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Glycosylated platinum(iv) prodrugs demonstrated significant therapeutic efficacy in cancer cells and minimized side-effects.
- Source :
-
Dalton transactions (Cambridge, England : 2003) [Dalton Trans] 2016 Jul 19; Vol. 45 (29), pp. 11830-8. - Publication Year :
- 2016
-
Abstract
- Conjugates (A1-A5) of the Pt(iv) derivative (A6) with amino groups from peracetyl glucose, rhamnose and mannose with a propyl amino or ethyl amino linker at the reducing end were synthesized and exhibited significant therapeutic efficacy in tumour cells, especially for prostate cancer (PCa). The antitumor activities are greatly affected by glycosyl groups. Cytotoxic experiments in vitro indicated that the antitumor activities were increased by 5-fold when its Pt(iv) derivative was conjugated to S18 (IC50 = 4.82 ± 0.45 μM) and by 12-fold when conjugated to S21 (IC50 = 1.9 ± 0.67 μM). The mannose substituted Pt(iv) complexes A4 and A5 were also over an order of magnitude more potent towards HeLa, A549, MCF-7 and PC3 than cisplatin and oxaliplatin. Importantly, the glycosylated Pt(iv) derivatives A4 and A5 displayed potential safety for clinical therapeutic exposure with IC50 of 84 μM and 169 μM compared with cisplatin (IC50 = 8 μM) to 3T3. Cellular uptake and DNA platination are higher than cisplatin and oxaliplatin. ESI-MS analysis of A5 binding to 5'-dGMP revealed that bifunctional DNA lesions were formed. The antitumor activities in vivo showed that the MTD and LD50 for A4 and A5 are nearly 4-fold higher than that of oxaliplatin indicating the potential safety for the glycosylated Pt(iv) complexes.
- Subjects :
- 3T3 Cells
Animals
Cell Line, Tumor
Cell Survival drug effects
DNA metabolism
Glycosylation
Humans
Lethal Dose 50
Maximum Tolerated Dose
Mice
Antineoplastic Agents chemistry
Antineoplastic Agents pharmacology
Antineoplastic Agents therapeutic use
Platinum chemistry
Platinum pharmacology
Platinum therapeutic use
Prodrugs chemistry
Prodrugs pharmacology
Prodrugs therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1477-9234
- Volume :
- 45
- Issue :
- 29
- Database :
- MEDLINE
- Journal :
- Dalton transactions (Cambridge, England : 2003)
- Publication Type :
- Academic Journal
- Accession number :
- 27373800
- Full Text :
- https://doi.org/10.1039/c6dt02207c