O

Figure 34 Structure of a substituted chalcone.

Figure 34 Structure of a substituted chalcone.

[ NR2 > Br > NHCOR = OR > Ft)

Figure 35 Chalcone SAR.

A series of quinolones was synthesized, inspired by the activity of flavoloids. In an initial screen a collection of 2-phenyl quinolones were synthesized with substitutions at the 6-, 7-, and 8-positions of the ring (Figures 36 and 37).179 Substitutions at the 8-position resulted in poor cytotoxicity; however, substituents at the 6- and 7-positions were well tolerated. Activity was destroyed by both methylation of the quinolone nitrogen and aromatization to the corresponding quinoline. The more potent molecules were tested in the NCI 60-cell-line panel where they showed a similar profile to colchicine. Subsequently it was established that these molecules inhibited tubulin polymerization at similar concentrations to colchicine; however, they were only competitive inhibitors of colchicine at high concentrations. Further studies showed that the 6-methoxy and 6,7-methylenedioxy substitution led to submicromolar cytotoxicity and compounds that could inhibit colchicine-tubulin binding.180 Replacement of the phenyl ring with heteroaromatic rings or constraining it through an extra ring resulted in no activity. Substitution of the phenyl ring at the para position with substituents larger than a methyl group resulted in no activity, suggesting a steric requirement. By contrast, meta halo, amino, and alkyl groups gave compounds with high nanomolar activity.181

By replacing the methylenedioxy group with a heterocyclic group at the 6-position, low-nanomolar compounds were obtained, with the pyrrolinyl compound 79 being the most potent. This compound is a strong inhibitor of tubulin

6- > 6,7-OCH2O > 7-substitution OPTIMAL : 6-OMe, ^O

6- > 6,7-OCH2O > 7-substitution OPTIMAL : 6-OMe, ^O

NH2, NHR, OH, OR, co2r IMPROVE potency

Figure 36 Quinolone SAR.

Figure 36 Quinolone SAR.

binding. The analogous dihydroquinazoline 80 shows a similar ability to inhibit tubulin polymerization through binding to the colchicine-binding site.182 The corresponding strylyquinazolinones have also been shown to be potent molecules, which appear to show a similar SAR to the quinolones.183 A number of alternative scaffolds have been tested, including naphthyridinones (e.g., 81)184 and 3-formyl-2-phenylindoles 82.185 The indoles again show similar SAR elements to that of the quinolone series.

7.04.2.2.7 Conclusion

Binding to tubulin, either in the vinca domain or at the colchicine site, is an effective method of disrupting microtubule dynamics. This results in cell cycle arrest in the G2/M phase and ultimately apoptosis. Within the vinca domain, several overlapping sites are targeted by a structurally diverse set of peptide, depsipeptide, and polyketide compounds that inhibit the binding of vinca alkaloids to tubulin. These vinca domain inhibitors have received significant clinical interest; however, only the vinca bis-indole alkaloids and closely related structural analogs are currently in clinical use. Human clinical trials involving analogs of halichondrin, dolastatin, and hemiasterlin are presently under way. Although tubulin binding at the colchicines site was first observed with colchicine, it is not limited to this molecule. Indeed, there are many compounds with a variety of structures that bind in this region. Since the exact nature of each interaction is unknown, it is impossible to know whether they bind in exactly the same area and it is probably the case that they do not; however, there appears to be a considerable overlap between the structures. Most classes are characterized by a di- or trimethoxyaryl group which appears to be analogous to the A ring of colchicine and has been determined to make the initial binding contact. The binding pocket in this region is often restricted with specific steric requirements. The remainder of the molecules varies more widely. However, there are many examples of molecules with a second aromatic group that mimics the tropolone functionality found in colchicine. A number of molecules have Michael acceptors, which are used to take advantage of the Cys-239 residue that appears to be in the colchicine-binding site.

One disadvantage of the colchicines site inhibitors appears to be their associated toxicity. While there are a number of examples that have been taken into trials, there are few examples of molecules that have made it to market. However, the more recent finding that these molecules are very effective at preventing angiogenesis, a requirement for tumors,186 may spur further investigation in this field.

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