Hyun-soon Chong

Name:

Organization: Illinois Institute of Technology

Department: Chemistry Division, Biological, Chemical, and Physical Sciences Department

Title:

Chemicals
References

Synthetic and theoretical investigation on the one-pot halogenation of β-amino alcohols and nucleophilic ring opening of aziridinium ions

Co-reporter:Yunwei Chen, Xiang Sun, Ningjie Wu, Jingbai Li, Shengnan Jin, Yongliang Zhong, Zirui Liu, Andrey Rogachev and Hyun-Soon Chong

Organic & Biomolecular Chemistry 2016 vol. 14(Issue 3) pp:920-939

Publication Date(Web):26 Nov 2015

DOI:10.1039/C5OB01692D

Aziridinium ions are useful reactive intermediates for the synthesis of enantiomerically enriched building blocks. However, N,N-dialkyl aziridinium ions are relatively underutilized in the synthesis of optically active molecules as compared to other three-membered ring cogeners, aziridines and epoxides. The characterization of both optically active aziridinium ions and secondary β-halo amines as the precursor molecules of aziridinium ions has been scarcely reported and is often unclear. In this paper, we report for the first time the preparation and experimental and theoretical characterization of optically active aziridinium ions and secondary β-halo amines. Optically active secondary N,N-substituted β-halo amines were efficiently synthesized from N,N-substituted alaninol via formation and ring opening at the more hindered carbon of aziridinium ions by halides. Optically active β-halo amines and aziridinium ions were characterized by NMR and computational analyses. The structure of an optically active β-chloro amine was confirmed via X-ray crystallographic analysis. The aziridinium ions derived from N,N-dibenzyl alaniol remained stable only for several hours, which was long enough for analyses of NMR and optical activity. The stereospecific ring opening of aziridinium ions by halides was computationally studied using DFT and highly-accurate DLPNO-CCSD(T) methods. The highly regioselective and stereoselective ring opening of aziridinium ions was applied for efficient one-pot conversion of β-alaninols to enantiomerically enriched β-amino alcohols, β-amino nitriles, and vicinal diamine derivatives.

Transferrin conjugates of triazacyclononane-based bifunctional NE3TA chelates for PET imaging: Synthesis, Cu-64 radiolabeling, and in vitro and in vivo evaluation

Co-reporter:Chi Soo Kang, Ningjie Wu, Yunwei Chen, Xiang Sun, Nilantha Bandara, Dijie Liu, Michael R. Lewis, Buck E. Rogers, Hyun-Soon Chong

Journal of Inorganic Biochemistry 2016 Volume 154() pp:60-66

Publication Date(Web):January 2016

DOI:10.1016/j.jinorgbio.2015.10.012

•Synthesis of three triazacyclononane-based bifunctional chelates (NE3TAs) for potential use in Cu-64-PET imaging.•Rapid Cu-64 radiolabeling of NE3TA-transferrin (Tf) conjugates at room temperature.•Excellent complex stability of 64Cu-NE3TA-Tf conjugates in human serum.•Rapid blood clearance and increasing tumor uptake of 64Cu-N-NE3TA-Tf in tumor-bearing mice.Three different polyaminocarboxylate-based bifunctional NE3TA (7-[2-[carboxymethyl)amino]ethyl]-1,4,7-triazacyclononane-1,4-diacetic acid) chelating agents were synthesized for potential use in copper 64-PET imaging applications. The bifunctional chelates were comparatively evaluated using transferrin (Tf) as a model targeting vector that binds to the transferrin receptor overexpressed in many different cancer cells. The transferrin conjugates of the NE3TA-based bifunctional chelates were evaluated for radiolabeling with 64Cu. In vitro stability and cellular uptake of 64Cu-radiolabeled conjugates were evaluated in human serum and prostate (PC-3) cancer cells, respectively. Among the three NE3TA–Tf conjugates tested, N-NE3TA–Tf was identified as the best conjugate for radiolabeling with 64Cu. N-NE3TA–Tf rapidly bound to 64Cu (> 98% radiolabeling efficiency, 1 min, RT), and 64Cu–N-NE3TA–Tf remained stable in human serum for 2 days and demonstrated high uptake in PC-3 cancer cells. 64Cu–N-NE3TA–Tf was shown to have rapid blood clearance and increasing tumor uptake in PC-3 tumor bearing mice over a 24 h period. This bifunctional chelate presents highly efficient chelation chemistry with 64Cu under mild condition that can be applied for radiolabeling of various tumor-specific biomolecules with 64Cu for potential use in PET imaging applications.Three different NE3TA (7-[2-[carboxymethyl)amino]ethyl]-1,4,7-triazacyclononane-1,4-diacetic acid)-based bifunctional chelating agents were comparatively evaluated for potential use in copper 64-PET imaging applications using transferrin as a model targeting vector. The biological data indicate that N-NE3TA attached to transferrin more rapidly and stably bound with 64Cu than the other NE3TA chelating agents.

Promising bifunctional chelators for copper 64-PET imaging: practical 64Cu radiolabeling and high in vitro and in vivo complex stability

Co-reporter:Ningjie Wu;Chi Soo Kang;Inseok Sin

JBIC Journal of Biological Inorganic Chemistry 2016 Volume 21( Issue 2) pp:177-184

Publication Date(Web):2016 April

DOI:10.1007/s00775-015-1318-7

Positron emission tomography (PET) using copper-64 is a sensitive and non-invasive imaging technique for diagnosis and staging of cancer. A bifunctional chelator that can present rapid radiolabeling kinetics and high complex stability with 64Cu is a critical component for targeted PET imaging. Bifunctional chelates 3p-C-NE3TA, 3p-C-NOTA, and 3p-C-DE4TA were evaluated for complexation kinetics and stability with 64Cu in vitro and in vivo. Hexadentate 3p-C-NOTA and heptadentate 3p-C-NE3TA possess a smaller TACN-based macrocyclic backbone, while nonadentate 3p-C-DE4TA is constructed on a larger CYCLEN-based ring. The frequently explored chelates of 64Cu, octadentate C-DOTA and hexadentate C-NOTA were also comparatively evaluated. Radiolabeling kinetics of bifunctional chelators with 64Cu was assessed under mild conditions. All bifunctional chelates instantly bound to 64Cu in excellent radiolabeling efficiency at room temperature. C-DOTA was less efficient in binding 64Cu than all other chelates. All 64Cu-radiolabeled bifunctional chelates remained stable in human serum without any loss of 64Cu for 2 days. When challenged by an excess amount of EDTA, 64Cu complexes of C-NOTA, 3p-C-NE3TA and 3p-C-NOTA were shown to be more stable than 64Cu-C-DOTA and 64Cu-3p-C-DE4TA. 64Cu complexes of the new chelates 3p-C-NE3TA and 3p-C-NOTA displayed comparable in vitro and in vivo complex stability to 64Cu-C-NOTA. In vivo biodistribution result indicates that the 64Cu-radiolabeled complexes of 3p-C-NOTA and 3p-C-NE3TA possess excellent in vivo complex stability, while 64Cu-3p-C-DE4TA was dissociated as evidenced by high renal and liver retention in mice. The results of in vitro and in vivo studies suggest that the bifunctional chelates 3p-C-NE3TA and 3p-C-NOTA offer excellent chelation chemistry with 64Cu for potential PET imaging applications.

Application of aziridinium ring opening for preparation of optically active diamine and triamine analogues: highly efficient synthesis and evaluation of DTPA-based MRI contrast enhancement agents

Co-reporter:Xiang Sun, Yunwei Chen, Ningjie Wu, Chi Soo Kang, Hyun A. Song, Shengnan Jin, Yao Fu, Henry Bryant, Joseph A. Frank and Hyun-Soon Chong

RSC Advances 2015 vol. 5(Issue 115) pp:94571-94581

Publication Date(Web):03 Nov 2015

DOI:10.1039/C5RA11306G

Ring opening of aziridinium ions with nitrogen nucleophiles was applied to the highly efficient synthesis of optically active vicinal diamines and diethylene triamine pentaacetic acid (DTPA) analogues as potential magnetic resonance imaging (MRI) contrast enhancement agents. The synthetic method features a column-free isolation of the regiospecific and stereospecific nucleophilic substitution products of enantiomerically enriched aziridinium ions in excellent yield.

Synthesis, characterization, and nucleophilic ring opening reactions of cyclohexyl-substituted β-haloamines and aziridinium ions

Co-reporter:Hyun-Soon Chong, Xiang Sun, Yunwei Chen, Meng Wang

Tetrahedron Letters 2015 Volume 56(Issue 7) pp:946-948

Publication Date(Web):11 February 2015

DOI:10.1016/j.tetlet.2014.12.101

Cyclohexyl-substituted β-haloamines and aziridinium ions were prepared and characterized. Stereospecific ring opening of aziridinium ions was applied for efficient synthesis of vicinal amine, β-amino acid, and tetrahydroisoquinoline (THIQ) analogues. Nucleophilic ring opening reactions of aziridinium ions and N-protected aziridine analogues were for the first time comparatively studied. The result of nucleophilic reactions clearly indicates that aziridinium ions were significantly more reactive toward nucleophilic ring opening than the aziridine analogues.

Novel 64Cu-radiolabeled bile acid conjugates for targeted PET imaging

Co-reporter:Hyun-Soon Chong, Yunwei Chen, Chi Soo Kang, Xiang Sun, Ningjie Wu

Bioorganic & Medicinal Chemistry Letters 2015 Volume 25(Issue 5) pp:1082-1085

Publication Date(Web):1 March 2015

DOI:10.1016/j.bmcl.2015.01.008

A promising bifunctional chelate (N-NE3TA) was conjugated to bile acids, cholic acid (CA), deoxycholic acid (DCA), and chenodeoxycholic acid (CDCA) as tumor targeting vectors. Bile acid conjugates of N-NE3TA (CA–N-NE3TA, DCA–N-NE3TA, and CDCA–N-NE3TA) were comparatively evaluated for complexation with 64Cu, an imaging probe for positron emission tomography (PET). N-NE3TA–bile acid conjugates were evaluated for radiolabeling kinetics with 64Cu, and the corresponding 64Cu-radiolabeled conjugates were screened for complex stability in human serum and EDTA solution. The NE3TA–bile acid conjugates instantly bound to 64Cu with excellent radiolabeling efficiency at room temperature. All NE3TA–bile acid conjugates radiolabeled with 64Cu remained inert in human serum for 2 days without releasing a considerable amount of the radioactivity. The 64Cu-radiolabeled complexes were further challenged by EDTA in a 100-fold molar excess. Bile acid–N-NE3TA conjugates radiolabeled with 64Cu were quite stable with a minimal transfer of 64Cu to EDTA at 4 h time point. The in vitro data indicate that the bile acid–N-NE3TA conjugates deserve further biological evaluation for 64Cu-based targeted PET imaging applications.

Synthesis and comparative biological evaluation of bifunctional ligands for radiotherapy applications of 90Y and 177Lu

Co-reporter:Hyun-Soon Chong, Xiang Sun, Yunwei Chen, Inseok Sin, Chi Soo Kang, Michael R. Lewis, Dijie Liu, Varyanna C. Ruthengael, Yongliang Zhong, Ningjie Wu, Hyun A. Song

Bioorganic & Medicinal Chemistry 2015 23(5) pp: 1169-1178

Publication Date(Web):

DOI:10.1016/j.bmc.2014.12.035

Synthesis and Evaluation of an Enantiomerically Enriched Bifunctional Chelator for 64Cu-Based Positron Emission Tomography (PET) Imaging

Co-reporter:Hyun-Soon Chong;Xiang Sun;Yongliang Zhong;Kamil Bober;Michael R. Lewis;Dijie Liu;Varyanna C. Ruthengael;Inseok Sin;Chi Soo Kang

European Journal of Organic Chemistry 2014 Volume 2014( Issue 6) pp:1305-1313

Publication Date(Web):

DOI:10.1002/ejoc.201301499

Abstract

We report the synthesis and evaluation of an enantiomerically enriched bifunctional chelator, (S)-C-NE3TA. The bifunctional chelator was efficiently prepared by regioselective and stereoselective ring opening of an aziridinium ion. The new chiral chelator instantly and almost completely bound to ⁶⁴Cu at room temperature. The corresponding ⁶⁴Cu-radiolabeled complex remained intact in human serum for 48 h without any measurable transchelation and was tolerant to a rigorous EDTA challenge for 24 h. The ⁶⁴Cu-radiolabeled (S)-C-NE3TA complex was stable in mice and produced an excellent biodistribution profile. The results of the in vitro and in vivo evaluations indicate that the new optically active chelator is a promising candidate for PET imaging applications.

Novel hexadentate and pentadentate chelators for 64Cu-based targeted PET imaging

Co-reporter:Inseok Sin, Chi Soo Kang, Nilantha Bandara, Xiang Sun, Yongliang Zhong, Buck E. Rogers, Hyun-Soon Chong

Bioorganic & Medicinal Chemistry 2014 Volume 22(Issue 8) pp:2553-2562

Publication Date(Web):15 April 2014

DOI:10.1016/j.bmc.2014.02.041

A series of new hexadentate and pentadentate chelators were designed and synthesized as chelators of 64Cu. The new pentadentate and hexadentate chelators contain different types of donor groups and are expected to form neutral complexes with Cu(II). The new chelators were evaluated for complex kinetics and stability with 64Cu. The new chelators instantly bound to 64Cu with high labeling efficiency and maximum specific activity. All 64Cu-radiolabeled complexes in human serum remained intact for 2 days. The 64Cu-radiolabeled complexes were further challenged by EDTA in a 100-fold molar excess. Among the 64Cu-radiolabeled complexes evaluated, 64Cu-complex of the new chelator E was well tolerated with a minimal transfer of 64Cu to EDTA. 64Cu-radiolabeled complex of the new chelator E was further evaluated for biodistribution studies using mice and displayed rapid blood clearance and low organ uptake. 64Cu-chelator E produced a favorable in vitro and in vivo complex stability profiles comparable to 64Cu complex of the known hexadentate NOTA chelator. The in vitro and in vivo data highlight strong potential of the new chelator E for targeted PET imaging application.

Stereoselective and Regioselective Intramolecular Friedel–Crafts Reaction of Aziridinium Ions for Synthesis of 4-Substituted Tetrahydroisoquinolines

Co-reporter:Hyun-Soon Chong and Yunwei Chen

Organic Letters 2013 Volume 15(Issue 23) pp:5912-5915

Publication Date(Web):November 18, 2013

DOI:10.1021/ol4013537

Optically active 4-substituted tetrahydroisoquinolines were synthesized via intramolecular Friedel–Crafts (FC) reactions of aziridinium ions in a highly regio- and stereoselective manner. Control experiments suggest the formation and ring-opening of aziridinium ions as the key intermediates in the Lewis acid catalyzed FC reactions.

Synthesis and Preclinical Evaluation of Bifunctional Ligands for Improved Chelation Chemistry of 90Y and 177Lu for Targeted Radioimmunotherapy

Co-reporter:Chi Soo Kang, Xiang Sun, Fang Jia, Hyun A Song, Yunwei Chen, Michael Lewis, and Hyun-Soon Chong

Bioconjugate Chemistry 2012 Volume 23(Issue 9) pp:1775

Publication Date(Web):August 10, 2012

DOI:10.1021/bc200696b

We report a practical and high-yield synthesis of a bimodal bifunctional ligand 3p-C-NETA-NCS containing the isothiocyanate group for conjugation to a tumor targeting antibody. 3p-C-NETA-NCS was conjugated to a tumor-targeting antibody, trastuzumab, and the corresponding 3p-C-NETA-trastuzumab conjugate was evaluated and compared to trastuzumab conjugates of the known bifunctional ligands C-DOTA, C-DTPA, and 3p-C-DEPA for radiolabeling kinetics with 90Y and 177Lu. 3p-C-NETA-trastuzumab conjugate exhibited extremely rapid complexation kinetics with 90Y and 177Lu. 90Y-3p-C-NETA-trastuzumab and 177Lu-3p-C-NETA-trastuzumab conjugates were stable in human serum for 2 weeks. A pilot biodistribution study was conducted to evaluate in vivo stability and tumor targeting of 177Lu-radiolabeled trastuzumab conjugate using nude mice bearing ZR-75-1 human breast cancer. 177Lu-3p-C-NETA-trastuzumab conjugate displayed low radioactivity level at blood (1.6%), low organ uptake (<2.2%), and high tumor-to-blood ratio (6.4) at 120 h. 3p-C-NETA possesses favorable in vitro and in vivo profiles and is an excellent bifunctional chelator that can be used for targeted RIT applications using 90Y and 177Lu and has the potential to replace DOTA and DTPA analogues in current clinical use.

A highly effective bifunctional ligand for radioimmunotherapy applications

Co-reporter:Hyun-Soon Chong, Hyun A. Song, Chi Soo Kang, Thien Le, Xiang Sun, Mamta Dadwal, Hyunbeom Lee, Xiaoli Lan, Yunwei Chen and Anzhi Dai

Chemical Communications 2011 vol. 47(Issue 19) pp:5584-5586

Publication Date(Web):05 Apr 2011

DOI:10.1039/C0CC05707J

A novel bifunctional ligand (3p-C-NETA) for antibody-targeted radioimmunotherapy (RIT) of β-emitting radioisotopes 90Y and 177Lu was efficiently synthesized via an unexpected regiospecific ring opening of an aziridinium ion. 3p-C-NETA instantly formed a very stable complex with 90Y or 177Lu. 3p-C-NETA is an excellent bifunctional ligand for RIT.

Efficient Bifunctional Decadentate Ligand 3p-C-DEPA for Targeted α-Radioimmunotherapy Applications

Co-reporter:Hyun A Song, Chi Soo Kang, Kwamena E. Baidoo, Diane E. Milenic, Yunwei Chen, Anzhi Dai, M. W. Brechbiel, and Hyun-Soon Chong

Bioconjugate Chemistry 2011 Volume 22(Issue 6) pp:1128

Publication Date(Web):May 23, 2011

DOI:10.1021/bc100586y

A new bifunctional ligand 3p-C-DEPA was synthesized and evaluated for use in targeted α-radioimmunotherapy. 3p-C-DEPA was efficiently prepared via regiospecific ring opening of an aziridinium ion and conjugated with trastuzumab. The 3p-C-DEPA-trastuzumab conjugate was extremely rapid in binding 205/6Bi, and the corresponding 205/6Bi-3p-C-DEPA-trastuzumab complex was stable in human serum. Biodistribution studies were performed to evaluate in vivo stability and tumor targeting of 205/6Bi-3p-C-DEPA-trastuzumab conjugate in tumor bearing athymic mice. 205/6Bi-3p-C-DEPA-trastuzumab conjugate displayed excellent in vivo stability and targeting as evidenced by low organ uptake and high tumor uptake. The results of the in vitro and in vivo studies indicate that 3p-C-DEPA is a promising chelator for radioimmunotherapy of 212Bi and 213Bi.

Convenient Synthesis and Evaluation of a Heptadentate Bifunctional Ligand for Radioimmunotherapy Applications (Eur. J. Org. Chem. 33/2011)

Co-reporter:Hyun-Soon Chong;Xiang Sun;Pengfei Dong ;Chi Soo Kang

European Journal of Organic Chemistry 2011 Volume 2011( Issue 33) pp:

Publication Date(Web):

DOI:10.1002/ejoc.201190094

Abstract

The cover picture shows the phase contrast image of colon cancer cells (HT29) taken by a confocal microscope as the background image. Bifunctional ligands are an essential component in the biomedical and radiopharmaceutical application of biologically active metals as cytotoxic agents or imaging probes. We herein present the efficient synthesis and evaluation of the bifunctional ligand C-NE3TA for antibody-targeted radiation cancer therapy. The synthetic methods to construct the bifunctional ligand are centered on the regiospecific ring opening of aziridine and the aziridinium cation. Details are discussed in the article by H.-S. Chong et al. on p. 6641 ff.

Convenient Synthesis and Evaluation of a Heptadentate Bifunctional Ligand for Radioimmunotherapy Applications

Co-reporter:Hyun-Soon Chong;Xiang Sun;Pengfei Dong ;Chi Soo Kang

European Journal of Organic Chemistry 2011 Volume 2011( Issue 33) pp:6641-6648

Publication Date(Web):

DOI:10.1002/ejoc.201101063

Abstract

An efficient synthetic route to a bifunctional chelating agent C-NE3TA-NCS for antibody-targeted radioimmunotherapy (RIT) applications was developed. Various synthetic methods centered on key reaction steps, including bimolecular cyclization, ring-opening reactions of aziridine and aziridinium cations, and reductive amination, were explored to optimize the preparation of a tetraaza-based chelate TANPA and C-NE3TA analogues. Heptadentate C-NE3TA-NCS was conjugated to a tumor-targeting antibody and compared with hexadentate C-NOTA-NCS for radiolabeling reaction kinetics with lanthanides for RIT. The C-NE3TA–antibody conjugate displayed significantly enhanced complexation kinetics with ⁹⁰Y compared with the C-NOTA–antibody conjugate. The synthetic methods for TANPA and C-NE3TA-NCS reported herein have broad applications for the preparation of bifunctional and macrocyclic chelating agents.

Synthesis and evaluation of a bifunctional chelate for development of Bi(III)-labeled radioimmunoconjugates

Co-reporter:Mamta Dadwal, Chi Soo Kang, Hyun A. Song, Xiang Sun, Anzhi Dai, Kwamena E. Baidoo, Martin W. Brechbiel, Hyun-Soon Chong

Bioorganic & Medicinal Chemistry Letters 2011 Volume 21(Issue 24) pp:7513-7515

Publication Date(Web):15 December 2011

DOI:10.1016/j.bmcl.2011.06.107

A new bifunctional ligand C-DEPA was designed and synthesized as a component for antibody-targeted radiation therapy (radioimmunotherapy, RIT) of cancer. C-DEPA was conjugated to a tumor targeting antibody, trastuzumab, and the corresponding C-DEPA-trastuzumab conjugate was evaluated for radiolabeling kinetics with 205/6Bi. C-DEPA-trastuzumab conjugate rapidly bound 205/6Bi, and 205/6Bi-C-DEPA-trastuzumab conjugate was stable in human serum for 72 h. The in vitro radiolabeling kinetics and serum stability data suggest that C-DEPA is a potential chelate for preclinical RIT applications using 212Bi and 213Bi.

Stable Aziridinium Salts as Versatile Intermediates: Isolation and Regio- and Stereoselective Ring-Opening and Rearrangement

Co-reporter:HyunA. Song;Mamta Dadwal;Yeseul Lee;Emily Mick

Angewandte Chemie 2010 Volume 122( Issue 7) pp:

Publication Date(Web):

DOI:10.1002/ange.201090014

No abstract is available for this article.

Stable Aziridinium Salts as Versatile Intermediates: Isolation and Regio- and Stereoselective Ring-Opening and Rearrangement

Co-reporter:HyunA. Song;Mamta Dadwal;Yeseul Lee;Emily Mick

Angewandte Chemie International Edition 2010 Volume 49( Issue 7) pp:

Publication Date(Web):

DOI:10.1002/anie.201090014

No abstract is available for this article.

Bile acid-based polyaminocarboxylate conjugates as targeted antitumor agents

Co-reporter:Hyun-Soon Chong, Hyun A. Song, Xiang Ma, Sooyoun Lim, Xiang Sun and Santosh B. Mhaske

Chemical Communications 2009 (Issue 21) pp:3011-3013

Publication Date(Web):01 May 2009

DOI:10.1039/B823000E

Bile acid–polyaminocarboxylate conjugates containing NE3TA, a potential iron chelator displayed significant cytotoxicities in both HeLa and HT29 colon cancer cells, and cholic acid–NE3TA attached to an organic fluorophore was shown to enter the HT29 cancer cells.

Stable Aziridinium Salts as Versatile Intermediates: Isolation and Regio- and Stereoselective Ring-Opening and Rearrangement

Co-reporter:HyunA. Song;Mamta Dadwal;Yeseul Lee;Emily Mick

Angewandte Chemie 2009 Volume 121( Issue 7) pp:1354-1356

Publication Date(Web):

DOI:10.1002/ange.200805244

Stable Aziridinium Salts as Versatile Intermediates: Isolation and Regio- and Stereoselective Ring-Opening and Rearrangement

Co-reporter:HyunA. Song;Mamta Dadwal;Yeseul Lee;Emily Mick

Angewandte Chemie International Edition 2009 Volume 48( Issue 7) pp:1328-1330

Publication Date(Web):

DOI:10.1002/anie.200805244

Synthesis and Evaluation of Novel Polyaminocarboxylate-Based Antitumor Agents

Co-reporter:Hyun-Soon Chong ; Xiang Ma ; Haisung Lee ; Phuong Bui ; Hyun A. Song ;Noah Birch

Journal of Medicinal Chemistry 2008 Volume 51(Issue 7) pp:2208-2215

Publication Date(Web):March 18, 2008

DOI:10.1021/jm701307j

Iron depletion, using iron chelators targeting transferrin receptor (TfR) and ribonucleotide reductase (RR), is proven to be effective in the treatment of cancer. We synthesized and evaluated novel polyaminocarboxylate-based chelators NETA, NE3TA, and NE3TA-Bn and their bifunctional versions C-NETA, C-NE3TA, and N-NE3TA for use in iron depletion tumor therapy. The cytotoxic activities of the novel polyaminocarboxylates were evaluated in the HeLa and HT29 colon cancer cell lines and compared to the clinically available iron depletion agent DFO and the frequently explored polyaminocarboxylate DTPA. All new chelators except C-NETA displayed enhanced cytotoxicities in both HeLa and HT29 cancer cells compared to DFO and DTPA. Incorporation of the nitro functional unit for conjugation to a targeting moiety into the two potent non-functionalized chelators NE3TA and NE3TA-Bn (C-NE3TA and N-NE3TA) was well-tolerated and resulted in a minimal decrease in cytotoxicity. Cellular uptake of C-NE3TA, examined using a confocal microscope, indicates that the chelator is taken up into HT29 cancer cells.

Novel Bimodal Bifunctional Ligands for Radioimmunotherapy and Targeted MRI

Co-reporter:Hyun-Soon Chong, Hyun A. Song, Xiang Ma, Diane E. Milenic, Erik D. Brady, Sooyoun Lim, Haisung Lee, Kwamena Baidoo, Dengfeng Cheng and Martin W. Brechbiel

Bioconjugate Chemistry 2008 Volume 19(Issue 7) pp:1439

Publication Date(Web):June 20, 2008

DOI:10.1021/bc800050x

The structurally novel bifunctional ligands C-NETA and C-NE3TA, each possessing both acyclic and macrocyclic moieties, were prepared and evaluated as potential chelates for radioimmunotherapy (RIT) and targeted magnetic resonance imaging (MRI). Heptadentate C-NE3TA was fortuitously discovered during the preparation of C-NETA. An optimized synthetic method to C-NETA and C-NE3TA including purification of the polar and tailing reaction intermediates, tert-butyl C-NETA (2) and tert-butyl C-NE3TA (3) using semiprep HPLC was developed. The new Gd(III) complexes of C-NETA and C-NE3TA were prepared as contrast enhancement agents for use in targeted MRI. The T1 relaxivity data indicate that Gd(C-NETA) and Gd(C-NE3TA) possess higher relaxivity than Gd(C-DOTA), a bifunctional version of a commercially available MRI contrast agent; Gd(DOTA). C-NETA and C-NE3TA were radiolabeled with 177Lu, 90Y, 203Pb, 205/6Bi, and 153Gd; and in vitro stability of the radiolabeled corresponding complexes was assessed in human serum. The in vitro studies indicate that the evaluated radiolabeled complexes were stable in serum for 11 days with the exception being the 203Pb complexes of C-NETA and C-NE3TA, which dissociated in serum. C-NETA and C-NE3TA radiolabeled 177Lu, 90Y, or 153Gd complexes were further evaluated for in vivo stability in athymic mice and possess excellent or acceptable in vivo biodistribution profile. 205/6Bi-C-NE3TA exhibited extremely rapid blood clearance and low radioactivity level at the normal organs, while 205/6Bi-C-NETA displayed low radioactivity level in the blood and all of the organs except for the kidney where relatively high renal uptake of radioactivity is observed. C-NETA and C-NE3TA were further modified for conjugation to the monoclonal antibody Trastuzumab.

A novel cholic acid-based contrast enhancement agent for targeted MRI

Co-reporter:Hyun-Soon Chong, Hyun A. Song, Sooyoun Lim, Keith Macrenaris, Xiang Ma, Haisung Lee, Phuong Bui, Thomas Meade

Bioorganic & Medicinal Chemistry Letters 2008 Volume 18(Issue 7) pp:2505-2508

Publication Date(Web):1 April 2008

DOI:10.1016/j.bmcl.2008.01.044

The novel Gd(III) complexes of heptadentate ligands NE3TA and NE3TA-Bn were prepared, and their relaxivities were measured and favorably compared to the commercially available MRI contrast enhancement agent Gd(DOTA). NE3TA was conjugated with cholic acid (CA) to produce CA-NE3TA. TEM images of Gd(CA-NE3TA) indicate that the complex self-assembles forming nano-sized micelles and displays an over threefold increased relaxivity compared to Gd(DOTA). The new cholic acid-conjugated nanoparticle MR contrast enhancement agent, Gd(CA-NE3TA) possesses great promise for use in targeted MRI.

Synthesis and biological evaluation of a novel decadentate ligand DEPA

Co-reporter:Hyun-Soon Chong, Sooyoun Lim, Kwamena E. Baidoo, Diane E. Milenic, Xiang Ma, Fang Jia, Hyun A. Song, Martin W. Brechbiel, Michael R. Lewis

Bioorganic & Medicinal Chemistry Letters 2008 Volume 18(Issue 21) pp:5792-5795

Publication Date(Web):1 November 2008

DOI:10.1016/j.bmcl.2008.09.063

An efficient and short synthetic route to a novel decadentate ligand 7-[2-(bis-carboxymethyl-amino)-ethyl]-4,10-bis-carboxymethyl-1,4,7,10-tetraaza-cyclododec-1-yl-acetic acid (DEPA) with both macrocyclic and acyclic binding moieties is reported. A reproducible and scalable synthetic method to a precursor molecule of DEPA, 1,4,7-tris(tert-butoxycarbonylmethyl)tetraazacyclododecane was developed. DEPA was evaluated as a chelator of 177Lu, 212Bi, and 213Bi for potential use in an antibody-targeted cancer therapy, radioimmunotherapy (RIT) using Arsenazo III based spectroscopic complexation kinetics, in vitro serum stability, and in vivo biodistribution studies.

Novel synthetic ligands for targeted PET imaging and radiotherapy of copper

Co-reporter:Hyun-Soon Chong, Santosh Mhaske, Mai Lin, Sankar Bhuniya, Hyun A. Song, Martin W. Brechbiel, Xiankai Sun

Bioorganic & Medicinal Chemistry Letters 2007 Volume 17(Issue 22) pp:6107-6110

Publication Date(Web):15 November 2007

DOI:10.1016/j.bmcl.2007.09.052

Novel ligands, NBEA, NBPA, NETA, NE3TA, and NE3TA–Bn, were synthesized and evaluated as potential chelators of copper radioisotopes for use in targeted positron emission tomography (PET) imaging or radiation therapy. The new ligands were radiolabeled with 64Cu, and in vitro stability of the radiolabeled complexes was assessed in rat serum. Serum stability results suggest that among the ligands tested, NETA, NE3TA, and NE3TA–Bn form stable complexes with 64Cu.

Synthesis and evaluation of a new bifunctional NETA chelate for molecular targeted radiotherapy using90Y or177Lu

Co-reporter:Chi Soo Kang, Yunwei Chen, Hyunbeom Lee, Dijie Liu, ... Hyun-Soon Chong

Nuclear Medicine and Biology (March 2015) Volume 42(Issue 3) pp:242-249

Publication Date(Web):1 March 2015

DOI:10.1016/j.nucmedbio.2014.10.004

IntroductionTherapeutic potential of β-emitting cytotoxic radionuclides 90Y and 177Lu has been demonstrated in numerous preclinical and clinical trials. A bifunctional chelate that can effectively complex with the radioisotopes is a critical component for molecular targeted radiotherapy 90Y and 177Lu. A new bifunctional chelate 5p-C-NETA with a relatively long alkyl spacer between the chelating backbone and the functional unit for conjugation to a tumor targeting moiety was synthesized. 5p-C-NETA was conjugated to a model targeting moiety, a cyclic Arg-Gly-Asp-D-Tyr-Lys (RGDyK) peptide binding integrin αvβ3 protein overexpressed on various cancers. 5p-C-NETA was conjugated to c(RGDyK) peptide and evaluated for potential use in molecular targeted radiotherapy of 90Y and 177Lu.Methods5p-C-NETA conjugated with c(RGDyK) was evaluated in vitro for radiolabeling, serum stability, binding affinity, and the result of the in vitro studies of 5p-C-NETA-c(RGDyK) was compared to that of 3p-C-NETA-c(RGDyK). 177Lu-5p-C-NETA-c(RGDyK) was further evaluated for in vivo biodistribution using gliobastoma bearing mice.ResultThe new chelate rapidly and tightly bound to a cytotoxic radioisotope for cancer therapy, 90Y or 177Lu with excellent radiolabeling efficiency and maximum specific activity under mild condition (> 99%, RT, < 1 min). 90Y- and 177Lu-radiolabeled complexes of the new chelator remained stable in human serum without any loss of the radiolanthanide for 14 days. Introduction of the tumor targeting RGD moiety to the new chelator made little impact on complexation kinetics and stability with 90Y or 177Lu. 177Lu-radiolabeled 5p-C-NETA-c(RGDyK) conjugate was shown to target tumors in mice and produced a favorable in vivo stability profile.ConclusionThe results of in vitro and in vivo evaluation suggest that 5p-C-NETA is an effective bifunctional chelate of 90Y and 177Lu that can be applied for generation of versatile molecular targeted radiopharmaceuticals.

A highly effective bifunctional ligand for radioimmunotherapy applications

Co-reporter:Hyun-Soon Chong, Hyun A. Song, Chi Soo Kang, Thien Le, Xiang Sun, Mamta Dadwal, Hyunbeom Lee, Xiaoli Lan, Yunwei Chen and Anzhi Dai

Chemical Communications 2011 - vol. 47(Issue 19) pp:NaN5586-5586

Publication Date(Web):2011/04/05

DOI:10.1039/C0CC05707J

Synthetic and theoretical investigation on the one-pot halogenation of β-amino alcohols and nucleophilic ring opening of aziridinium ions

Co-reporter:Yunwei Chen, Xiang Sun, Ningjie Wu, Jingbai Li, Shengnan Jin, Yongliang Zhong, Zirui Liu, Andrey Rogachev and Hyun-Soon Chong

Organic & Biomolecular Chemistry 2016 - vol. 14(Issue 3) pp:NaN939-939

Publication Date(Web):2015/11/26

DOI:10.1039/C5OB01692D

Bile acid-based polyaminocarboxylate conjugates as targeted antitumor agents

Co-reporter:Hyun-Soon Chong, Hyun A. Song, Xiang Ma, Sooyoun Lim, Xiang Sun and Santosh B. Mhaske