Synthesis, Biological Evaluation of 1,1‐Diarylethylenes as a Novel Class of Antimitotic Agents

Abstract

The cytotoxic activities of 23 new isocombretastatin A derivatives with modifications on the B-ring were investigated. Several compounds exhibited excellent antiproliferative activity at nanomolar concentrations against a panel of human cancer cell lines. Compounds isoFCA-4 (2 e), isoCA-4 (2 k) and isoNH(2)CA-4 (2 s) were the most cytotoxic, and strongly inhibited tubulin polymerization with IC(50) values of 4, 2 and 1.5 microM, respectively. These derivatives were found to be 10-fold more active than phenstatin and colchicine with respect to growth inhibition but displayed similar activities as tubulin polymerization inhibitors. In addition, cell cycle arrest in the G(2)/M phase and subsequent apoptosis was observed in three cancer cell lines when treated with these compounds. The disruptive effect of 2 e, 2 k and 2 s on the vessel-like structures formed by human umbilical vein endothelial cells (HUVEC) suggest that these compounds may act as vascular disrupting agents. Both compounds 2 k and 2 s have the potential for further prodrug modification and development as vascular disrupting agents for treatment of solid tumors.

IsoCombretaQuinazolines: Potent Cytotoxic Agents with Antitubulin Activity

“…Thus, we have demonstrated that it is possible to replacet he Z-1,2-diarylethylene scaffold of CA-4 with 1,1-diarylethylene to give isoCA-4, as tructural isomer of CA-4, with biological activities similar to those of the natural product. [18,19,22] We next showedt hat it is possible to reduce the double bond of isoCA4t of urnish (AE)-isoerianin 2a, [20] which also displayed excellent anticancer activities similartothose of natural erianin. [23] We recently prepared azaisoerianin derivatives 3 and were pleased to observe that such compounds are as potent as their C-congeners.…”

Synthesis and Structure–Activity Relationships of Constrained Heterocyclic Analogues of Combretastatin A4

“…Chemical shift values (d) are given in ppm relative to the residual solvent peak (CHCl 3 ) as the internal reference, and coupling constants (J) are given in Hertz. All 13 C NMR spectra were recorded with complete proton decoupling. Peak assignment was unambiguously performed using HMQC, HMBC, and NOESY techniques.…”

“…[12] Many linkers that constrain the two phenyl rings to a similar cis-restricted conformation have been reported to increase the activity and stability of the designed compounds relative to CA4. This approach was mainly achieved by replacement of the double bond with other rigid linkers [13] or different cyclic moieties, [14] or by introducing another ring. [15] These considerations led us to design a new series of conformationally restricted CA4 analogues by inserting an additional ring between the cis-olefinic bond and one of the aromatic moieties of the CA4 structure.…”

Regioselective hydrostannation of diarylalkynes directed by a labile ortho bromine atom: An easy access to stereodefined triarylolefins, hybrids of combretastatin A-4 and isocombretastatin A-4

“…By structural modifications on the B ring, we have also identified other promising antiproliferative agents such as isoFCA-4 and iso-NH 2 CA-4 ( Fig. 1) [37]. In addition, these apoptosis inductors substances were found to inhibit microtubules formation and to induce cell cycle arrest in G2/M phase.…”