Xanthones with various substituents on the three-membered heterocyclic ring skeleton exhibit diverse biological activities, such as antihypertensive, antioxidative, antithrombotic and anticancer activities.
Naturally existing xanthone analogues, including gentiakochianin, α-mangostin and psorospermin, have been identified to possess noticeable anticancer activities. Inspired by these natural xanthones with an excellent anti-proliferative eﬀect, many synthetic xanthones have been
derived from modification of xanthone scffolds. Bisfuranoxanthone, modified from the naturally isolated psorospermin, exhibited comparable anticancer activities to the natural compound. Besides, in consideration of epoxy-tethered natural xanthones, 1,3-bisepoxyxanthone was synthesized as a topoisomerase II inhibitor with significant antiproliferative activity.
Vadimezan was developed from xanthenone-4-acetic acid (XAA), and has been recognized as a xanthone anticancer candidate due to its excellent experimental antitumor activity as a vascular disrupting agent that attacks the blood supply of a cancerous tumor to cause tumor regression. Despite a phase III failure for vadimezan treating advanced non-small cell lung cancer (NSCLC) with carboplatin or paclitaxel, study on vadimezan is continuing. Ching’s group compared the activities of vadimezan analogues in murine or human cellular models to explain why clinical responses to vadimezan 6 were disappointing while the preclinical data were so encouraging, and tried to search for analogues with greater clinical potential for human use.
In this study the author focused on the synthesis, structural characterization and preliminary evaluation of the anticancer properties of a series of new xanthone derivativesmodified from
vadimezan with carboxyl substitution, in an attempt to further explore the therapeutic potential of this tricyclic framework..
Vadimezan was synthesized by coupling the salts of 2-hydroxy-phenylacetic acid with 2-iodo-3,4-dimethylbenzoic acid, which was iodinated from the corresponding aniline with cuprous chloride and tris(2-(2-methoxyethoxy)ethyl)amine (TDA-1) catalysts to give the diacid, followed by concentrated sulfuric acid catalyzed cyclodehydration, with a total yield of approximately 40% and the structure was confirmed by single crystal crystallography.
The esters of vadimezan were obtained in moderate to excellent yields with reactions of vadimezan and the corresponding alcohols catalyzed by diphenylammonium trifiate (DPAT) in refluxing toluene. The application of DPAT included merits from the viewpoint of green chemistry and avoided acylation of vadimezan. In addition, the products could be obtained easily by filtration after precipitation with cooling, thus simplifying the workup procedure.
Amidation of the acetic acid chain of vadimezan was simply achieved by reacting with amines using N,N’-dicyclohexyl-carbodiimide (DCC) and N-hydroxybenzotriazole (HOBt) under mild conditions. The introduction of HOBt in the DCC coupling was beneficial in increasing the yields.
Vadimezan was converted into hydrazide via its ethyl ester by refluxing with excess hydrazine hydrate in ethanol. Condensation of hydrazide with the appropriate arylaldehydes aﬀorded the corresponding arylidene hydrazides 10a–k with E and Z conformations mixed, which could be identified by resonance at diﬀerent frequencies from 1H NMR spectra.
Hydrazide was coupled with the corresponding carboxylic acids to produce diacylhydrazides of vadimezan in the presence of DCC and HOBt under mild conditions. The introduction of HOBt in the DCC coupling was superior to the use of 4-dimethylaminopyridine (DMAP) in increasing the yields of diacylhydrazides. 1,4-Disubstituted thiosemicarbazides were obtained by treating hydrazide with the requisite isothiocyanates.
Shi-Jie Zhang, Zhi-Shan Ding, Fu-Sheng Jiang, Wei-Xiao Hu*. Med. Chem. Commun.,2014, 5,512–520