Y

Imidazole I LESS activel

Figure 32 Pyridopyrazine SAR.

colchicine binding site.169 This molecule is orally active with good dose-dependent bioavailability and is currently undergoing both phase I and phase II clinical trials for nonsmall-cell lung, breast, and colorectal cancers.170

Further modification of this scaffold resulted in a group of N-(7-indole)-1,4-benzenesulfonamides, which inhibited cell cycle at the G1 phase and did not inhibit tubulin polymerization.171 One of these compounds (E7070) is currently in phase II trials. A pentafluorophenylsulfonamide (T138067) 73 has been reported to bind irreversibly to the Cys-239 of tubulin, which is found in the colchicine-binding site.172 It is thought that sulfhydryl group displaces the 4-fluoro group of the pentafluorophenyl ring. The molecule has undergone a phase II trial.

Since the beginning of the 1980s, carbamates of aromatic aminoaryl compounds have been reported to possess antimitotic activity. The pyridopyrazine core of NSC-330770 has been the subject of an SAR study in which the phenyl group at the 2-position was varied along with the substituent at the 3-position (Figure 32).173 It was found that the electron-donating groups on the aryl ring maintained or improved activity, while bulky groups diminished potency. The introduction of an alkyl group at the 2-position was generally beneficial. The pyrazinyl ring is significantly superior to the imidazole ring: this is thought to be due to the better positioning of the aromatic ring for binding (Figure 33).174

A set of aromatic ureas have also been shown to bind tubulin at the colchicine site. Molecules containing an N-(2-chloroethyl)urea were shown to bind covalently to tubulin thought to be through reaction of the Cys-239. Further structural modification is needed to improve the activity of these molecules; however, they represent another class of compounds that are able to bind tubulin. The most clinically advanced members of this class are nocadazole 74, NSC-330770 75, and tubulozole 76, all of which have been shown to inhibit tubulin polymerization by binding competitively with colchicine. Nocadozole and tubazole and the more water-soluble erbulozole 77 have undergone clinical evaluation, without reaching the market. Erbulozole showed acute central nervous system toxicity with symptoms similar to Wernicke's syndrome.176

The chalcones were a rationally designed group of compounds based on the A ring of colchicine and the presence of a sulfhydryl residue in the colchicine-tubulin binding site that could be used to generate an irreversible inhibitor (Figures 34 and 35). In this way a molecule containing a trimethoxy aryl group and a Michael acceptor enone 78 was produced. The molecule was found to display good antimitotic activity in vitro and an SAR study was carried out based on this scaffold.177

It was found that the trimethoxy aryl ring tolerated alkyl groups, halides, and amides; however, these did not increase the activity. Substitution at the 3-position lowered activity in all cases. Replacement of the amido substituent with a dialkyl amine improved the activity by 1000-fold. Again, moving this substituent to the 3-position destroyed activity. Substitution of the double bond at the alpha-position enhanced activity while at the beta-position, activity was lost. Inversion of the enone lowered potency. These molecules have been found to bind to tubulin and inhibit polymerization. They are inhibited by colchicine, suggesting that they share a similar binding site.178

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