Mechanistic and biological characteristics of different sugar conjugated 2-methyl malonatoplatinum(II) complexes as new tumor targeting agents

Gao, Xiangqian; Liu, Shengnan; Shi, Yunli; Huang, Zhenhua; Mi, Yi; Mi, Qian; Yang, Jinna; Gao, Qingzhi

doi:10.1016/j.ejmech.2016.09.047

Cited by 26 publications

(19 citation statements)

References 44 publications

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“…The relatively insignificant increase was observed for 5c, but it still exhibited 108 times increase compared with oxaliplatin. As compared with methyl containing platinum(II) glycoconjugates that we described in our previous research [32], the fluorine containing platinum(II) glycoconjugates exhibited even better water solubility. The most obvious enhancement could be observed from 5b, whose solubility was improved almost 16 times over the methyl substituted complex: (trans- R,R -cyclohexane-1,2-diamine)-2-methylmalonatoplatinum(II)-α-D-mannose conjugate (Man-Me-Pt).…”

Section: Resultsmentioning

confidence: 82%

GLUT1-mediated selective tumor targeting with fluorine containing platinum(II) glycoconjugates

Liu

Zhao

et al. 2017

Oncotarget

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Increased glycolysis and overexpression of glucose transporters (GLUTs) are physiological characteristics of human malignancies. Based on the so-called Warburg effect, 18flurodeoxyglucose-positron emission tomography (FDG-PET) has successfully developed as clinical modality for the diagnosis and staging of many cancers. To leverage this glucose transporter mediated metabolic disparity between normal and malignant cells, in the current report, we focus on the fluorine substituted series of glucose, mannose and galactose-conjugated (trans-R,R-cyclohexane-1,2-diamine)-2-flouromalonato-platinum(II) complexes for a comprehensive evaluation on their selective tumor targeting. Besides highly improved water solubility, these sugar-conjugates presented improved cytotoxicity than oxaliplatin in glucose tranporters (GLUTs) overexpressing cancer cell lines and exhibited no cross-resistance to cisplatin. For the highly water soluble glucose-conjugated complex (5a), two novel in vivo assessments were conducted and the results revealed that 5a was more efficacious at a lower equitoxic dose (70% MTD) than oxaliplatin (100% MTD) in HT29 xenograft model, and it was significantly more potent than oxaliplatin in leukemia-bearing DBA/2 mice as well even at equimolar dose levels (18% vs 90% MTD). GLUT inhibitor mediated cell viability analysis, GLUT1 knockdown cell line-based cytotoxicity evaluation, and platinum accumulation study demonstrated that the cellular uptake of the sugar-conjugates was regulated by GLUT1. The higher intrinsic DNA reactivity of the sugar-conjugates was confirmed by kinetic study of platinum(II)-guanosine adduct formation. The mechanistic origin of the antitumor effect of the fluorine complexes was found to be forming the bifunctional Pt-guanine-guanine (Pt-GG) intrastrand cross-links with DNA. The results provide a rationale for Warburg effect targeted anticancer drug design.

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Section: Resultsmentioning

confidence: 82%

GLUT1-mediated selective tumor targeting with fluorine containing platinum(II) glycoconjugates

Liu

Zhao

et al. 2017

Oncotarget

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“…One major purpose of the present study was to improve the solubility and the toxic profiles of CA4 by leveraging our expertise in drug-glycoconjugation and related technologies. [20][21][22][23] As summarized in Table 2, all three sugar conjugates had markedly increased water solubilities compared with CA4. Conjugation with glucose, mannose, and galactose resulted in a 610-, 1963-, and 853-fold increase in the water solubility of CA4, respectively.…”

Section: Water Solubility Of Ca4 and Its Sugar Conjugatesmentioning

confidence: 97%

Deciphering the origins of molecular toxicity of combretastatin A4 and its glycoconjugates: interactions with major drug transporters and their safety profiles in vitro and in vivo

Huang

Wang

et al. 2017

Med. Chem. Commun.

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Cellular uptake and transport mechanisms directly correlate with the drug-like profiles of lead compounds. To decipher the molecular origin of the toxicity of combretastatin A4 (CA4), an important microtubule targeting agent, we investigated the interactions between CA4 and six key drug transporters, namely hOAT1, hOAT3, hOCT1, hOCT2, hOATP1B3, and hOATP2B1. Three combretastatin-based glycoconjugates, namely ,, and with glucose, mannose, and galactose respectively, were synthesized and their and biological characteristics were evaluated. CA4 exhibited significant inhibition against hOAT3 and hOATP2B1, moderate inhibition of hOAT1 and hOCT2, and weak inhibitory effects on hOCT1 and hOATP1B3. Compared to CA4, the inhibitory activities of on the six transporters were minimal. The glycoconjugates were found to have a superior safety profile with their maximum tolerated dose (MTD) values exhibiting a 16-34-fold increase compared to CA4. Given the drawbacks of CA4, the enhanced solubility and safety profiles of CA4 glycoconjugates augur well for further investigation into these intriguing candidates' efficacy.

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“…In recent years, this histopathological behavior was exploited by a few research groups, in particular those of Gao and Lippard, who conjugated oxaliplatin to functionalized monosaccharides at different positions of the pyranose ring and tested the obtained Pt II complexes for anticancer properties with promising results.…”

Section: Introductionmentioning

confidence: 99%

“…[9][10][11][12] Most neoplastic cells therefore overexpress glucose-transporter proteins,i n particulart hose belonging to the GLUT family,i nt heir cell membrane, and this phenomenon is correlated with poor patient prognosis. [13][14][15] In recent years, this histopathological behavior wase xploited by af ew research groups,i np articular those of Gao [16][17][18][19][20] and Lippard, [21,22] who conjugated oxaliplatin to functionalized monosaccharides at different positions of the pyranose ring and tested the obtained Pt II complexes for anticancer properties with promising results.…”

Section: Introductionmentioning

confidence: 99%

Cu^II and Au^III Complexes with Glycoconjugated Dithiocarbamato Ligands for Potential Applications in Targeted Chemotherapy

et al. 2019

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This work is focused on the synthesis, characterization, and preliminary biological evaluation of bio‐conjugated AuIII and CuII complexes with the aim of overcoming the well‐known side effects of chemotherapy by improving the selective accumulation of an anticancer metal payload in malignant cells. For this purpose, carbohydrates were chosen as targeting agents, exploiting the Warburg effect that accounts for the overexpression of glucose‐transporter proteins (in particular GLUTs) in the phospholipid bilayer of most neoplastic cells. We linked the dithiocarbamato moiety to the C1 position of three different monosaccharides: d‐glucose, d‐galactose, and d‐mannose. Altogether, six complexes with a 1:2 metal‐to‐ligand stoichiometry were synthesized and in vitro tested as anticancer agents. One of them showed high cytotoxic activity toward the HCT116 colorectal human carcinoma cell line, paving the way to future in vivo studies aimed at evaluating the role of carbohydrates in the selective delivery of whole molecules into cancerous cells.

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Mechanistic and biological characteristics of different sugar conjugated 2-methyl malonatoplatinum(II) complexes as new tumor targeting agents

Cited by 26 publications

References 44 publications

GLUT1-mediated selective tumor targeting with fluorine containing platinum(II) glycoconjugates

GLUT1-mediated selective tumor targeting with fluorine containing platinum(II) glycoconjugates

Deciphering the origins of molecular toxicity of combretastatin A4 and its glycoconjugates: interactions with major drug transporters and their safety profiles in vitro and in vivo

Cu^II and Au^III Complexes with Glycoconjugated Dithiocarbamato Ligands for Potential Applications in Targeted Chemotherapy

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Mechanistic and biological characteristics of different sugar conjugated 2-methyl malonatoplatinum(II) complexes as new tumor targeting agents

Cited by 26 publications

References 44 publications

GLUT1-mediated selective tumor targeting with fluorine containing platinum(II) glycoconjugates

GLUT1-mediated selective tumor targeting with fluorine containing platinum(II) glycoconjugates

Deciphering the origins of molecular toxicity of combretastatin A4 and its glycoconjugates: interactions with major drug transporters and their safety profiles in vitro and in vivo

CuII and AuIII Complexes with Glycoconjugated Dithiocarbamato Ligands for Potential Applications in Targeted Chemotherapy

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Product

Resources

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Cu^II and Au^III Complexes with Glycoconjugated Dithiocarbamato Ligands for Potential Applications in Targeted Chemotherapy