Combretastatin Dinitrogen-Substituted Stilbene Analogues as Tubulin-Binding and Vascular-Disrupting Agents

Abstract

Several stilbenoid compounds having structural similarity to the combretastatin group of natural products and characterized by the incorporation of two nitrogen-bearing groups (amine, nitro, serinamide) have been prepared by chemical synthesis and evaluated in terms of biochemical and biological activity. The 2',3'-diamino B-ring analogue 17 demonstrated remarkable cytotoxicity against selected human cancer cell lines in vitro (average GI 50 = 13.9 nM) and also showed good activity in regard to inhibition of tubulin assembly (IC 50 = 2.8 microM). In addition, a single dose (10 mg/kg) of compound 17 caused a 40% tumor-selective blood flow shutdown in tumor-bearing SCID mice at 24 h, thus suggesting the potential value of this compound and its corresponding salt formulations as new vascular-disrupting agents.

ortho-Formylation of oxygenated phenols

“…For the synthesis of the dinitro compound 173, 4-methoxy-2-nitro-benzealdehyde (171) was treated with nitric acid in fuming sulphuric acid (Scheme 12). 105 An approximately 1:1 mixture of the 2,3-and 2,5-dinitro benzadehydes, 172 and 173, were isolated. Roughly 10% of the aldehydes were oxidized to the benzoic acid observed by 1 H-and 13 C-NMR analyses.…”

Design, synthesis, and biological evaluation of water-soluble amino acid prodrug conjugates derived from combretastatin, dihydronaphthalene, and benzosuberene-based parent vascular disrupting agents

“…Among these, compounds 7-10 , 13 , 15 , 15,16 32 , 42,43 33 , 37 , 39 , 46,47 3' CA4-amine, 3' CA4-L-serinamide and AVE8062 36,53 were re-synthesized for the purpose of further biological evaluation.…”

“…34 Subsequently, our studies showed that the di-amino variant of combretastatin A-1 (CA1-diamine, Fig. 1 ) 16 was strongly cytotoxic against human cancer cell lines (average GI 50 = 13.9 nM) and also demonstrated potent activity in regard to inhibition of tubulin assembly (IC 50 = 2.8 μM). 16 It is fairly common for compounds that interact with tubulin in the low μM range (cell free assay) to demonstrate nM cytotoxicity against human cancer cell lines; a variety of factors are postulated to influence this activity differential.…”

“…18,29–31 The relative structural simplicity of the combretastatins has motivated synthetic chemists to develop libraries of structurally inspired analogues through alteration of the A–ring, the B–ring, and the ethylene bridge. 6,15,16,32–35 …”

“…1 ) 16 was strongly cytotoxic against human cancer cell lines (average GI 50 = 13.9 nM) and also demonstrated potent activity in regard to inhibition of tubulin assembly (IC 50 = 2.8 μM). 16 It is fairly common for compounds that interact with tubulin in the low μM range (cell free assay) to demonstrate nM cytotoxicity against human cancer cell lines; a variety of factors are postulated to influence this activity differential. 38 The trimethoxyphenyl moiety, the p -methoxyphenyl moiety, the Z -configuration of the two aryl rings, and the optimal 4-5 Å aryl-aryl distance all proved important for enhanced tubulin binding activity of the combretastatin analogues.…”