Design, Synthesis and Antitumor Activity of Novel Artemisinin Derivatives Using Hybrid Approach

Abstract

Despite cancer chemotherapy has entered a new era of molecularly targeted therapeutics and some forms of cancer have been successfully treated by modern therapies, the successful treatment of cancer remains a significant challenge in the future because chemotherapy is limited by the drug resistance and adverse side effects.1) In order to develop more effective and reliable anticancer agents that circumvent these limitations, the search for novel anti-tumor agents has turned to natural products, in particular plants used in traditional folk medicines. 2)In recent years, artemisinin and its derivatives have been widely studied for their anticancer activities. Some of them showed excellent anti-tumor activity toward different cancer cell lines in vitro. [3][4][5][6][7][8][9] Also, several studies demonstrated that artemisinin analogues were effective to many drug-and radiation-resistant cancer cell lines due to their multiple mechanisms. 10,11) The main mode likely involves a similar metalinduced free-radical formation leading to induce apoptosis in cancer cells and inhibit the tumor angiogenesis. [12][13][14][15][16] Recently, considerable attention has been focused on chalcones, which are a class of privileged structures that are easily prepared and have a wide range of biological properties, [17][18][19][20][21] which makes them an attractive pharmacophoric scaffold. An area of particular interest is their potential as antitumor agents, for which several modes of action have been proposed. The key mechanism is the inhibition of tubulin polymerization, while also including the inhibition of angiogenesis and the induction of apoptosis. [22][23][24] Chalcones and artemisinin analogues represent two classes of natural products, whose antitumor effects appear to be consistent via different molecular mechanisms. As the application of hybrid strategy to synthesize artemisinin analogues are continuously emerging, 9,25) it is reasonable to combine their structure analogues to form a single molecular framework with a linker, which would allow us to find more potent anti-tumor agents, in which these 'merge' pharmacophore may be addressing the active site of different targets and offering the possibility to overcome drug resistance. Intrigued by these observations, we designed and synthesized two new series of novel artemisinin derivatives by replacement of oxygen at C-10 with nitrogen, in which the substituted chalcone group is bonded to the artemisinin nucleus through an oxyacetyl linkage.Chemistry The synthetic routes of compounds are outlined in Chart 1. Separable diastereomeric mixture of 10b-azidodihydroartemisinin (2) and 10a-azidodihydroartemisinin (3) were obtained by treating 1 with trimethylsilyl chloride, sodium azide and sodium iodide at room temperature for 28 h, according to ref 6. The a and b isomers appeared as two distinct spots on TLC and were separated by column chromatography, with b-isomers as the major products. The reduction of azido compounds (2, 3) with Staudinger reaction afforded the correspondin...

Synthesis and Cytotoxicity of Novel 10-Substituted Dihydroartemisinin Derivatives Containing N-Arylphenyl-ethenesulfonamide Groups

“…So far the majority of the artemisinin derivatizations were carried out on the C-10 acetal and to a lesser extent on the C-13 carbon [8]. The observation that dihydroartemisinin C-10 ester, ether or amide derivatives ( Figure 1) possess significant antitumor activity prompted previous efforts, both within our group [9,10] and by others [11][12][13]. Hybrid drugs are formed by covalently linking two distinct chemical moieties with different biological modes of action with the aim of creating binary therapies with improved biological activity and less susceptible to the development of drug resistance [14,15].…”

Preclinical Efficacy and Safety Assessment of Artemisinin-Chemotherapeutic Agent Conjugates for Ovarian Cancer

“…Recently, increasing attention has been focused on designation and synthesis of new ARS derivatives and on evaluating their antitumor activity (Buragohain et al, 2015, Crespo-Ortiz and Wei, 2012, Njuguna et al, 2012). Several studies demonstrate that ARS related compounds were effective to many types of cancer cell lines and even multiple drug- and radiation-resistant ones due to their multiple mechanisms (Sadava et al, 2002, Xie et al, 2011). As the applications of pharmacophore hybridization strategy to synthesize ARS derivatives are emerging (Sadava et al, 2002, Yang et al, 2009), it is reasonable to combine ARS pharmacophoric scaffold with clinically used chemotherapeutic agents to form a single molecular framework, which would enable us to find more potent antitumor agents.…”

Natural sesquiterpenoids

“…167 The biosynthesis of artemisinin has been reinvestigated using 13 C labelled compounds. 170 The design, synthesis and anti-tumour activity of artemisinin-chalcone hybrids have been described, 171 whilst the discovery of artemisinin-glycolipid hybrids as anti-oral cancer agents has been reported. 169 The asymmetric synthesis of 10-epi-dihydro-epideoxyarteannuin B has been published.…”