Synthesis and evaluation of a radioiodinated 4,6-diaryl-3-cyano-2-pyridinone derivative as a survivin targeting SPECT probe for tumor imaging

Fuchigami, Takeshi; Mizoguchi, Tatsuya; Ishikawa, Natsumi; Haratake, Mamoru; Yoshida, Sakura; Magata, Yasuhiro; Nakayama, Morio

doi:10.1016/j.bmcl.2015.12.046

Cited by 9 publications

(8 citation statements)

References 18 publications

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“…These INC [16][17][18][19][20][21][22] derivatives also showed saturation and fitted well with the one binding site model ( Figure S1G-I). Both INC [15][16][17][18][19][20][21][22] and INC [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] , which have longer sequences than INC [16][17][18][19][20][21][22] , showed moderate binding affinities (K d = 248 and 160 nmol L −1 , respectively), as shown in Table 2.…”

Section: Synthesis and Binding Affinity Assessment Of Inc 16-22 Dermentioning

confidence: 99%

“…[27][28][29][30] For cancer-specific diagnosis, we have recently reported several radioiodinated small molecules targeting the survivin dimer site as nuclear medicine imaging agents; however, these agents have limitations, such as the lack of in vivo pharmacokinetics and specificity. 31,32 Survivin contains a single N-terminal baculovirus IAP repeat domain linked to a long C-terminal α-helix coiled domain. 33 In solution, purified survivin exists in a bow tie-shaped dimerization form.…”

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Discovery of inner centromere protein‐derived small peptides for cancer imaging and treatment targeting survivin

et al. 2020

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Survivin belongs to the inhibitor of apoptosis protein family, which is consistently overexpressed in most cancer cells but rarely expressed in normal adult tissues. Therefore, the detection and inhibition of survivin are regarded as attractive strategies for cancer-specific treatment. In this study, we designed and synthesized 7-19 residues of inner centromere protein (INCENP)-derived small peptides (INC peptides) as novel survivin-targeting agents. The INC peptides showed binding affinity for the human survivin protein (K d = 91.4-255 nmol L −1 ); INC 16-22 , which contains residues 16-22 of INCENP, showed the highest affinity (91.4 nmol L −1 ). Confocal fluorescence imaging showed consistent colocalization of FITC-INC 16-22 and survivin in cell lines. Nona-arginine-linked INC 16-22 (r9-INC 16-22 ) rendered INC 16-22 cells penetrable and strongly inhibited cell growth of MIA PaCa-2 cells (52% inhibition at 1.0 µmol L −1 ) and MDA-MB-231 cells (60% inhibition at 10 µmol L −1 ) as determined by MTT assays. The exposure of MIA PaCa-2 cells to 40 µmol L −1 r9-INC 16-22 apparently reduced the intracellular protein expression levels of survivin. However, cleaved caspase-3 was significantly increased in cells treated with r9-INC 16-22 , even at 10 µmol L −1 , compared to untreated cells. Flow cytometry revealed that r9-INC 16-22 strongly induced apoptosis in MIA PaCa-2 cells. These results indicate that the cytotoxic effects of r9-INC 16-22 could be mediated mainly through the disruption of survivin-dependent antiapoptotic functions and partly because of the direct degradation of the survivin protein. Our findings suggest that INC peptides can act as useful scaffolds for novel cancer imaging and anticancer agents. K E Y W O R D S anticancer, apoptosis, cancer imaging, peptide, survivin 1 | INTRODUC TI ON Survivin, the smallest protein (16.5 kDa) among the inhibitor of apoptosis protein (IAP) family, is one of the most cancer-specific proteins 1,2 ; it is highly overexpressed in most cancers, but barely detected in the majority of normal cells. 3-6 Survivin is involved in at least 2 essential cellular processes, inhibition of apoptosis and regulation of the cell cycle. 5 Furthermore, it participates in another antiapoptotic effect by S U PP O RTI N G I N FO R M ATI O N Additional supporting information may be found online in the Supporting Information section. How to cite this article: Fuchigami T, Ishikawa N, Nozaki I, et al. Discovery of inner centromere protein-derived small peptides for cancer imaging and treatment targeting survivin.

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Section: Synthesis and Binding Affinity Assessment Of Inc 16-22 Dermentioning

confidence: 99%

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confidence: 99%

Discovery of inner centromere protein‐derived small peptides for cancer imaging and treatment targeting survivin

et al. 2020

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“…). Many pyridone derivatives containing cyano and carboxamide derivatives have been synthesized using novel methods and screened for their potent biological activity . Hence, synthesis of carboxamide and cyano functionalized pyridones has gained much chemical and pharmaceutical importance in recent years.…”

Section: Introductionmentioning

confidence: 99%

An Efficient One‐Pot Synthesis of Highly Substituted Pyridone Derivatives and Their Antimicrobial and Antifungal Activity

Pandit¹,

Savant²,

Ladva³

2018

Journal of Heterocyclic Chem

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A series of carboxamide and cyano functionalized pyridone derivatives 4a-q have been synthesized via one-pot synthesis of various aldehydes 1a-q, acetoacetanilide 2, and cyanoacetamide 3. The reaction was simple and afforded pyridone derivatives in good yield, 89 to 93%. The novel pyridone derivatives were achieved by Hantzch one-pot synthesis. Moreover, the synthesized compounds were screened against Gram-positive and Gram-negative bacteria and fungi for their activity. Among them, compound 4c shows highest inhibition at 4.25 mm against Staphylococcus aureus and 3.75 mm against Escherichia coli Grampositive and Gram-negative bacteria, respectively.

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“…The electrophilic radioiodination of β-CIT was performed using either Chloramine T or Iodo-Gen ® as an oxidizing agent followed by SPE purification according to previous methods [14,15,23,24,25], with some modifications. The precursor TMS-β-CIT was purchased from ABX Advanced Biochemical Compounds GmbH (Radeberg, Germany).…”

Section: Methodsmentioning

confidence: 99%

Comparative Study of Two Oxidizing Agents, Chloramine T and Iodo-Gen®, for the Radiolabeling of β-CIT with Iodine-131: Relevance for Parkinson’s Disease

et al. 2019

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Parkinson’s disease (PD) is a neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta, leading to alteration of the integrity of dopaminergic transporters (DATs). In recent years, some radiopharmaceuticals have been used in the clinic to evaluate the integrity of DATs. These include tropane derivatives such as radiolabeled β-CIT and FP-CIT with iodine-123 (123I), and TRODAT-1 with metastable technetium-99 (99mTc). Radiolabeling of β-CIT with radioactive iodine is based on electrophilic radioiodination using oxidizing agents, such as Chloramine T or Iodo-Gen®. For the first time, the present work performed a comparative study of the radiolabeling of β-CIT with iodine-131 (131I), using either Chloramine T or Iodo-Gen® as oxidizing agents, in order to improve the radiolabeling process of β-CIT and to choose the most advantageous oxidizing agent to be used in nuclear medicine. Both radiolabeling methods were similar and resulted in high radiochemical yield (> 95%), with suitable 131I-β-CIT stability up to 72 h. Although Chloramine T is a strong oxidizing agent, it was as effective as Iodo-Gen® for β-CIT radiolabeling with 131I, with the advantage of briefer reaction time and solubility in aqueous medium.

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Synthesis and evaluation of a radioiodinated 4,6-diaryl-3-cyano-2-pyridinone derivative as a survivin targeting SPECT probe for tumor imaging

Cited by 9 publications

References 18 publications

Discovery of inner centromere protein‐derived small peptides for cancer imaging and treatment targeting survivin

Discovery of inner centromere protein‐derived small peptides for cancer imaging and treatment targeting survivin

An Efficient One‐Pot Synthesis of Highly Substituted Pyridone Derivatives and Their Antimicrobial and Antifungal Activity

Comparative Study of Two Oxidizing Agents, Chloramine T and Iodo-Gen®, for the Radiolabeling of β-CIT with Iodine-131: Relevance for Parkinson’s Disease

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