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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, Tc-99m)


Sulieman, Samer; Can, Daniel; Mertens, John; N'Dongo, Harmel W Peindy; Liu, Yu; Schmutz, Paul; Bauwens, Matthias; Spingler, Bernhard; Alberto, Roger (2012). 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, Tc-99m). Organometallics, 31(19):6880-6886.

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)Tc-99m(CO)(3)]-type complexes,(1-S) 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, Tc-99m). Starting from fully protected HC5H5-aa (aa = amino acid), (Cp-aa)Tc-99m(CO)(3)] complexes are accessible in quantitative yields and in a one-step synthesis from (TcO4)-Tc-99m](-). The rhenium and manganese analogues were prepared and structurally characterized to confirm the authenticity of the Tc-99m complex. The inhibition constant of natural phenylalanine (phe) for LAT1 is in the range 70 +/- 10 mu M. The K-i value of (Cp-CH(NH2)COOH)Mn(CO)(3)] (1a) is 53 +/- 11 mu M, whereas K-i for the ``true'' phe analogue (Cp-CH2CH(NH2)COOH)Mn(CO)(3)] (2) was surprisingly high at 277 +/- 37 mu M. Complex la caused efflux when exposed to cells, underlining its active transport by LAT1 into the cell. Tc-99m 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.

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)Tc-99m(CO)(3)]-type complexes,(1-S) 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, Tc-99m). Starting from fully protected HC5H5-aa (aa = amino acid), (Cp-aa)Tc-99m(CO)(3)] complexes are accessible in quantitative yields and in a one-step synthesis from (TcO4)-Tc-99m](-). The rhenium and manganese analogues were prepared and structurally characterized to confirm the authenticity of the Tc-99m complex. The inhibition constant of natural phenylalanine (phe) for LAT1 is in the range 70 +/- 10 mu M. The K-i value of (Cp-CH(NH2)COOH)Mn(CO)(3)] (1a) is 53 +/- 11 mu M, whereas K-i for the ``true'' phe analogue (Cp-CH2CH(NH2)COOH)Mn(CO)(3)] (2) was surprisingly high at 277 +/- 37 mu M. Complex la caused efflux when exposed to cells, underlining its active transport by LAT1 into the cell. Tc-99m 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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Department of Chemistry
Dewey Decimal Classification:540 Chemistry
Language:English
Date:2012
Deposited On:01 Mar 2013 13:02
Last Modified:07 Dec 2017 20:09
Publisher:American Chemical Society
ISSN:0276-7333
Publisher DOI:https://doi.org/10.1021/om300695k

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