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Michael R Zalutsky - One of the best experts on this subject based on the ideXlab platform.
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observations on the effects of residualization and dehalogenation on the utility of n succinimidyl ester acylation agents for radioiodination of the internalizing antibody trastuzumab
Molecules, 2019Co-Authors: Satish K Chitneni, Ganesan Vaidyanathan, Eftychia Koumarianou, Michael R ZalutskyAbstract:Trastuzumab is an antibody used for the treatment of human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancers. Since trastuzumab is an internalizing antibody, two factors could play an important role in achieving high uptake and prolonged retention of radioactivity in HER2-positive tumors after radioiodination—residualizing capacity after receptor-mediated internalization and susceptibility to dehalogenation. To evaluate the contribution of these two factors, trastuzumab was radiolabeled using the residualizing reagent N-succinimidyl 4-guanidinomethyl-3-[*I]iodobenzoate ([*I]SGMIB) and the nonresidualizing reagent N-succinimidyl-3-[*I]iodobenzoate ([*I]SIB), both of which are highly dehalogenation-resistant. Paired-label uptake and intracellular retention of [125I]SGMIB-trastuzumab and [131I]SIB-trastuzumab was compared on HER2-expressing BT474 human breast carcinoma cells. Tumor uptake and normal tissue distribution characteristics for the two labeled conjugates were assessed in mice bearing BT474M1 xenografts. The internalization and intracellular retention of initially-bound radioactivity in BT474 cells was similar for the two labeled conjugates up to 4 h, but were significantly higher for [125I]SGMIB-trastuzumab at 6 and 24 h. Similarly, [*I]SGMIB labeling resulted in significantly higher uptake and retention of radioactivity in BT474M1 xenografts at all studied time points. Moreover, tumor-to-tissue ratios for [125I]SGMIB-trastuzumab were consistently higher than those for [131I]SIB-trastuzumab starting at 12 h postinjection. Thus, optimal targeting of HER2-positive breast cancers with a radioiodinated trastuzumab conjugate requires an acylation agent that imparts residualizing capacity in addition to high stability towards dehalogenation in vivo.
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Improved tumor targeting of anti-HER2 nanobody through N-succinimidyl 4guanidinomethyl-3-iodobenzoate radiolabeling. J Nucl Med 2014;55:1-7 . First paper that describes the theranostic potential of radioiodinated nanobodies
2016Co-Authors: Marek Pruszynski, Ganesan Vaidyanathan, Eftychia Koumarianou, Kim H Lyerly, Hilde Revets, Nick Devoogdt, Tony Lahoutte, Michael R ZalutskyAbstract:Nanobodies are approximately 15-kDa proteins based on the smallest functional fragments of naturally occurring heavy chain– only antibodies and represent an attractive platform for the devel-opment of molecularly targeted agents for cancer diagnosis and therapy. Because the human epidermal growth factor receptor type 2 (HER2) is overexpressed in breast and ovarian carcinoma, as well as in othermalignancies,HER2-specificNanobodiesmaybevaluable radiodiagnostics and therapeutics for these diseases. The aim of the present study was to evaluate the tumor-targeting potential of anti-HER2 5F7GGC Nanobody after radioiodination with the residualiz-ing agentN-succinimidyl 4-guanidinomethyl 3-125/131I-iodobenzoate (*I-SGMIB).Methods: The 5F7GGC Nanobody was radiolabeled us-ing *I-SGMIBand, for comparison,withNe-(3-*I-iodobenzoyl)-Lys5-Nα-maleimido-Gly1-GEEEK (*I-IB-Mal-D-GEEEK), another residualizing agent, andbydirect radioiodinationusing IODO-GEN (125I-Nanobody)
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n succinimidyl guanidinomethyl iodobenzoate protein radiohalogenation agents influence of isomeric substitution on radiolabeling and target cell residualization
Nuclear Medicine and Biology, 2014Co-Authors: Jaeyeon Choi, Ganesan Vaidyanathan, Eftychia Koumarianou, Darryl Mcdougald, Marek Pruszynski, Takuya Osada, T Lahoutte, Kim H Lyerly, Michael R ZalutskyAbstract:Abstract Introduction N -succinimidyl 4-guanidinomethyl-3-[ ⁎ I]iodobenzoate ([ ⁎ I]SGMIB) has shown promise for the radioiodination of monoclonal antibodies (mAbs) and other proteins that undergo extensive internalization after receptor binding, enhancing tumor targeting compared to direct electrophilic radioiodination. However, radiochemical yields for [ 131 I]SGMIB synthesis are low, which we hypothesize is due to steric hindrance from the Boc-protected guanidinomethyl group ortho to the tin moiety. To overcome this, we developed the isomeric compound, N -succinimidyl 3-guanidinomethyl-5-[ 131 I]iodobenzoate ( iso -[ 131 I]SGMIB) wherein this bulky group was moved from ortho to meta position. Methods Boc 2 - iso -SGMIB standard and its tin precursor, N -succinimidyl 3-((1,2-bis( tert -butoxycarbonyl)guanidino)methyl)-5-(trimethylstannyl)benzoate (Boc 2 - iso -SGMTB), were synthesized using two disparate routes, and iso -[*I]SGMIB synthesized from the tin precursor. Two HER2-targeted vectors — trastuzumab (Tras) and a nanobody 5F7 (Nb) — were labeled using iso -[ ⁎ I]SGMIB and [ ⁎ I]SGMIB. Paired-label internalization assays in vitro with both proteins, and biodistribution in vivo with trastuzumab, labeled using the two isomeric prosthetic agents were performed. Results When the reactions were performed under identical conditions, radioiodination yields for the synthesis of Boc 2 - iso -[ 131 I]SGMIB were significantly higher than those for Boc 2 -[ 131 I]SGMIB (70.7±2.0% vs 56.5±5.5%). With both Nb and trastuzumab, conjugation efficiency also was higher with iso -[ 131 I]SGMIB than with [ 131 I]SGMIB (Nb, 33.1±7.1% vs 28.9±13.0%; Tras, 45.1±4.5% vs 34.8±10.3%); however, the differences were not statistically significant. Internalization assays performed on BT474 cells with 5F7 Nb indicated similar residualizing capacity over 6h; however, at 24h, radioactivity retained intracellularly for iso -[ 131 I]SGMIB-Nb was lower than for [ 125 I]SGMIB-Nb (46.4±1.3% vs 56.5±2.5%); similar results were obtained using Tras. Likewise, a paired-label biodistribution of Tras labeled using iso -[ 125 I]SGMIB and [ 131 I]SGMIB indicated an up to 22% tumor uptake advantage at later time points for [ 131 I]SGMIB-Tras. Conclusion Given the higher labeling efficiency obtained with iso -SGMIB, this residualizing agent might be of value for use with shorter half-life radiohalogens.
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Synthesis of N-succinimidyl 4-guanidinomethyl-3-[^*I]iodobenzoate: a radio-iodination agent for labeling internalizing proteins and peptides
Nature Protocols, 2007Co-Authors: Ganesan Vaidyanathan, Michael R ZalutskyAbstract:This protocol describes a detailed procedure for the synthesis of N -succinimidyl 4-guanidinomethyl-3-[^*I]iodobenzoate ([^*I]SGMIB), an agent useful in the radio-iodination of proteins, including monoclonal Abs, and peptides that undergo internalization after receptor or antigen binding. In this procedure, the tin precursor N -succinimidyl 4-[ N ^1, N ^2-bis( tert -butyloxycarbonyl)guanidinomethyl]-3-(trimethylstannyl)benzoate (Boc-SGMTB, 3) was first radio-iodinated to [^*I]Boc-SGMIB, a derivative of [^*I]SGMIB with the guanidine function protected with Boc groups. Treatment of [^*I]Boc-SGMIB with trifluoroacetic acid delivered the final product. The total time for the synthesis and purification of [^*I]Boc-SGMIB and its subsequent de-protection is approximately 140 min.
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radioiodination of internalizing monoclonal antibodies using n succinimidyl 5 iodo 3 pyridinecarboxylate
Cancer Research, 1996Co-Authors: Craig J Reist, Pradeep K. Garg, Kevin L Alston, Darell D Bigner, Michael R ZalutskyAbstract:Abstract Monoclonal antibodies (mAbs) that internalize following binding to cell-surface receptors require radiolabeling approaches that minimize loss of radioactivity from the cell after intracellular processing. One class of internalizing mAbs of great interest for imaging and radioimmunotherapy are those specific for EGFRvIII, a truncated form of the epidermal growth factor receptor found on gliomas, non-small cell lung carcinomas, breast carcinomas, and ovarian carcinomas. Because lysosomes are known to retain positively charged compounds, N-succinimidyl 5-iodo-3-pyridinecarboxylate (SIPC) might be ideal for radioiodination of these mAbs because of the positive charge on its pyridine ring. To investigate this hypothesis, the anti-EGFRvIII mAb L8A4 was labeled using SIPC, and internalization assays were performed using the EGFRvIII-positive cell lines HC2 20 d2 and NR6M. Compared with L8A4 labeled using Iodogen or N-succinimidyl 3-iodobenzoate, SIPC increased intracellular retention of activity by up to 65%. Reverse-phase high-performance liquid chromatography analyses indicated that a significantly higher fraction of the low molecular weight catabolites from mAbs labeled via SIPC were retained within cells (SIPC, 28.1%; Iodogen, 7.6% at 1 h). With SIPC, the primary labeled species in cell lysates was the 5-iodonicotinic acid (INA)-lysine conjugate, whereas in the supernatant, both INA-lysine and INA were seen. A 3–4-fold higher percentage of these catabolites were charged at lysosomal pH in comparison with those from mAb labeled using N-succinimidyl 3-iodobenzoate, in concert with the differences in cellular retention observed between these two labeling methods. In mice bearing HC2 20 d2 xenografts, a significant improvement in tumor retention of radioiodine and tumor:normal tissue ratios was seen when L8A4 was labeled using SIPC instead of the Iodogen method. These results suggest that SIPC is a promising reagent for the radioiodination of anti-EGFRvIII L8A4 and, possibly, other internalizing mAbs.
Michael D Threadgill - One of the best experts on this subject based on the ideXlab platform.
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5 nitroisocoumarins from tandem castro stephens coupling 6 endo dig cyclisation of 2 iodo 3 nitrobenzoic acid and arylethynes and ring closure of methyl 2 alkynyl 3 nitrobenzoates with electrophiles
Tetrahedron, 2006Co-Authors: Esther C Y Woon, Archana Dhami, Mary F Mahon, Michael D ThreadgillAbstract:Abstract Reaction of 2-iodo-3-nitrobenzoic acid with arylalkynyl copper(I) reagent gave 3-aryl-5-nitroisocoumarins. Castro–Stephens coupling was followed by in situ Cu-catalysed ring-closure. 1H NMR and X-ray crystallography showed the cyclisations to be 6-endo, contrasting with reports of 5-exo cyclisation of analogous 2-Iodobenzoate esters with alkynes. Sonogashira couplings of methyl 2-iodo-3-nitrobenzoate with phenylacetylene and with trimethylsilylacetylene gave the corresponding 2-alkynyl-3-nitrobenzoate esters. With HgSO4, the phenylalkyne underwent 6-endo cyclisation to give 5-nitro-3-phenylisocoumarin. The disubstituted alkyne esters gave 4-phenylselenylisocoumarins with PhSeCl. 5-Nitro-3-phenyl-4-phenylselenylisocoumarin shows significant sterically-driven distortion of the isocoumarin ring. Reaction of methyl 3-nitro-2-phenylethynylbenzoate with ICl gave the 4-iodoisocoumarin. Thus the nitro group tends to direct these electrophile-driven cyclisations towards the 6-endo mode.
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5-Nitroisocoumarins from tandem Castro–Stephens coupling—6-endo-dig cyclisation of 2-iodo-3-nitrobenzoic acid and arylethynes and ring-closure of methyl 2-alkynyl-3-nitrobenzoates with electrophiles
Tetrahedron, 2006Co-Authors: Esther C Y Woon, Archana Dhami, Mary F Mahon, Michael D ThreadgillAbstract:Abstract Reaction of 2-iodo-3-nitrobenzoic acid with arylalkynyl copper(I) reagent gave 3-aryl-5-nitroisocoumarins. Castro–Stephens coupling was followed by in situ Cu-catalysed ring-closure. 1H NMR and X-ray crystallography showed the cyclisations to be 6-endo, contrasting with reports of 5-exo cyclisation of analogous 2-Iodobenzoate esters with alkynes. Sonogashira couplings of methyl 2-iodo-3-nitrobenzoate with phenylacetylene and with trimethylsilylacetylene gave the corresponding 2-alkynyl-3-nitrobenzoate esters. With HgSO4, the phenylalkyne underwent 6-endo cyclisation to give 5-nitro-3-phenylisocoumarin. The disubstituted alkyne esters gave 4-phenylselenylisocoumarins with PhSeCl. 5-Nitro-3-phenyl-4-phenylselenylisocoumarin shows significant sterically-driven distortion of the isocoumarin ring. Reaction of methyl 3-nitro-2-phenylethynylbenzoate with ICl gave the 4-iodoisocoumarin. Thus the nitro group tends to direct these electrophile-driven cyclisations towards the 6-endo mode.
Chien-hong Cheng - One of the best experts on this subject based on the ideXlab platform.
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Palladium-Catalyzed C-H Activation and Cyclization of Anilides with 2-Iodoacetates and 2-Iodobenzoates: An Efficient Method Toward Oxindoles and Phenanthridones.
ChemInform, 2016Co-Authors: Parthasarathy Gandeepan, Pachaiyappan Rajamalli, Chien-hong ChengAbstract:A concise approach to the synthesis of oxindoles and phenanthridones from anilides is described. In the presence of catalytic amount of Pd(OAc) 2 , 2-iodoacetates and 2-Iodobenzoates can be used to functionalize ortho C–H bond of anilides, which subsequently undergo intramolecular cyclization to give the products. A possible reaction mechanism that involves a Pd II /Pd IV catalytic cycle is proposed with the support of detailed mechanistic studies.
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Palladium-Catalyzed C–H Activation and Cyclization of Anilides with 2-Iodoacetates and 2-Iodobenzoates: An Efficient Method toward Oxindoles and Phenanthridones
Synthesis, 2016Co-Authors: Parthasarathy Gandeepan, Pachaiyappan Rajamalli, Chien-hong ChengAbstract:A concise approach to the synthesis of oxindoles and phenanthridones from anilides is described. In the presence of catalytic amount of Pd(OAc) 2 , 2-iodoacetates and 2-Iodobenzoates can be used to functionalize ortho C–H bond of anilides, which subsequently undergo intramolecular cyclization to give the products. A possible reaction mechanism that involves a Pd II /Pd IV catalytic cycle is proposed with the support of detailed mechanistic studies.
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Highly Efficient Cyclization of o‐Iodobenzoates with Aldehydes Catalyzed by Cobalt Bidentate Phosphine Complexes: A Novel Entry to Chiral Phthalides
Chemistry (Weinheim an der Bergstrasse Germany), 2007Co-Authors: Hong-tai Chang, Masilamani Jeganmohan, Chien-hong ChengAbstract:Methyl 2-Iodobenzoates 1 a-c undergo cyclization reactions with various aromatic aldehydes 2 a-m (RC6H4CHO: R=H 2 a, 4-CH3 2 b, 4-tBu 2 c, 4-OMe 2 d, 3-OMe 2 e, 4-Cl 2 f, 4-CF3 2 g, 4-CN 2 h, 4-Ph 2 i; benzo[d][1,3]dioxole-5-carbaldehyde (2 j), 1-napthaldehyde (2 k), benzofuran-2-carbaldehyde (2 l), and isonicotinaldehyde (2 m)) in the presence of [CoI2(dppe)] (dppe=1,2-bis(diphenylphosphino)ethane) and Zn powder in dry THF at 75 degrees C for 24 h to give the corresponding phthalide derivatives 3 a-m and 3 q-t in good to excellent yields. Under similar reaction conditions, less reactive aliphatic aldehydes, heptanal (2 n), butyraldehyde (2 o), and 2-phenylacetaldehyde (2 p) also underwent cyclization reactions with 1 a to provide 3 n-p, respectively, in fair to good yields. The catalytic reaction can be further extended to cinnamyl aldehyde (2 q) with 1 a to give the corresponding phthalide derivative 3 u. This synthetic method is compatible with a variety of functional groups on the aryl ring of 2. The high efficiency of the cobalt catalyst containing a dppe (dppe=1,2-bis(diphenylphosphino)ethane) ligand encouraged us to investigate the asymmetric version of the present catalytic reaction by employing bidentate chiral ligands. Thus, aromatic aldehydes 2 a-c, 2 f, and 2 g undergo cyclization with 2-Iodobenzoate (1 a) smoothly in the presence of [CoI2{(S,S)-dipamp}] ((S,S)-dipamp=(1S,2S)-(+)-bis[2-methoxyphenyl]phenylphosphino)ethane) and zinc powder in THF at 75 degrees C for 24 h, giving the corresponding (S)-phthalides 4 a-e in 81-89% yields with 70-98% ee. A possible mechanism for the present catalytic reaction is proposed.
Tuncer H& - One of the best experts on this subject based on the ideXlab platform.
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catena-Poly[[aqua(2-iodobenzoato-κO)cobalt(II)]-μ-aqua-μ-2-iodobenzoato-κ2O:O′]
International Union of Crystallography, 2012Co-Authors: Nagihan &, Hacali Necefo&, Tuncer H&Abstract:The asymmetric unit of the polymeric title compound, [Co(C7H4IO2)2(H2O)2]n, contains one CoII cation, two iodobenzoate anions and two water molecules. One iodobenzoate anion and one water molecule bridge adjacent Co cations, forming a polymeric chain running along the a axis, while the other iodobenzoate anion and water molecule coordinate in a monodentate manner to the CoII cation, completing the slightly distorted octahedral geometry. In the two independent anionic ligands, the carboxylate groups are twisted away from the attached benzene rings by 51.38 (18) and 39.89 (11)°, and the two benzene rings are nearly perpendicular to each other with a dihedral angle of 86.09 (10)°. Intramolecular O—H...O hydrogen bonds between coordinating water molecules and adjacent carboxylate O atoms help to stabilize the molecular structure. In the crystal, weak C—H...O hydrogen bonds link the polymeric chains into a three-dimentional supramolecular network
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Tetrakis(μ-2-iodobenzoato-κ2O:O′)bis[aquacopper(II)]
International Union of Crystallography, 2012Co-Authors: Nagihan &, Hacali Necefo&, Tuncer H&Abstract:In the centrosymmetric binuclear title complex, [Cu2(C7H4IO2)4(H2O)2], the two CuII ions [Cu...Cu = 2.6009 (5) Å] are bridged by four 2-Iodobenzoate (IB) ligands. The four nearest O atoms around each CuII ion form a distorted square-planar arrangement, the distorted square-pyramidal coordination being completed by the O atom of the water molecule at a distance of 2.1525 (16) Å. The dihedral angle between the benzene ring and the carboxylate group is 25.67 (13)° in one of the independent IB ligands and 6.44 (11)° in the other. The benzene rings of the two independent IB ligands are oriented at a dihedral angle of 86.61 (7)°. In the crystal, O—H...O interactions link the molecules into a two-dimensional network. π–π contacts between the benzene rings [centroid–centroid distances = 3.810 (2) and 3.838 (2) Å] may further stabilize the structure
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Diaquabis(2-iodobenzoato-κO)bis(nicotinamide-κN1)copper(II)
International Union of Crystallography, 2012Co-Authors: Nagihan &, Hacali Necefo&, Tuncer H&Abstract:In the title complex, [Cu(C7H4IO2)2(C6H6N2O)2(H2O)2], the CuII cation is located on an inversion center and is coordinated by two monodentate 2-Iodobenzoate (IB) anions, two nicotinamide (NA) ligands and two water molecules in a distorted octahedral coordination geometry. The dihedral angle between the carboxylate group and the adjacent benzene ring is 32.12 (14)°, while the pyridine ring and the benzene ring are oriented at a dihedral angle of 82.02 (5)°. The coordinating water molecule links with the carboxylate group via an intramolecular O—H...O hydrogen bond. In the crystal, N—H...O, O—H...O and weak C—H...O hydrogen bonds link the molecules into a three-dimensional supramolecular network
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Diaquabis(2-iodobenzoato-κO)bis(nicotinamide-κN1)cobalt(II)
International Union of Crystallography, 2012Co-Authors: Nagihan &, Hacali Necefo&, Tuncer H&Abstract:In the title complex, [Co(C7H4IO2)2(C6H6N2O)2(H2O)2], the CoII cation is located on an inversion center and is coordinated by two monodentate 2-Iodobenzoate (IB) anions, two nicotinamide (NA) ligands and two water molecules. The four O atoms in the equatorial plane around the CoII cation form a slightly distorted square-planar arrangement, while the slightly distorted octahedral coordination is completed by the two N atoms of the NA ligands in the axial positions. The dihedral angle between the carboxylate group and the adjacent benzene ring is 22.3 (3)°, while the pyridine ring and the benzene ring are oriented at a dihedral angle of 84.59 (13)°. Intramolecular O—H...O hydrogen bonding occurs between the carboxylate group and coordinated water molecule. In the crystal, N—H...O, O—H...O and weak C—H...O hydrogen bonds link the molecules into a three-dimensional supramolecular network
Jerome Waser - One of the best experts on this subject based on the ideXlab platform.
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Access to Vinyl Ethers and Ketones with Hypervalent Iodine Reagents as Oxy‐Allyl Cation Synthetic Equivalents
Angewandte Chemie (International ed. in English), 2020Co-Authors: Nina Declas, Jerome WaserAbstract:We report an Umpolung strategy of enol ethers to generate oxy-allyl cation equivalents based on the use of hypervalent iodine reagents. Under mild basic conditions, the addition of nucleophiles to aryloxy-substituted vinylbenziodoxolone (VBX) reagents, easily available in two steps from silyl alkynes, resulted in the stereoselective formation of substituted aryl enol ethers. The reaction was most efficient with phenols as nucleophiles, but preliminary results were also achieved for C- and N- nucleophiles. In absence of external nucleophiles, the 2-Iodobenzoate group of the reagent was transferred. The obtained aryl enol ethers could then be transformed into α-difunctionalized ketones by oxidation. The described "allyl cation"-like reactivity contrast with the well-established "vinyl-cation" behavior of alkenyl iodonium salts.
