13 research outputs found
Somatostatin subtype-2 receptor-targeted metal-based anticancer complexes
Conjugates of a dicarba analogue of octreotide, a potent somatostatin agonist whose receptors are overexpressed on tumor cells, with [PtCl 2(dap)] (dap = 1-(carboxylic acid)-1,2-diaminoethane) (3), [(η 6-bip)Os(4-CO 2-pico)Cl] (bip = biphenyl, pico = picolinate) (4), [(η 6-p-cym)RuCl(dap)] + (p-cym = p-cymene) (5), and [(η 6-p-cym)RuCl(imidazole-CO 2H)(PPh 3)] + (6), were synthesized by using a solid-phase approach. Conjugates 3-5 readily underwent hydrolysis and DNA binding, whereas conjugate 6 was inert to ligand substitution. NMR spectroscopy and molecular dynamics calculations showed that conjugate formation does not perturb the overall peptide structure. Only 6 exhibited antiproliferative activity in human tumor cells (IC 50 = 63 ± 2 Ό in MCF-7 cells and IC 50 = 26 ± 3 Ό in DU-145 cells) with active participation of somatostatin receptors in cellular uptake. Similar cytotoxic activity was found in a normal cell line (IC 50 = 45 ± 2.6 Ό in CHO cells), which can be attributed to a similar level of expression of somatostatin subtype-2 receptor. These studies provide new insights into the effect of receptor-binding peptide conjugation on the activity of metal-based anticancer drugs, and demonstrate the potential of such hybrid compounds to target tumor cells specifically. © 2012 American Chemical Society
Transition metal catalyzed elementâelementâČ additions to alkynes
The efficient and stereoselective synthesis of, or precursors to, multi-substituted alkenes has attracted substantial interest due to their existence in various industrially and biologically important compounds. One of the most atom economical routes to such alkenes is the transition metal catalyzed hetero elementâelementâČ Ï-insertion into alkynes. This article provides a thorough up-to-date review on this area of chemistry, including discussions on the mechanism, range of Esingle bondEâČ bonds accessible and the stoichiometric/catalytic transition metal mediators employed
Cyclopentadienyl Chemistry in Water: Synthesis and Properties of Bifunctionalized [(η<sup>5</sup>âC<sub>5</sub>H<sub>3</sub>{COOR}<sub>2</sub>)M(CO)<sub>3</sub>] (M = Re and <sup>99m</sup>Tc) Complexes
Complexes of the [(η<sup>5</sup>-C<sub>5</sub>H<sub>4</sub>COOR)ÂMÂ(CO)<sub>3</sub>] type (M
= <sup>99m</sup>Tc, Re; R =
targeting function) are basic bioorganometallic structures with the
potential of combining molecular imaging (<sup>99m</sup>Tc) with therapy
(cold Re or <sup>186/188</sup>Re). So far, the single carboxylate
group on the cyclopentadienyl ring (Cp<sup>â</sup>) limited
targeting to one function. The concept of Cp<sup>â</sup> as
a scaffold for attaching biological molecules could be extended substantially
with two or more functionalities bound to the Cp<sup>â</sup> ligand. Accordingly, the rarely studied bis-substituted cyclopentadienyl
ligands [C<sub>5</sub>H<sub>3</sub>(1,2-COOMe)<sub>2</sub>]<sup>â</sup> and [C<sub>5</sub>H<sub>3</sub>(1,3-COOMe)<sub>2</sub>]<sup>â</sup> were synthesized and their coordination to the <i>fac</i>-{MÂ(CO)<sub>3</sub>}<sup>+</sup> moiety was studied in water. Both
ligands are deprotonated at physiological pH and do not undergo DielsâAlder
reactions. In water, they react directly with [ReÂ(OH<sub>2</sub>)<sub>3</sub>Â(CO)<sub>3</sub>]<sup>+</sup> to form [(η<sup>5</sup>-C<sub>5</sub>H<sub>3</sub>{1,2-COOMe}<sub>2</sub>)ÂReÂ(CO)<sub>3</sub>] and [(η<sup>5</sup>-C<sub>5</sub>H<sub>3</sub>{1,3-COOMe}<sub>2</sub>)ÂReÂ(CO)<sub>3</sub>]. Controlled hydrolysis at neutral
to alkaline pH gives the monoesters and fully hydrolyzed [(η<sup>5</sup>-C<sub>5</sub>H<sub>3</sub>{1,2-COOH}<sub>2</sub>)ÂReÂ(CO)<sub>3</sub>] and [(η<sup>5</sup>-C<sub>5</sub>H<sub>3</sub>{1,3-COOH}<sub>2</sub>)ÂReÂ(CO)<sub>3</sub>]. Thermal treatment leads to decarboxylation
and formation of [(η<sup>5</sup>-C<sub>5</sub>H<sub>4</sub>COOH)ÂReÂ(CO)<sub>3</sub>]. The corresponding <sup>99m</sup>Tc homologues are directly
accessible under slightly acidic conditions from [<sup>99m</sup>TcO<sub>4</sub>]<sup>â</sup> in high yields. In the presented strategy,
the Cp<sup>â</sup> ring acts as a scaffold for attaching multiple
targeting agents or pharmacophores at the same time
Aqueous syntheses of [(Cp-R)M(CO)3] type complexes (Cp = cyclopentadienyl, M = Mn, 99mTc, Re) with bioactive functionalities
We describe reactions of [99mTc(H2O)3(CO)3)]+ (1) with DielsâAlder products of cyclopentadiene such as âThieleâs acidâ (HCp-COOH)2 (2) and derivatives thereof in which the corresponding [(Cp-COOH)99mTc(CO)3)] (3) complex did form in water. We propose a metal mediated DielsâAlder reaction mechanism. To show that this reaction was not limited to carboxylate groups, we synthesized conjugates of 2 (HCp-CONHR)2 (4aâc) (4a, R = benzyl amine; 4b, R = Nα-Boc-l-2,3-diaminopropionic acid and 4c, R = glycine). The corresponding 99mTc complexes [(4a)99mTc(CO)3)] 6a, [(4b)99mTc(CO)3)] 6b and [(4c)99mTc(CO)3)] 6c have been prepared along the same route as for Thieleâs acid in aqueous media demonstrating the general applicability of this synthetic strategy. The authenticity of the 99mTc complexes on the no carrier added level have been confirmed by chromatographic comparison with the structurally characterized manganese or rhenium complexes.
Studies of the reaction of 1 with Thieleâs acid bound to a solid phase resin demonstrated the formation of [(Cp-COOH)99mTc(CO)3)] 3 in a heterogeneous reaction. This is the first evidence for the formation of no carrier added 99mTc radiopharmaceuticals containing cyclopentadienyl ligands via solid phase syntheses. Macroscopically, the manganese analogue 5a and the rhenium complexes 5bâc have been prepared and characterized by IR, NMR, ESI-MS and X-ray crystallography for 5a (monoclinic, P21/c, a = 9.8696(2) Ă
, b = 25.8533(4) Ă
, c = 11.8414(2) Ă
, ÎČ = 98.7322(17)°) in order to unambiguously assign the authenticity of the corresponding 99mTc complexes
Subcellular IR imaging of a metal-carbonyl moiety using photothermally induced resonance.
International audienc
Subcellular IR Imaging of a Metal-Carbonyl Moiety Using Photothermally Induced Resonance
Cyclopentadienyl-Based Amino Acids (Cp-aa) As Phenylalanine Analogues for Tumor Targeting: Syntheses and Biological Properties of [(Cp-aa)M(CO)<sub>3</sub>](M = Mn, Re, <sup>99m</sup>Tc)
Due to an enhanced demand for amino acids, the l-type
amino acid transporter 1 (LAT1) is overexpressed in many tumor cell
lines. LAT1 represents therefore an attractive target for cancer therapy
and diagnosis. On the basis of our reported aqueous synthesis of [(Cp-R)<sup>99m</sup>TcÂ(CO)<sub>3</sub>]-type complexes,â we describe the preparation of unnatural amino acid
analogues [(Cp-CH<sub>2</sub>CHÂ(NH<sub>2</sub>)ÂCOOH)ÂMnÂ(CO)<sub>3</sub>] and [(Cp-CHÂ(NH<sub>2</sub>)ÂCOOH)ÂMÂ(CO)<sub>3</sub>] (M = Mn, Re, <sup>99m</sup>Tc). Starting from fully protected HC<sub>5</sub>H<sub>5</sub>-aa (aa = amino acid), [(Cp-aa)<sup>99m</sup>TcÂ(CO)<sub>3</sub>]
complexes are accessible in quantitative yields and in a one-step
synthesis from [<sup>99m</sup>TcO<sub>4</sub>]<sup>â</sup>.
The rhenium and manganese analogues were prepared and structurally
characterized to confirm the authenticity of the <sup>99m</sup>Tc
complex. The inhibition constant of natural phenylalanine (phe) for
LAT1 is in the range 70 ± 10 ÎŒM. The <i>K</i><sub>i</sub> value of [(Cp-CHÂ(NH<sub>2</sub>)ÂCOOH)ÂMnÂ(CO)<sub>3</sub>] (<b>1a</b>) is 53 ± 11 ÎŒM, whereas <i>K</i><sub>i</sub> for the âtrueâ phe analogue [(Cp-CH<sub>2</sub>CHÂ(NH<sub>2</sub>)ÂCOOH)ÂMnÂ(CO)<sub>3</sub>] (<b>2</b>) was surprisingly high at 277 ± 37 ÎŒM. Complex <b>1a</b> caused efflux when exposed to cells, underlining its active
transport by LAT1 into the cell. <sup>99m</sup>Tc analogues of small
biological lead structures such as amino acids are generally not recognized
anymore by their targets, in particular by trans-membrane transporters.
The bioorganometallic analogues presented here are, however, actively
transported and corroborate the importance of organometallic complexes
as mimics of organic lead structures in life sciences
Subcellular IR Imaging of a Metal-Carbonyl Moiety Using Photothermally Induced Resonance
Photocontrolled DNA binding of a receptor-targeted organometallic ruthenium(II) complex
A photoactivated ruthenium(II) arene complex has been conjugated to two receptor-binding peptides, a dicarba analogue of octreotide and the Arg-Gly-Asp (RGD) tripeptide. These peptides can act as âtumor-targeting devicesâ since their receptors are overexpressed on the membranes of tumor cells. Both rutheniumâpeptide conjugates are stable in aqueous solution in the dark, but upon irradiation with visible light, the pyridyl-derivatized peptides were selectively photodissociated from the ruthenium complex, as inferred by UVâvis and NMR spectroscopy. Importantly, the reactive aqua species generated from the conjugates, [(η6-p-cym)Ru(bpm)(H2O)]2+, reacted with the model DNA nucleobase 9-ethylguanine as well as with guanines of two DNA sequences, 5âČdCATGGCT and 5âČdAGCCATG. Interestingly, when irradiation was performed in the presence of the oligonucleotides, a new ruthenium adduct involving both guanines was formed as a consequence of the photodriven loss of p-cymene from the two monofunctional adducts. The release of the arene ligand and the formation of a ruthenated product with a multidentate binding mode might have important implications for the biological activity of such photoactivated ruthenium(II) arene complexes. Finally, photoreactions with the peptideâoligonucleotide hybrid, Phac-His-Gly-Met-linker-p5âČdCATGGCT, also led to arene release and to guanine adducts, including a GG chelate. The lack of interaction with the peptide fragment confirms the preference of such organometallic ruthenium(II) complexes for guanine over other potential biological ligands, such as histidine or methionine amino acids