Structural requirements for the interaction of combretastatins with tubulin: how important is the trimethoxy unit?

Abstract

A series of combretastatins possessing both a trimethoxy unit and other substituents on ring A has been synthesised and tested for cytotoxicity and their ability to interact with the protein tubulin. All previous studies have indicated that the trimethoxy unit is essential for interaction with tubulin. The studies herein show that molecules possessing functionalities other than trimethoxy can also interact with tubulin. Importantly a trimethyl substituted agent 52a has shown reduced cytotoxicity, but increased potency in its ability to inhibit the assembly of tubulin.

Lead identification of conformationally restricted benzoxepin type combretastatin analogs: synthesis, antiproliferative activity, and tubulin effects

“…A common substitution pattern of 3,4,5-trimethoxy or 2,3,4-trimethoxyphenyl for the aryl ring located on position 4 of the benzoxepin scaffold was present in these compounds, together with 4-methoxy, 4-hydroxy, 4,5-dimethoxy, and 4-fluoro-5-methoxyphenyl substitution at C-5. Compound 11e was designed to mimic a fluorinated combretastatin CA-4 analog in which the hydroxy group on ring B was replaced with a fluorine without substantial loss of activity 31,32 . However, compound 11e was found to exhibit only moderate antiproliferative activity, with IC 50 = 10.7 μM.…”

TR-644 a novel potent tubulin binding agent induces impairment of endothelial cells function and inhibits angiogenesis

“…Previous structure-activity relationship studies demonstrated that both the 3 0 ,4 0 ,5 0 -trimethoxy substitution pattern on the A-ring and the cis-olefin configuration at the bridge were fundamental requirements for optimal activity, while B-ring structural modifications were tolerated by the target [6]. However, the cis-configuration of CA-4 is prone to isomerize to the thermodynamically more stable trans-form during storage and metabolism, resulting in a dramatic decrease in its activity [7].…”

Synthesis and Cytotoxic Activity of a New Group of Heterocyclic Analogues of the Combretastatins

“…Compounds having а 2,3,4-trimethoxyphenyl moiety (compounds 6, 9) show week cytotoxic activity, while several derivatives containing a 3,4,5-trimethoxyphenyl residue (compounds 2, 4) shown improved activity. The latter effect is unsurprising, since it is well established that the replacement of A-ring in combretastatins [28,29] and phenstatin [30] is highly detrimental for the activity of the compounds. In the 3,9-disubstituted furocoumarins 12,13 cytotoxicity does not seem to greatly influence by the substituent in the aromatic ring, however, the (4-methylpiperazin-1-ylmethyl) substitution on the 9th-position in 3-styrylfurocoumarin core gave increase in cytotoxic activity of compounds (compare 10 and 12 or 11 and 13), especially, on the human monocyte-lines U-937.…”

“…118-120 °С (ether). IR (KBr, ν, cm (29). Compound 29 (119 mg) was prepared from 2-isopropyl-9-((4-methylpiperazin-1-yl)methyl)-7-oxo-7H-furo[3,2-g]chromen-3-yl trifluoromethanesulfonate (24, 195 mg, 0.4 mmol) and 1-ethynyl-5-formyl-2-hydroxy-3-methoxybenzene (21e, 5 mg, 0.44 mmol) using the procedure described for 25.…”