Novel Combretastatin Analogues Effective against Murine Solid Tumors:  Design and Structure−Activity Relationships

Abstract

A series of combretastatin A-4 (CA-4) analogues were synthesized, and their cytotoxic effects against murine Colon 26 adenocarcinoma and inhibitory activity on tubulin polymerization were evaluated. Since CA-4 has limited aqueous solubility, the target compounds were designed to improve solubility by introduction of a nitrogen-containing group. Among the compounds synthesized, those with an amino moiety in place of the phenolic OH of CA-4 showed potent antitubulin activity and cytotoxicity against murine Colon 26 adenocarcinoma in vitro. Some of the compounds which were potent in vitro were evaluated in the murine tumor model Colon 26 in vivo. Among these, 13bHCl, 21aHCl, and 21bHCl showed significant antitumor activity in the animal model, while CA-4 was ineffective. 13bHCl and 21aHCl were further evaluated in two murine tumor models (Colon 38 and 3LL) and human xenografts HCT-15. These compounds showed potent antitumor activity comparable or superior to that of CDDP. The structure-activity relationships of this series of compounds are also discussed.

Synthesis and biological properties of bioreductively targeted nitrothienyl prodrugs of combretastatin A-4

“…The residue was purified on silica (33% ethyl acetate/hexane) and then on a second silica column (dichloromethane) to give a pale yellow oil (150 mg, 31%). 1 (14). DIAD (128 mg, 0.63 mmol) was added dropwise to a solution of 10 (54 mg, 0.22 mmol), 1 (100 mg, 0.32 mmol), triphenylphosphine (166 mg, 0.63 mmol), and tetrahydrofuran (1 mL).…”

Anticancer agents from medicinal plants

“…Several of them are currently in clinical trials or preclinical trials or (12) (Pettit et al, 1987). Combretastatin A-4 (14) is active against colon, lung and leukemia cancers and it is expected that this molecule is the most cytotoxic phytomolecule isolated so far (Ohsumi et al, 1998;Pettit et al, 1995).…”

Synthesis and Antibacterial Activity Study of C-3 α, β-Unsaturated Ketone Linked Benzofuran Derivatives

“…Substitution of the double bond linker with furan moiety is an effective method of structural modification in designing new derivatives from natural oligostilbene [1][2][3][4]. For example, natural product corsifuran C, a furan-substituted oligostilbene analogue bearing 4-methoxyphenyl group at the C-2′ position ( Figure 1) was reported as a neuron-protective and anti-tumor agent.…”

“…It is presumed that the C-3 position of benzofuran ring was a potential functional site, and the single or double hydroxyl substituted phenyl and mathanone linker on C-3 position were essential for antibacterial activity of benzofuran families. Meanwhile, it was noticed that introducing electron-rich groups into the leading compound is a conventional way of molecular structural modification, and may result better biological performance, for example, the ethylene group in Combrestastatin A-4 derivatives [1,3,4] and Chalcone family analogues [10][11][12][13][14][15][16][17]. To examine the effect of antibacterial activities induced by C-3′ linkers, we achieved a further structural modification on C-2 methoxyphenyl substituted benzofuran skeleton by introducing substituted phenyl groups through α, β-unsaturated ketone linker at the C-3′ position in this paper.…”