UVA chemical filters: a systematic study.

Sunscreens are a popular and effective method of protecting against the damaging effects of solar radiation including skin cancer and immune system suppression. Chemical sunscreen filters achieve this by absorbing ultraviolet radiation and can be classified as UVB (280 – 320 nm) or UVA (320 – 400 nm) sunscreens depending on the wavelengths in which they absorb energy. An efficient sunscreen must afford protection against both UVB and UVA. The majority of chemical filters approved for use worldwide are UVB absorbers and the few UVA filters approved provide minimal UVA protection or show only moderate photostability. For example, the enol form of the β-diketone, BMDBM (I), absorbs strongly in the UVA region but is prone to photodegradation via the keto form (II). The purpose of the research presented has been to investigate methods aimed at improving sunscreen protection against wavelengths in the UVA region. The first approach involves adaptation of the commonly used sunscreen filter, BMDBM, to enhance its effectiveness as a UVA sunscreen filter. The emphasis has been on improving the photostability and absorption properties whilst maintaining the chemical identity of the sunscreen. This can be achieved by chelation of either Zn(II) or Al(III) by the enol form (I) of BMDBM. The results of a systematic study including potentiometric titration, spectroscopic analysis and laser flash photolysis studies are presented. A second approach has been the encapsulation of the β-diketone, BMDBM, in cyclodextrins. Cyclodextrins are cyclic oligosaccharides having a hydrophobic central cavity. The interest in cyclodextrins comes from their ability to encapsulate other molecules (guest) within their annuli to form host-guest complexes held by non-covalent forces. The formation of such inclusion complexes often results in the modification of the guest characteristics. The inclusion complexes formed between BMDBM and either β- cyclodextrin (βCD) or hydroxypropyl-β-cyclodextrin (HPβCD) has been characterized by 1H and 1H ROESY NMR spectroscopic methods. The further method aimed at improving UVA protection has involved exploring the use of theoretical methods as a tool in the design of potentially new sunscreens. In particular, the ability of the SAC-CI method to represent the trends and properties important to the photochemistry of a series of known β-diketones has been investigated. This information can then be used to complement experimental methods in the design of candidate sunscreen filters having the desired properties.Thesis (Ph.D.) - University of Adelaide, School of Chemistry and Physics, 2010

Ion Exchange in Hydroxyapatite with Lanthanides

Naturally occurring hydroxyapatite, Ca₅(PO₄)₃(OH) (HAP), is the main inorganic component of bone matrix, with synthetic analogues finding applications in bioceramics and catalysis. An interesting and valuable property of both natural and synthetic HAP is the ability to undergo cationic and anionic substitution. The lanthanides are well-suited for substitution for the Ca²⁺ sites within HAP, because of their similarities in ionic radii, donor atom requirements, and coordination geometries. We have used isothermal titration calorimetry (ITC) to investigate the thermodynamics of ion exchange in HAP with a representative series of lanthanide ions, La³⁺, Sm³⁺, Gd³⁺, Ho³⁺, Yb³⁺ and Lu³⁺, reporting the association constant (<i>K</i>_a), ion-exchange thermodynamic parameters (Δ<i>H</i>, Δ<i>S</i>, Δ<i>G</i>), and binding stoichiometry (<i>n</i>). We also probe the nature of the La³⁺:HAP interaction by solid-state nuclear magnetic resonance (³¹P NMR), X-ray diffraction (XRD), and inductively coupled plasma–optical emission spectroscopy (ICP-OES), in support of the ITC results

Evaluation of the H₂<b>dedpa</b> Scaffold and its cRGDyK Conjugates for Labeling with ⁶⁴Cu

Studies of the acyclic ligand scaffold H₂<b>dedpa</b> and its derivatives with the peptide cRGDyK for application in copper radiopharmaceuticals are described. Previously shown to be a superb ligand for ^67/68Ga, the chelate is now shown to coordinate ⁶⁴Cu in its derivatized and nonderivatized forms rapidly under mild reaction conditions (10 min, RT, pH 5.5 10 mM sodium acetate buffered solution). The hexadentate, distorted octahedral coordination of H₂<b>dedpa</b> is confirmed in the corresponding solid state X-ray crystal structure of [Cu­(<b>dedpa</b>)]. Cyclic voltammetry determined the reduction potential of [Cu­(<b>dedpa</b>)] to be below values found for common bioreductants. Reduction and reoxidation were irreversible but reproducible, indicating a potential change of coordination mode upon reduction of Cu­(II) to Cu­(I). The thermodynamic stability constant log K_CuL was determined to be 19.16(5), comparable to other frequently used ⁶⁴Cu chelates. Serum stability of the ⁶⁴Cu labeled chelate revealed only 3% transchelation/association to serum proteins after 2 h, while the conjugates reveal 10% ([Cu­(<b>RGD1</b>)]) and 6% ([Cu­(<b>RGD2</b>)]) transchelation at the same time point

H₂<i>CHX</i>dedpa and H₄<i>CHX</i>octapaChiral Acyclic Chelating Ligands for ^67/68Ga and ¹¹¹In Radiopharmaceuticals

The chiral acyclic ligands H₂<i>CHX</i>dedpa (N₄O₂), H₂<i>CHX</i>dedpa-bb (N₄O₂), and H₄<i>CHX</i>octapa (N₄O₄) (<i>CHX</i> = cyclohexyl/cyclohexane, H₂dedpa = 1,2-[[6-carboxy-pyridin-2-yl]-methylamino]­ethane, bb = <i>N</i>,<i>N</i>′-dibenzylated, H₄octapa = <i>N</i>,<i>N</i>′-bis­(6-carboxy-2-pyridylmethyl)-ethylenediamine-<i>N</i>,<i>N</i>′-diacetic acid) were synthesized, complexed with Ga­(III) and/or In­(III), and evaluated for their potential as chelating agents in radiopharmaceutical applications. The ligands were compared to the previously studied hexadentate H₂dedpa and octadentate H₄octapa ligands to determine the effect adding a chiral 1<i>R</i>,2<i>R</i>-<i>trans</i>-cyclohexane to replace the ethylenediamine backbone would have on metal complex stability and radiolabeling kinetics. It was found that [Ga­(<i>CHX</i>dedpa)]⁺ showed very similar properties to those of [Ga­(dedpa)]⁺, with only one isomer in solution observed by NMR spectroscopy, and minimal structural changes in the solid-state X-ray structure. Like [Ga­(dedpa)]⁺, [Ga­(<i>CHX</i>dedpa)]⁺ exhibited exceptionally high thermodynamic stability constants (log <i>K</i>_ML = 28.11(8)), and the chelate retained the ability to label ⁶⁷Ga quantitatively in 10 min at room temperature at ligand concentrations of 1 × 10^–5 M. In vitro kinetic inertness assays demonstrated the [⁶⁷Ga­(<i>CHX</i>dedpa)]⁺ complex to be more stable than [⁶⁷Ga­(dedpa)]⁺ in a human serum competition, with 90.5% and 77.8% of ⁶⁷Ga remaining chelate-bound after 2 h, respectively. Preliminary coordination studies of H₄<i>CHX</i>octapa with In­(III) demonstrated [In­(<i>CHX</i>octapa)]⁻ to have an equivalently high thermodynamically stable constant as [In­(octapa)]⁻, with log <i>K</i>_ML values of 27.16(9) and 26.76(14), respectively. The [¹¹¹In­(<i>CHX</i>octapa)]⁻ complex showed exceptionally high in vitro kinetic inertness over 120 h in human serum, comparing well with previously reported [¹¹¹In­(octapa)]⁻ values, and an improved stability compared to the current industry “gold standards” 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and diethylenetriaminepentaacetic acid (DTPA). Initial investigations reveal that the chiral acyclic hexadentate H₂<i>CHX</i>dedpa and octadentate H₄<i>CHX</i>octapa ligands are ideal candidates for radiopharmaceutical elaboration of gallium or indium isotopes, respectively

Evaluation of the H₂<b>dedpa</b> Scaffold and its cRGDyK Conjugates for Labeling with ⁶⁴Cu

Studies of the acyclic ligand scaffold H₂<b>dedpa</b> and its derivatives with the peptide cRGDyK for application in copper radiopharmaceuticals are described. Previously shown to be a superb ligand for ^67/68Ga, the chelate is now shown to coordinate ⁶⁴Cu in its derivatized and nonderivatized forms rapidly under mild reaction conditions (10 min, RT, pH 5.5 10 mM sodium acetate buffered solution). The hexadentate, distorted octahedral coordination of H₂<b>dedpa</b> is confirmed in the corresponding solid state X-ray crystal structure of [Cu­(<b>dedpa</b>)]. Cyclic voltammetry determined the reduction potential of [Cu­(<b>dedpa</b>)] to be below values found for common bioreductants. Reduction and reoxidation were irreversible but reproducible, indicating a potential change of coordination mode upon reduction of Cu­(II) to Cu­(I). The thermodynamic stability constant log K_CuL was determined to be 19.16(5), comparable to other frequently used ⁶⁴Cu chelates. Serum stability of the ⁶⁴Cu labeled chelate revealed only 3% transchelation/association to serum proteins after 2 h, while the conjugates reveal 10% ([Cu­(<b>RGD1</b>)]) and 6% ([Cu­(<b>RGD2</b>)]) transchelation at the same time point

H₂<i>CHX</i>dedpa and H₄<i>CHX</i>octapaChiral Acyclic Chelating Ligands for ^67/68Ga and ¹¹¹In Radiopharmaceuticals

The chiral acyclic ligands H₂<i>CHX</i>dedpa (N₄O₂), H₂<i>CHX</i>dedpa-bb (N₄O₂), and H₄<i>CHX</i>octapa (N₄O₄) (<i>CHX</i> = cyclohexyl/cyclohexane, H₂dedpa = 1,2-[[6-carboxy-pyridin-2-yl]-methylamino]­ethane, bb = <i>N</i>,<i>N</i>′-dibenzylated, H₄octapa = <i>N</i>,<i>N</i>′-bis­(6-carboxy-2-pyridylmethyl)-ethylenediamine-<i>N</i>,<i>N</i>′-diacetic acid) were synthesized, complexed with Ga­(III) and/or In­(III), and evaluated for their potential as chelating agents in radiopharmaceutical applications. The ligands were compared to the previously studied hexadentate H₂dedpa and octadentate H₄octapa ligands to determine the effect adding a chiral 1<i>R</i>,2<i>R</i>-<i>trans</i>-cyclohexane to replace the ethylenediamine backbone would have on metal complex stability and radiolabeling kinetics. It was found that [Ga­(<i>CHX</i>dedpa)]⁺ showed very similar properties to those of [Ga­(dedpa)]⁺, with only one isomer in solution observed by NMR spectroscopy, and minimal structural changes in the solid-state X-ray structure. Like [Ga­(dedpa)]⁺, [Ga­(<i>CHX</i>dedpa)]⁺ exhibited exceptionally high thermodynamic stability constants (log <i>K</i>_ML = 28.11(8)), and the chelate retained the ability to label ⁶⁷Ga quantitatively in 10 min at room temperature at ligand concentrations of 1 × 10^–5 M. In vitro kinetic inertness assays demonstrated the [⁶⁷Ga­(<i>CHX</i>dedpa)]⁺ complex to be more stable than [⁶⁷Ga­(dedpa)]⁺ in a human serum competition, with 90.5% and 77.8% of ⁶⁷Ga remaining chelate-bound after 2 h, respectively. Preliminary coordination studies of H₄<i>CHX</i>octapa with In­(III) demonstrated [In­(<i>CHX</i>octapa)]⁻ to have an equivalently high thermodynamically stable constant as [In­(octapa)]⁻, with log <i>K</i>_ML values of 27.16(9) and 26.76(14), respectively. The [¹¹¹In­(<i>CHX</i>octapa)]⁻ complex showed exceptionally high in vitro kinetic inertness over 120 h in human serum, comparing well with previously reported [¹¹¹In­(octapa)]⁻ values, and an improved stability compared to the current industry “gold standards” 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and diethylenetriaminepentaacetic acid (DTPA). Initial investigations reveal that the chiral acyclic hexadentate H₂<i>CHX</i>dedpa and octadentate H₄<i>CHX</i>octapa ligands are ideal candidates for radiopharmaceutical elaboration of gallium or indium isotopes, respectively

H₄octapa-Trastuzumab: Versatile Acyclic Chelate System for ¹¹¹In and ¹⁷⁷Lu Imaging and Therapy

A bifunctional derivative of the versatile acyclic chelator H₄octapa, <i>p</i>-SCN-Bn-H₄octapa, has been synthesized for the first time. The chelator was conjugated to the HER2/<i>neu</i>-targeting antibody trastuzumab and labeled in high radiochemical purity and specific activity with the radioisotopes ¹¹¹In and ¹⁷⁷Lu. The <i>in vivo</i> behavior of the resulting radioimmunoconjugates was investigated in mice bearing ovarian cancer xenografts and compared to analogous radioimmunoconjugates employing the ubiquitous chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). The H₄octapa-trastuzumab conjugates displayed faster radiolabeling kinetics with more reproducible yields under milder conditions (15 min, RT, ∼94–95%) than those based on DOTA-trastuzumab (60 min, 37 °C, ∼50–88%). Further, antibody integrity was better preserved in the ¹¹¹In- and ¹⁷⁷Lu-octapa-trastuzumab constructs, with immunoreactive fractions of 0.99 for each compared to 0.93–0.95 for ¹¹¹In- and ¹⁷⁷Lu-DOTA-trastuzumab. These results translated to improved <i>in vivo</i> biodistribution profiles and SPECT imaging results for ¹¹¹In- and ¹⁷⁷Lu-octapa-trastuzumab compared to ¹¹¹In- and ¹⁷⁷Lu-DOTA-trastuzumab, with increased tumor uptake and higher tumor-to-tissue activity ratios

H₄octapa: An Acyclic Chelator for ¹¹¹In Radiopharmaceuticals

This preliminary investigation of the octadentate acyclic chelator H₄octapa (N₄O₄) with ¹¹¹In/¹¹⁵In³⁺ has demonstrated it to be an improvement on the shortcomings of the current industry “gold standards” DOTA (N₄O₄) and DTPA (N₃O₅). The ability of H₄octapa to radiolabel quantitatively ¹¹¹InCl₃ at ambient temperature in 10 min with specific activities as high as 2.3 mCi/nmol (97.5% radiochemical yield) is presented. In vitro mouse serum stability assays have demonstrated the ¹¹¹In complex of H₄octapa to have improved stability when compared to DOTA and DTPA over 24 h. Mouse biodistribution studies have shown that the radiometal complex [¹¹¹In­(octapa)]⁻ has exceptionally high in vivo stability over 24 h with improved clearance and stability compared to [¹¹¹In­(DOTA)]⁻, demonstrated by lower uptake in the kidneys, liver, and spleen at 24 h. ¹H/¹³C NMR studies of the [In­(octapa)]⁻ complex revealed a 7-coordinate solution structure, which forms a single isomer and exhibits no observable fluxional behavior at ambient temperature, an improvement to the multiple isomers formed by [In­(DTPA)]^2– and [In­(DOTA)]⁻ under the same conditions. Potentiometric titrations have determined the thermodynamic formation constant of the [In­(octapa)]⁻ complex to be log <i>K</i>_ML = 26.8(1). Through the same set of analyses, the [^111/115In­(decapa)]^2– complex was found to have nonoptimal stability, with H₅decapa (N₅O₅) being more suitable for larger metal ions due to its higher potential denticity (e.g., lanthanides and actinides). Our initial investigations have revealed the acyclic chelator H₄octapa to be a valuable alternative to the macrocycle DOTA for use with ¹¹¹In, and a significant improvement to the acyclic chelator DTPA

1,1′-Disubstituted Ferrocenyl Carbohydrate Chloroquine Conjugates as Potential Antimalarials

This work presents a new class of organometallic antimalarials, based on a ferrocene scaffold, bearing a chloroquine derivative and a 1,2;3,5-(diisopropylidene)-α-d-glucofuranose moiety in a 1,1′-heteroannular substitution pattern. Synthesis proceeds via orthogonal functionalization of ferrocene, giving 1-acetoxy-1′-(1,3-dioxan-2-yl)­ferrocene (<b>15</b>) as the precursor for modular introduction of the carbohydrate (<b>16</b>, <b>17</b>) followed by subsequent reductive amination with chloroquine building blocks <b>8</b>–<b>10</b>, yielding the 1-[3-(7-chloroquinolin-4-ylamino)­alkylamino]-1′-[6-(1,2;3,5-diisopropylidene)-α-d-glucofuranosidyl]­ferrocenes <b>18</b>–<b>20</b>. After complete characterization of these new, trifunctional conjugates, they were examined for their antiplasmodial activity in a chloroquine-susceptible strain of Plasmodium falciparum (D10) and in two chloroquine-resistant strains (Dd2 and K1). Their activity was compared to that of the monosubstituted reference conjugates <b>1</b>–<b>3</b> and the 1,2-disubstituted regioisomers <b>4</b>–<b>6</b>. Compounds <b>19</b> and <b>20</b> exhibited consistently high activity in in vitro antiplasmodial activity assays performed in Dd2 and K1 strains, performing better than the reference compounds chloroquine and the monosubstituted and 1,2-disubstituted compounds <b>1</b>–<b>6</b>

Dipicolinate Complexes of Gallium(III) and Lanthanum(III)

Three dipicolinic acid amine-derived compounds functionalized with a carboxylate (H₃dpaa), phosphonate (H₄dppa), and bisphosphonate (H₇dpbpa), as well as their nonfunctionalized analogue (H₂dpa), were successfully synthesized and characterized. The 1:1 lanthanum­(III) complexes of H₂dpa, H₃dpaa, and H₄dppa, the 1:2 lanthanum­(III) complex of H₂dpa, and the 1:1 gallium­(III) complex of H₃dpaa were characterized, including via X-ray crystallography for [La₄(dppa)₄(H₂O)₂] and [Ga­(dpaa)­(H₂O)]. H₂dpa, H₃dpaa, and H₄dppa were evaluated for their thermodynamic stability with lanthanum­(III) via potentiometric and either UV–vis spectrophotometric (H₃dpaa) or NMR spectrometric (H₂dpa and H₄dppa) titrations, which showed that the carboxylate (H₃dpaa) and phosphonate (H₄dppa) containing ligands enhanced the lanthanum­(III) complex stability by 3–4 orders of magnitude relative to the unfunctionalized ligand (comparing log β_ML and pM values) at physiological pH. In addition, potentiometric titrations with H₃dpaa and gallium­(III) were performed, which gave significantly (8 orders of magnitude) higher thermodynamic stability constants than with lanthanum­(III). This was predicted to be a consequence of better size matching between the dipicolinate cavity and gallium­(III), which was also evident in the aforementioned crystal structures. Because of a potential link between lanthanum­(III) and osteoporosis, the ligands were tested for their bone-directing properties via a hydroxyapatite (HAP) binding assay, which showed that either a phosphonate or bisphosphonate moiety was necessary in order to elicit a chemical binding interaction with HAP. The oral activity of the ligands and their metal complexes was also assessed by experimentally measuring log <i>P</i>_o/w values using the shake-flask method, and these were compared to a currently prescribed osteoporosis drug (alendronate). Because of the potential therapeutic applications of the radionuclides ^67/68Ga, radiolabeling studies were performed with ⁶⁷Ga and H₃dpaa. Quantitative radiolabeling was achieved at pH 6.5 in 10 min at room temperature with concentrations as low as 10^–5 M, and human serum stability studies were undertaken