Glycosylated platinum(iv) prodrugs demonstrated significant therapeutic efficacy in cancer cells and minimized side-effects

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.

Protected and De-protected Platinum(IV) Glycoconjugates With GLUT1 and OCT2-Mediated Selective Cancer Targeting: Demonstrated Enhanced Transporter-Mediated Cytotoxic Properties in vitro and in vivo

“…Due to the special inertia of platinum(IV) complexes, unwanted side reactions with biological nucleophiles are resisted to reduce undesired side effects and to increase the lifetime in biological fluids. We have reported the glycoconjugation of platinum(II) and platinum(IV) prodrugs (Chen et al, 1999 ; Ma et al, 2016 , 2017a , b ; Wang et al, 2016 ). However, in the following experiments, we found that there is a slight dependency between the transporters and the reported compounds 1-8 (Figure 1 ) (Ma et al, 2017a ).…”

Antitumor platinum(IV) derivatives of carboplatin and the histone deacetylase inhibitor 4-phenylbutyric acid

“…1). Furthermore, phosphatase 2A inhibitors [8], the vitamin E analog α-tocopheryl succinate [9], carbohydrates [10,11], nucleotide excision repair inhibitors [12], alkylating agents [13] as well as redox modulators [14] have been attached to the cisplatin and oxaliplatin scaffold.…”

Current Developments in Pt(IV) Prodrugs Conjugated with Bioactive Ligands

“…It has been reported that novel glycosylated Pt(II) agents showed obviously reduced toxicity and enhanced antitumor activity. Recently, several glycosylated Pt(IV) prodrugs have been synthesized and explored for their bioactivity [ 115 – 117 ]. These glycosylated Pt(IV) complexes ( Figure 19( 70 – 73 ) ), with various sugars (glucose, mannose, galactose, or rhamnose) conjugated to a platinum core (cisplatin or oxaliplatin), were found to be comparable or even superior to cisplatin or oxaliplatin.…”