cervical cancers by lesional stages analogous to those in humans. In this study the angiogenic phenotype was characterized, revealing intense angiogenesis in high-grade cervical intraepithelial neoplasias (CIN-3) and carcinomas. MMP-9, a proangiogenic protease implicated in mobilization of VEGF, appeared in the stroma concomitant with the angiogenic switch, expressed by infiltrating macrophages, similar to what has been observed in humans. Preclinical trials sought to target MMP-9 and angiogenesis with a prototypical MMP inhibitor and with a bisphosphonate, zoledronic acid (ZA), revealing both to be antiangiogenic, producing effects comparable to a Mmp9 gene KO in impairing angiogenic switching, progression of premalignant lesions, and tumor growth. ZA therapy increased neoplastic epithelial and endothelial cell apoptosis without affecting hyperproliferation, indicating that ZA was not antimitotic. The analyses implicated cellular and molecular targets of ZA’s actions: ZA suppressed MMP-9 expression by infiltrating macrophages and inhibited metalloprotease activity, reducing association of VEGF with its receptor on angiogenic endothelial cells. Given its track record in clinical use with limited toxicity, ZA holds promise as an “unconventional” MMP-9 inhibitor for antiangiogenic therapy of cervical cancer and potentially for additional cancers and other diseases where MMP-9 expression by infiltrating macrophages is evident.

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An amino-bisphosphonate targets MMP-9–expressing macrophages and angiogenesis to impair cervical carcinogenesis

An ideal therapeutic agent for bone diseases should act solely on bone tissue with no pharmacological activity at other anatomical sites. Current therapeutic agents, however, do not usually display a preferential affinity to bones and non-specifically distribute throughout the body after administration. Attempts to design bone-specific agents have relied on engineering a desired therapeutic agent with bone-seeking molecules so that the latter delivers the therapeutic agents specifically to bones. In this critical review, we summarize the latest attempts to engineer bone-seeking therapeutic agents based on formulating therapeutic agents with bisphosphonates, a class of compounds with high affinity to biological apatite. We first provide a relevant summary of the structure of bone mineral and bisphosphonates, highlighting the mode of interaction between these two entities. The use of bisphosphonates in the diagnosis of bone diseases is then presented, since this application helps us to understand the bone-carrier properties of bisphosphonates under physiological conditions. A summary of recent attempts to formulate bisphosphonates with traditional therapeutic agents to restrict their activities to bone tissues is then provided, with special emphasis on the structure–function relationships of the engineered compounds. Finally, attempts to use bisphosphonates to deliver macromolecular therapeutics (i.e., proteins) are summarized, based on recent data from the authors' lab. The collective research into bone-seeking medicinal agents is progressively laying the foundation for next-generation ‘magic bullets’ that display desirable activities at the disease sites with no undesirable activity on other organ systems. (164 references.)

‘Magic bullets’ for bone diseases: progress in rational design of bone-seeking medicinal agents

Supramolecular chemistry and complexation abilities of diphosphonic acids

Phosphonates, their complexes and bio-applications: A spectrum of surprising diversity

The noncovalent binding of the antitumour drugs daunomycin and nogalamycin to duplex DNA has been studied using electrospray ionisation mass spectrometry (ESI-MS). The conditions for the preparation of drug/duplex DNA complexes and for their detection by ESI-MS have been optimised. Ions corresponding to these complexes were most abundant relative to free DNA when prepared in the pH range 8–9, and using gentle ESI interface conditions. Self-complementary oligonucleotides, 5′-d(GGCTAGCC)-3′ or 5′-d(CGGCGCCG)-3′, annealed in the presence of a 5-fold molar excess of either nogalamycin or daunomycin gave ESI mass spectra in which the most intense ions corresponded to three molecules of drug bound to duplex DNA, with some evidence for four drug molecules bound. For binding to 5′-d(TGAGCTAGCTCA)2-3′, complexes containing up to four nogalamycin and six daunomycin molecules were observed. These data are consistent with the neighbour exclusion principle whereby intercalation occurs between every other base pair such that up to four bound drugs would be expected for the 8 mers and up to six for the 12 mer. Competition experiments involving a single drug in an equimolar mixture of two oligonucleotides (5′-d(TGAGCTAGCTCA)2-3′ with either 5′-d(CGGCGCCG)2-3′ or 5′-d(GGCTAGCC)2-3′) showed ions arising from complexes of drug/5′-d(CGGCGCCG)2-3′ were more intense than complexes of drug/5′-d(GGCTAGCC)2-3′, relative to those from the 12 mer in each mixture. While this suggests ESI-MS has the potential to detect differences in sequence selectivity, more detailed experiments involving a comparison of the relative ionisation efficiency of different oligonucleotides and a wider range of intercalators are required to establish this definitively. ESI mass spectra from experiments in which both drugs were reacted with the same oligonucleotide were more complex, such that a clear preference for one drug could not be established.

© 1999 John Wiley & Sons, Ltd.

Observation of daunomycin and nogalamycin complexes with duplex DNA using electrospray ionisation mass spectrometry.

Potentiometric and spectroscopic (EPR and absorption) studies have shown that two phosphonic groups bound to the same carbon atom serve as a very powerful binding site for Cu2+ ion in spite of the very high negative charge centred on these groups. The steric effects as well as a high negative charge enforce unusual geometries around the metal ion and the formation of 1:2 complexes is less favourable. These features of the diphosphonic moiety mean that alkoxo-bridged dimer formation via the adjacent hydroxyl groups is less likely.

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1-Hydroxyalkane-1,1-diyldiphosphonates as potent chelating agents for metal ions. Potentiometric and spectroscopic studies of copper(II) co-ordination

Synthesis of symmetrical diesters derived from hydroxy methylene diphosphonic acids 1 to 8 is described either in one step or via the corresponding α ketophosphonate 1a to 8a. Study of the diphosphonates (1 to 6) → phosphate-phosphonates (1b to 6b) isomerization has been realized. Results related to peculiar cases in connection with nonsymmetrical esters 10, 11, 17 and study of the hydrolysis reaction of diphosphonates are presented.

α CÉTOPHOSPHONATES ET ESTERS CYCLIQUES D'HYDROXYMÉTHYLÈNES DIPHOSPHONATES SYNTHESES, STRUCTURES ET HYDROLYSE

The molecular structure of an anhydrous hydroxybisphosphonic acid was determined by X-ray diffraction techniques and compared to the corresponding hydrated crystalline form. The hydrogen bond network and intermolecular interactions show that the polar bisphosphonic group undergoes a rotation to accomodate a different distribution in the hydrophobic/polar zones observed in the crystal packing, while the rest of the amino side chain connected to the functional carbon atom has identical conformation.

The molecular structure of 4-amino 1-hydroxy butylidene-1 bisphosphonic acid (ahbbpa); an uncommon anhydrous hydroxybisphosphonic acid

https://www.jbc.org/content/271/26/15558.full.pdf

A continuous transition from A-DNA to B-DNA in the 1:1 complex between nogalamycin and the hexamer dCCCGGG.

As part of a general study of hydroxy-bisphosphonic acids (HEBP), R-C(OH)(PO3H)2, three Cu (II) complexes with R˭CH3; R˭-(CH2)3-NH2 and R˭-(CH2)5-NH2, were prepared and analysed by X-Ray diffraction methods. The substitution of the methyl group in HEBP (3) by an aminopropyl (1) or by an aminopentyl (2) chain led to a drastic modification of the ionic self-assembly in the crystal and completely different polyhedral complexation networks around the Cu (II). A polymeric chain formation is observed in (3), whereas (1) and (2) display discrete tetrameric and dimeric arrangements. The results are discussed on the basis of the environment of the phosphorus atoms and the molecular geometry around the central carbon atom of the hydroxy-bisphosphonic moiety. These results are further compared to their ability for ionic transport and/or extraction.

Driss El Manouni

Papers

1-Hydroxyalkane-1,1-diyldiphosphonates as potent chelating agents for metal ions. Potentiometric and spectroscopic studies of copper(II) co-ordination

α CÉTOPHOSPHONATES ET ESTERS CYCLIQUES D'HYDROXYMÉTHYLÈNES DIPHOSPHONATES SYNTHESES, STRUCTURES ET HYDROLYSE

The molecular structure of 4-amino 1-hydroxy butylidene-1 bisphosphonic acid (ahbbpa); an uncommon anhydrous hydroxybisphosphonic acid

A continuous transition from A-DNA to B-DNA in the 1:1 complex between nogalamycin and the hexamer dCCCGGG.

Supramolecular assembly of substituted hydroxy-bisphosphonates with cupric ion. Influence of the chain functionalization