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)

Abstract

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 K i value of [(Cp-CH(NH2)COOH)Mn(CO)3] (1a) is 53 ± 11 μM, whereas K i for the “true” phe analogue [(Cp-CH2CH(NH2)COOH)Mn(CO)3] (2) was surprisingly high at 277 ± 37 μM. Complex 1a 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.

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

“…9,12− 16 We previously reported studies on the preparation of [(Cp-R) 99m Tc(CO) 3 ] and its rhenium homologues. 10,11,17 The reaction of [ 99m Tc(OH 2 ) 3 (CO) 3 ] + (1) 18 with stable HCp-R monomers or Diels−Alder dimerized Cp derivatives (Thiele's acid [(C 5 H 5 -COOH) 2 ]) leads straight to [ ( C p -R ) 9 9 m T c ( C O ) 3 ] t y p e c o m p l e x e s i n h i g h yields. 10,11,17,19−21 Exploring the possibility of attaching more than one bioactive group, the soluble and water stable ligands Na[C 5 H 3 (1,2-COOMe) 2 ] (2) and Na[C 5 H 3 (1,3-COOMe) 2 ] (3) came to our attention.…”

Nazarov cyclization of dienylaziridines: synthesis of cyclopentadienyl/hydrinedienyl/indenyl glycines

“…Similar yield of 6a (72%) was obtained with 1 equiv of AlCl 3 (entry 3). The reaction performed with other Lewis acids, Cu(OTf) 2 and Sc(OTf) 3 gave 6a in 70% and 73% yields, respectively, and slightly longer reaction times (entries [4][5], whereas with BF 3 .OEt 2 provided 79% yield within 15 min (entry 6). Reaction with protic acids such as triflic and methanesulfonic acids gave slightly lower yields 60% and 68%, respectively (entries 7-8).…”

New neutral and lipophilic technetium complexes based on a cytectrene moiety: synthesis, characterization and biological evaluation

“…While Alberto reported that the metal-mediated retro Diels-Alder reaction is a convenient method to prepare cytectrenes in aqueous solution [5,7], we demonstrated recently the use of microwave heating gave a novel impetus to the double-ligand transfer reaction [13]. Thus, using these conditions, i.e.…”

“…Thus, [{R-Cp} 99m Tc(CO) 3 ] (R = organic part or biomolecule) were obtained in good yield by reacting the fac-[ 99m Tc(CO) 3 (H 2 O) 3 ] + core or directly the sodium pertechnetate, with Diels-Alder dimerized compounds like Thiele's acid [5,6]. Additionally, he exploited a similar procedure with monomeric Cp derivatives which yielded piano-stool complexes as well, after reaction with Tc(I) or Tc(VII) precursors in water [7]. The second and the oldest approach was first reported by Wenzel [8] and developed by Katzenellenbogen [9], Jaouen [10] and our group [11].…”