Abstract
We have synthesized a series of new β-lactam-azide derivatives as orally active anti-tumor agents by targeting tubulin colchicine binding site and examined their structure activity relationship (SAR). Among them, compound 28 exhibited the most potent antiproliferative activity against MGC-803 cells with an IC50 value of 0.106 μM by induction of G2/M arrest and apoptosis and inhibition of the epithelial to mesenchymal transition. 28 acted as a novel inhibitor of tubulin polymerization by its binding to the colchicine site. SAR analysis revealed that a hydrogen atom at the C-3 position of the β-lactam was required for the potent antiproliferative activity of β-lactam-azide derivatives. Oral administration of compound 28 also effectively inhibited MGC-803 xenograft tumor growth in vivo in nude mice without causing significant loss of body weight. These results suggested that compound 28 is a promising orally active anticancer agent with potential for development of further clinical applications.
Highlights
Β-Lactam skeleton has attracted much attention from medicinal chemists for many years because of their numerous biological activities[12,13], especially their antitumor activity[14,15,16]
To explore the effect of a large group or a long chain on the phenyl ring at the C-4 position of the β-lactam, 1,2,3-triazole analogues 29–32 in Fig. 2C as ring-closing products were synthesized through a Huisgen 1,3-dipolar cycloaddition34. β-Lactams-triflones 35–36 were prepared via a Staudinger [2 + 2] cycloaddition of imines with aryl trifly ketene generated in situ from 2-diazo-1-phenyl-2-(trifluoromethylsulfonyl) ethanone 34 by a Wolff rearrangement in satisfactory to good yields from the reported procedure[35]
During the SAR studies, we found that the substitution on the phenyl ring at the C-3 position of the β-lactam was important for the activity showing over 8-fold activity loss against the growth of MGC-803 cells, when the hydrogen atom (18) was replaced with the methoxy group (19). β-Lactam-azide derivatives 12–16 and 21–22 without 3,4,5-trimethoxyphenyl group at the N-1 position of the β-lactam displayed relatively lower antiproliferative activity (IC50 > 20 μM) toward three cancer cell lines, indicating that the 3,4,5-trimethoxyphenyl group at the N-1 position was crucial for their antiproliferative activity
Summary
Oral administration of compound 28 effectively inhibited MGC-803 xenograft tumor growth in vivo in nude mice without causing significant loss of body weight These results suggested that compound 28 is a promising orally active anticancer agent with potential for development of further clinical applications. 3′-(4-Azidophenyl)-3′-dephenylpaclitaxel 3 (Fig. 1A) was developed as a novel paclitaxel photoaffinity probe and shown to be as active as paclitaxel in tubulin assembly and cytotoxicity assays[29] These intriguing findings and our continuous quest to identify more potent antitumor candidates[30,31,32] led us to design novel β-lactam and azide hybrids. The detailed structure activity relationships in five regions of β-lactam-azides were explored (Fig. 1B) to provide further insight for developing more efficient tubulin targeting and antiproliferative agents for cancer therapy
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