Abstract
A series of novel 13- to 15-member hydroxyproline-based macrocycles, which contain alkyl-alkyl ether and alkyl-aryl ether moieties, have been synthesized by the strategy of macrocyclization utilising azide-alkyne cycloaddition, Mitsunobu protocol and amide formation. Their anti-tumor activities towards A549, MDA-MB-231 and Hep G2 cells were screened in vitro by an MTT assay. The results indicated that 13-member macrocycle 33 containing alkene chain showed the best results, exhibiting the highest inhibitory effects towards lung cancer cell line A549, which was higher than that of the reference cisplatin (IC50 value = 2.55 µmol/L).
Highlights
Macrocycles are commonly found in bioactive natural products and used as valuable source of bioactive molecules in drug discovery
Inhibitor K-13 [12,13], piperazinomycin [14,15,16], and serine-based macrocycles representing β-turn mimetics [17,18,19,20]
Some hydroxyproline-based macrocycles have been introduced into important drugs, such as ACE inhibitor zizyphine [21,22,23], alkaloid paliurine E [24], and the echinocandin family including anidulafungin, caspofungin, and micafungin [25,26,27,28]
Summary
Macrocycles are commonly found in bioactive natural products and used as valuable source of bioactive molecules in drug discovery They can demonstrate drug-like physicochemical and pharmacokinetic properties such as good solubility, lipophilicity, metabolite stability and bioavailability [1,2]. Macrocyclic structures could provide a compromise between structural pre-organization and sufficient flexibility to mould to a target protein surface and maximize binding interactions [3]. They have a favorable impact on other essential properties required for drugs, such as membrane permeability, metabolic stability, increased potencies, better receptor selectivity and overall pharmacokinetics [4,5,6,7]. HCV NS3 protease inhibitors vaniprevir (MK-7009) [29,30], ITMN-191 [31], and BILN 2601 [32] were advanced into clinical development
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