Abstract:
:A series of novel α-l-threose nucleoside phosphonate analogs, 4(R)-methyl-3-O-phosphonomethyl-α-l-threose nucleosides, were synthesized in multistep sequences starting from d-xylose. The synthetic sequence consisted of the following key stages: (i) the multistep synthesis of 1,2-O-isopropylidenyl-4(R)-methyl-3-O-phosphonomethyl-l-threose, (ii) the transformation of 1,2-O-isopropylidenyl sugar into suitable 1,2-di-O-acyl l-threose precursor, and (iii) the construction of target α-l-threose nucleoside phosphonate analogs by Vorbrüggen glycosidation reaction, deprotection of acyl group, and hydrolysis of diethyl group on phosphonate. The target nucleoside phosphonates were evaluated for their antitumour activities in cell culture-based assays. Compound 8g, 2-fluroadenosine phosphonate, showed remarkable activity against human breast cancer cell lines (MCF-7 and MDA-MB-231) with IC50 values of 0.476 and 0.391 μM, corresponding to 41- and 47-fold higher potency than the reference compound 5-FU, respectively. Subsequent investigations found that the compound 8g can inhibit the proliferation of breast cancer cells and cell cloning. The mechanistic studies indicated that compound 8g could cause DNA damage to breast cancer cells through the ATM-Chk1/Chk2-cdc25c pathway, leading to blockage of the G2/M phase cycle of breast cancer cells, which ultimately led to apoptosis. Moreover, 8g could inhibit the PI3K/AKT signaling pathway and induce apoptosis. These results indicate that compound 8g holds promising potential as an antitumour agent.
journal_name
Eur J Med Chemjournal_title
European journal of medicinal chemistryauthors
Liu FW,Ji S,Gao Y,Meng Y,Xu W,Wang H,Yang J,Huang H,Herdewijn P,Wang Cdoi
10.1016/j.ejmech.2021.113513keywords:
["Antitumour activity","Mechanistic investigations","d-xylose","α-l-threose nucleoside phosphonate analogs"]subject
Has Abstractpub_date
2021-10-05 00:00:00pages
113513eissn
0223-5234issn
1768-3254pii
S0223-5234(21)00362-7journal_volume
221pub_type
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