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 μ in MCF-7 cells and IC 50 = 26 ± 3 μ 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 μ 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 element–element′ 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 element–element′ π-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 bondE′ bonds accessible and the stoichiometric/catalytic transition metal mediators employed

Cyclopentadienyl Chemistry in Water: Synthesis and Properties of Bifunctionalized [(η⁵‑C₅H₃{COOR}₂)M(CO)₃] (M = Re and ^99mTc) Complexes

Complexes of the [(η⁵-C₅H₄COOR)­M­(CO)₃] type (M = ^99mTc, Re; R = targeting function) are basic bioorganometallic structures with the potential of combining molecular imaging (^99mTc) with therapy (cold Re or ^186/188Re). So far, the single carboxylate group on the cyclopentadienyl ring (Cp^–) limited targeting to one function. The concept of Cp^– as a scaffold for attaching biological molecules could be extended substantially with two or more functionalities bound to the Cp^– ligand. Accordingly, the rarely studied bis-substituted cyclopentadienyl ligands [C₅H₃(1,2-COOMe)₂]⁻ and [C₅H₃(1,3-COOMe)₂]⁻ were synthesized and their coordination to the <i>fac</i>-{M­(CO)₃}⁺ moiety was studied in water. Both ligands are deprotonated at physiological pH and do not undergo Diels–Alder reactions. In water, they react directly with [Re­(OH₂)₃­(CO)₃]⁺ to form [(η⁵-C₅H₃{1,2-COOMe}₂)­Re­(CO)₃] and [(η⁵-C₅H₃{1,3-COOMe}₂)­Re­(CO)₃]. Controlled hydrolysis at neutral to alkaline pH gives the monoesters and fully hydrolyzed [(η⁵-C₅H₃{1,2-COOH}₂)­Re­(CO)₃] and [(η⁵-C₅H₃{1,3-COOH}₂)­Re­(CO)₃]. Thermal treatment leads to decarboxylation and formation of [(η⁵-C₅H₄COOH)­Re­(CO)₃]. The corresponding ^99mTc homologues are directly accessible under slightly acidic conditions from [^99mTcO₄]⁻ in high yields. In the presented strategy, the Cp^– 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 Diels–Alder products of cyclopentadiene such as “Thiele’s acid” (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 Diels–Alder reaction mechanism. To show that this reaction was not limited to carboxylate groups, we synthesized conjugates of 2 (HCp-CONHR)2 (4a–c) (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 Thiele’s 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 Thiele’s 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 5b–c have been prepared and characterized by IR, NMR, ESI-MS and X-ray crystallography for 5a (monoclinic, P21/c, a = 9.8696(2) Å, b = 25.8533(4) Å, c = 11.8414(2) Å, β = 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

Cyclopentadienyl-Based Amino Acids (Cp-aa) As Phenylalanine Analogues for Tumor Targeting: Syntheses and Biological Properties of [(Cp-aa)M(CO)₃](M = Mn, Re, ^99mTc)

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)^99mTc­(CO)₃]-type complexes,− we describe the preparation of unnatural amino acid analogues [(Cp-CH₂CH­(NH₂)­COOH)­Mn­(CO)₃] and [(Cp-CH­(NH₂)­COOH)­M­(CO)₃] (M = Mn, Re, ^99mTc). Starting from fully protected HC₅H₅-aa (aa = amino acid), [(Cp-aa)^99mTc­(CO)₃] complexes are accessible in quantitative yields and in a one-step synthesis from [^99mTcO₄]⁻. The rhenium and manganese analogues were prepared and structurally characterized to confirm the authenticity of the ^99mTc complex. The inhibition constant of natural phenylalanine (phe) for LAT1 is in the range 70 ± 10 μM. The <i>K</i>_i value of [(Cp-CH­(NH₂)­COOH)­Mn­(CO)₃] (<b>1a</b>) is 53 ± 11 μM, whereas <i>K</i>_i for the “true” phe analogue [(Cp-CH₂CH­(NH₂)­COOH)­Mn­(CO)₃] (<b>2</b>) was surprisingly high at 277 ± 37 μM. Complex <b>1a</b> caused efflux when exposed to cells, underlining its active transport by LAT1 into the cell. ^99mTc 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

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 “tumor-targeting devices” since their receptors are overexpressed on the membranes of tumor cells. Both ruthenium–peptide 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 UV–vis 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, 5′dCATGGCT and 5′dAGCCATG. 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 peptide–oligonucleotide hybrid, Phac-His-Gly-Met-linker-p5′dCATGGCT, 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