Isocombrestatin (51)

Figure 20 Structure of isocombrestatin.

study, in which the molecule showed signs of efficacy, including one complete response.146 Replacing the phenol by a bioisosteric boronic acid is an alternative approach to increasing the aqueous solubility of the molecule. Molecule 53 was designed based on modeling studies and is expected to displace a water molecule, which is thought to make a hydrogen bond to the combretastatin phenol. It shows similar binding to tubulin as the natural product and nanomolar cytotoxicity (Figure 21).147

The linkage between the two aromatic rings has been varied both by nature and by chemical synthesis. This linkage helps to hold the two aromatic rings in the correct conformation for potency, which appears from crystal structures to be 66°.148 The saturated analogs of combretastatin A-4 are weaker, while the trans isomer has no cytotoxicity. Introduction of a carboxylic acid, ester, or amide off the alkene lowers the potency by at least two orders of magnitude.149 The ketone analog of combretastatin 54 is only weakly cytotoxic; however, when the linkage is shortened to a single carbon with a ketone, as in phenstatin 55,150 a potent molecule is obtained. The introduction of a further hydroxyl at the

Figure 23 Structures of weakly cytotoxic combrestatin analogs.

2-position of the B ring lowers the potency of the molecule (Figures 22-24).151 The prodrug of this molecule is significantly poorer than the corresponding combretastatin A-4 52 prodrug, while reduction of the ketone, hydroxyphenestatin 56, results in only weak activity. Replacement of the ketone with a sulfur or selenium results in significantly poorer compounds.152

The introduction of a heteroatom into the bridge in the form of a benzamine 57 is inactive while the benzamide 58 shows lower cytotoxicity.153 The cyclization to a biaryl ether system 59 results in weak tubulin binders; however, the binding site is maintained.154 Flavinoids

Screening the plant extract Polymniafruticosa against the NCI panel of tumor cell lines showed high correlations with the other microtubule-interacting compounds. The active compound, the flavanol centaureidin 60 (Figures 25 and 26), was isolated and found to compete with colchicine and podophyllotoxin for tubulin, suggesting that it bound to a similar site.155 Many more compounds of this class have since been isolated for a variety of plants with varying substitution about the rings.156,157

In this series of compounds, a twofold loss in activity is observed if the hydroxy and methoxy of the C ring are reversed. Introducing a further oxidation on to this ring lowers the activity. Compounds with a hydroxyl at the 3-position are generally better than the corresponding methoxy compounds, while a trimethoxy arrangement of the A ring results in superior activity, suggesting that it is binding in a similar place to that of the A ring of colchicine. Other natural products

Curacin A 61 was isolated from the marine cyanobacterium Lyngbya majuscula and shows nanomolar cytotoxicity against a range of cell lines (Figure 27).158 Although the molecule is very different in structure from other tubulin binders at the

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