Synthesis, biological evaluation, and structure–activity relationships of tri- and tetrasubstituted olefins related to isocombretastatin A-4 as new tubulin inhibitors

Abstract

The synthesis and structure-activity relationships associated with a series of 1,1-diarylethylene tubulin polymerization inhibitors 3 and 4 are described. The key step for their preparation involves a palladium-catalyzed coupling of N-arylsulfonylhydrazones with aryl halides, thus providing flexible and convergent access to tri- and tetrasubstituted 1,1-diarylolefins 3 and 4 related to isocombretastatin A-4 (isoCA-4). These compounds have been evaluated for tubulin polymerization inhibitory activity as well as for cytotoxic activity. The most potent compounds are 1,1-diaryl-2-methoxyethylenes 4b, 4d and 4e having a trisubstituted double bond. They exhibited good antiproliferative activity against various human cancer cell lines (GI(50) = 8-80 nM). Compounds 4b and 4e strongly inhibited tubulin polymerization with IC(50) values of 2 and 3 μM, respectively, and induced cell cycle arrest in the G(2)/M phase in the K562 cell line. Docking studies in the colchicine binding site of tubulin allowed identification of residues most likely to interact with these inhibitors and explain their potent anti-tubulin activity.

Optimization of antiproliferative activity of substituted phenyl 4-(2-oxoimidazolidin-1-yl) benzenesulfonates: QSAR and CoMFA analyses

“…Chemotherapy is a preferred method of treatment, although, various therapies like radiation, different types of surgeries etc. are available Chemotherapy for cancer treatment usually involves three or four anti-cancer drugs in combination (Aziz et al, 2013); (Natarajan et al, 2012); (Temirak et al, 2012). Few examples of anticancer drugs are presented in Figure 1.…”

Exploring Diverse-Ring Analogues on Combretastatin A4 (CA-4) Olefin as Microtubule-Targeting Agents

“…The synthetic method is simple without the control of cis-configuration [30,31]. The Alami group have completed plentiful studies on the modification of 1,1-diaryl double bond scaffold using naphthenic [32], naphthalene [33], arylchromenes [34], azaisoerianin [35], arylbenzoxepins [36], etc. In our previous works [37], dihydrofuran and dihydroisoxazole analogues of isoCA-4 were prepared through [3+2] reactions and could inhibit tubulin polymerization.…”

Selective Synthesis of Tetrasubstituted Olefins by Copper‐Mediated Acetoxythiolation of Internal Alkynes: Scope and Mechanistic Studies

“…[8][9][10][11][12][13][14][15][16][17][18] The interest in these particular substrates resides in their versatility as startingm aterials and in their pharmacological, photochemical, and electrochemical properties. [19][20][21][22][23][24] To mention some wellknown examples, (Z)-tamoxifen ( Figure 1) is used in the treatment and prevention of breast cancer, [21] isocombretastatine A-4s hows antitubulin activity, [22] rofecoxib (a selectivei nhibitor of cyclooxygenase-2) displays activity in the prevention of colorectal adenoma, [23] and nileprost was is considered ap romising antiulcer agent. [24] Some of the most general methods for the synthesis of tetrasubstituted olefins involvea ddition reactions to internal alkynes, usually carbometalations, which are followed by oxidative couplings, cross-couplings,o rt he addition of electrophiles.…”