Synthesis, Characterization And Biological Study Of New Crown Ether Prodrugs As Anticancer Agents

Abstract

In the present work,new Schiff’s bases prodrugs 4,4`-di[9-(2-hydroxyethoxy) methyl]-2-(methylidene amino)-1,9-dihydro-6H-purin-6-one- [6,7,9,10,17,18,20,21]- Octa hydro- [b, k] dibenzo [1,4,7,10,13,16] hexaoxacyclooctadecine, 4,4`-di-1-[3,4-dihydroxy-5-(hydroxymethyl) oxolan-2-yl]-4-[(E)-ethylideneamino] pyrimidin-2(1H)-one- [6,7,9,10,17,18,20,21]- Octa hydro- [b, k] dibenzo [1,4,7,10, 13, 16] hexaoxacyclooctadecine and 4,4`-di-5-[2-chloro-6-(methylideneamino)-9H-purin-9-yl]-2-(hydroxymethyl) oxolan-3-ol- [6,7,9,10,17,18,20,21]- Octa hydro- [b, k] dibenzo [1,4,7,10,13,16] hexaoxacyclooctadecine were designed bynucleophilic addition of primary amines and active carbonyl groups through a condensation reaction. These processes were started from the formylation reaction of dibenzo-18-crown-6-ether then linking of 4,4-diformyldibenzo-18-crown-6 ether with the desired nucleoside analogues(acyclovir, cytarabine and cladribine)to produce the previously mentioned prodrug A1, A2 and A3, respectively. These compounds were designed as carrier-mediated prodrugs to overcome some pharmaceutical and pharmacokinetic problems, improve physicochemical properties and provide structural modifications of the parent drugs to enhance their anticancer activities.The structures of the synthesized compounds were confirmed using UV, FT-IRspectroscopy, mass spectrometry, H1 and C13 NMR spectroscopy and some physiochemical properties. The prepared prodrugs offered high capacity to inhibit the proliferation of cancer cell lines in a concentration-dependent way when compared to the parent drugs.