Antivascular and anticancer activity of dihalogenated A-ring analogues of combretastatin A-4

Cytotoxic and antivascular 1-methyl-4-(3-fluoro-4-methoxyphenyl)-5-(halophenyl)-imidazoles

“…Their activities exceeded even that of the known trimethoxy derivative 3a. This confirms recent findings by Myers et al 15 who discovered that bigger bromo (1c) or iodo (1d), but not small fluoro substituents at both meta-positions of ring A of stilbenoid analogs of 1a led to enhanced potency against HUVEC cells. The dibromophenyl substituted imidazole 6g was a potent suppressor of HUVEC tube formation, of tubulin polymerization, and of the growth of KB-3-1 cervix and PC-3 prostate cancer cells.…”

“…3-Fluoro-4-methoxybenzaldehyde 4 was reacted with p-toluenesulfinic acid and formamide in the presence of camphorsulfonic acid (CSA) to give a tosylmethylformamide intermediate, which was dehydrated to 5 by POCl 3 . The halogenated benzaldehydes used for the van Leusen reaction with 5 were prepared according to known literature methods 12,15,20 and converted to their N-methylimines. Reaction of the latter with 5 and addition of HCl/dioxane finally afforded the imidazolium salts 6 (Scheme 1).…”

Current advances in the synthesis and biological potencies of tri- and tetra-substituted 1H-imidazoles

“…Signifi- cantly, an imidazole derivative which has 3,4,5-trimethoxy groups in its ring B 200 has been synthesized efficiently in good yields. It has been found that the presence of the 3,4,5-trimethoxy moiety on ring B of 200 is essential for the observed antitubulin and anticancer activity [169]. The mild reaction conditions, simple work-up procedure, and high yields make this strategy a practical and ideal approach, avoiding the common use of transition metal catalysts.…”

Anticancer Drugs and Potential Anticancer Leads Inspired by Natural Products

“…Because of a simple structural feature of 5 and its unique cytotoxicity, many research groups intensively modified the structure of 5; therefore, several potent anticancer combretastatin A4 analogs are obtained. Interestingly, substitution of the meta-methoxy groups of combretastatin A4 (5) with halogen atoms results in derivatives that are equipotent or more potent than the parent cis-stilbene 5 [33]. The serine amide derivative, AVE8062 (7), in combination with taxanes and platinum salts, is being evaluated in phase II clinical trial for advanced solid tumors, and phase II/III clinical trial for an advanced soft tissues sarcoma [32].…”

“…Because the resorcylic acid macrolactone 30 exhibits potent Hsp90 inhibitory activity, total synthesis, medicinal chemistry, and biology of 30 have been intensively explored; chemistry and biology of 30 were recently reviewed by Kitson and Moody [68]. Attachment of alkaloid scaffolds to the resorcinol moiety of radicicol resulted in potent anticancer derivatives, NVP-AUY922 (32), CCT018159 (33), and AT13387 (34) (Fig. Although 30 is one of the most potent natural Hsp90 inhibitors (IC 50 at nanomolar levels) [71,72], it was inactive in vivo, failing to inhibit the tumor growth in an animal model.…”