Combretastatin preparation

Davies et al. describe the preparation of both oxazole- and thiazole-containing derivatives of combretastatin. By formation of the ketoamide intermediate 60, in a 54% yield (Scheme 14), both classes of compounds may be obtained by altering the last step of the reaction [58]. To produce the oxazole 61 a cyclo-dehydration reaction was performed using triphenylphosphine-iodine-triethylamine, and the thiazole compound 62 was formed by thiona-tion using Lawesson s reagent, with an excellent yield (94%). 

Methoxy indole-containing combretastatin derivatives, (I), and prodrugs, (II), prepared by Pinney (2) were found effective as antimitotic and antitubulin polymerization agents and used in the selective destruction of tumor cell vasculature. 

Pettit (3) prepared water-soluble, trans-isomer derivatives, (III), of combretastatin A-4, which were used in the treatment of neoplastic diseases. 

Pettit (6) prepared phenstatin, (VII), and prodrug derivatives, (VIII), which were more effective tubulin polymerization inhibitors than colchicine and more effective as tubulin binder inhibitors than combretastatin. 

The combretastatins are a group of antimitotic agents isolated from the bark of the South African tree Combretum caffrum. A novel and highly stereoselective total synthesis of both the c/s and trans isomers of combretastatin A-4 was developed by J.A. Hadfield and co-workers.The (Z)-stereoisomer was prepared using the Perkin reaction as the key step in which 3,4,5-trimethoxyphenylacetic acid and 3-hydroxy-4-methoxbenzaldehyde was heated with triethylamine and acetic anhydride at reflux for several hours. The a,p-unsaturated acid was isolated in good yield after acidification and had the expected ( ) stereochemistry. Decarboxylation of this acid was effected by heating it with copper powder in quinoline to afford the natural product (Z)-combretastatin A-4. 

A series of arylbenzyl ethers and arylbenzylamines based on combretastatin A-4 was prepared and evaluated for anticancer activity against the K562 human chronic myelogenous leukaemia cell line [39]. Among them, the two benzyl ethers 62 and 64, which have the two aryl groups separated by two atoms, thereby mimicking more closely the arrangement present in Combretastatin A-4 were prepared (Schemes 15 and 16). 

A series of diarylamines and diaryl ethers based on combretastatin A-4 was prepared, via coupling of a benzyl protected phenol or aniline, and evaluated for anticancer activity [39]. The target ether 66 was prepared via the new copper-catalyzed Ullmann-type coupling recently described by Buchwald and co-workers (Scheme 17). 

The combretastatin A-4 diaryl aniline analogue 67 was prepared in a similar manner via Pd(II)-catalyzed coupling of 3,4,5-trimethoxy bromobenzene and a benzyl-protected aniline using another of the Buchwald protocols (Scheme 18). 

Ophthalmic preparation containing combretastatin A-4 for treating diabetic retinopathy was patented [111]. The ophthalmic preparation was composed of combretastatin A-4 and other auxiliary materials acceptable for treating eye diseases. The authors claimed the preparation could be used as eye drop, ointment, and gel for treating diabetic retinopathy by inhibiting angiogenesis in a dose-dependent manner without affecting the development of retina vascular system. 

Lion and colleagues prepared 5,6,7-trimethoxyindole for a molecular mimic of combretastatin [30], and indole 21 became the indole unit in rapalexin B in a synthesis of this cruciferous phytoalexin by Pedras and colleagues [31], Indole 22 was needed for a biosynthetic study of the paraherquamide natural products [32], and Corey s team employed 6,7-dimethoxyindole (16) (71%) in their synthesis of aspidophytine [33]. 

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