IsoCombretaQuinazolines: Potent Cytotoxic Agents with Antitubulin Activity

Abstract

A series of novel isocombretaquinazolines (isoCoQ) 4 were quickly prepared by coupling N-toluenesulfonylhydrazones with 4-chloroquinazolines under palladium catalysis. These compounds, which can be regarded as isocombretastatin A-4 (isoCA-4) analogues that lack the 3,4,5-trimethoxyphenyl ring, displayed nanomolar-level cytotoxicity against various human cancer cell lines and were observed to effectively inhibit tubulin polymerization. The isoCoQ compounds 2-methoxy-5-(1-(2-methylquinazolin-4-yl)vinyl)phenol (4 b), 4-[1-(3-fluoro-4-methoxyphenyl)vinyl]-2-methylquinazoline (4 c), and 2-methoxy-5-(1-(2-methylquinazolin-4-yl)vinyl)aniline (4 d), which respectively bear the greatest resemblance to isoCA-4, isoFCA-4, and isoNH2 CA-4, are able to arrest HCT116 cancer cells in the G2 /M cell-cycle phase at very low concentrations. Preliminary in vitro antivascular assay results show that 4 d is able to disrupt a network of capillary-like structures formed by human umbilical vein endothelial cells on Matrigel. All these results clearly demonstrate that replacement of the 3,4,5-trimethoxyphenyl ring of isoCA-4 with a quinazoline nucleus is a feasible approach toward new and highly promising derivatives with the potential for further development as antitubulin agents.

Design, synthesis and anticancer properties of IsoCombretaQuinolines as potent tubulin assembly inhibitors

“…methoxy substituent on B-ring exhibited a potent antiproliferative activity against U87 cells with an IC50 value of 21 nM. For comparison, its 2-methylquinazolinic analogue[23] displayed a slightly lowest cytotoxicity (IC50 = 40 nM), strengthening our ideas that nitrogen-containing heterocycles, as quinolines, are good surrogates for the 3,4,5-trimethoxyphenyl ring of isoCA-4. As it was previously observed in CA-4 and isoCA-4 series, introducing small substituents on the meta-position of the B-ring of 2a as hydroxyle function or a fluorine atom led to more potent derivatives having IC50 values inferiors to 5 nM.…”

“…It should be noted that, in the CA-4 series, the replacement of the 3,4,5trimethoxyphenyl A-ring [20,21,22] which is "crucial to obtain relevant cytotoxic and antitubulin responses" [9], by heterocyclic derivatives has received very little attention. Very recently, we have demonstrated for the first time, that changing the 3,4,5-trimethoxyphenyl A-ring by a quinazoline nucleus resulted in a novel series of antimitotic drugs, [23] with isoCoQ 1 as a lead compound, displaying a nanomolar level of cytotoxicity against various tumor cells. The possible binding mode on tubulin of the more potent quinazolines was studied and indicate that the N-1 atom of such quinazolines interacted with Cys 241 of tubulin whereas the position of the N-3 atom of these drugs was inadequate to interact with tubulin.…”

N,N-bis-heteroaryl methylamines: Potent anti-mitotic and highly cytotoxic agents

“…Finally, the 2-chloroquinoline derivative 1p was prepared in three steps from the Pd-coupling reaction between 9-methyl-9H-carbazol-3-amine and 2-hydroxyquinolin-4-yl triflate followed C2-chlorination and N-methylation reactions. Then, we have replaced the quinoline nucleus in compounds 1a and 1p by a quinazoline heterocycle as A-ring to provide the expected bis heterocycles N-methylamines 2a,b in accordance to our previous results in the isoCoQ series [19] and also by a pyridine ring (3) (Scheme 2). The synthesis of the desired targets 2a,b and 3 was achieved according to a similar strategy used for quinolines 1a-p (Scheme 2).…”

“…The compounds were all identified by usual physical methods, i.e. 1 H NMR, 13 C NMR, 19 F NMR, IR, HRMS. 1 H, 13 C and 19 F NMR spectra were measured in CDCl3 with a Bruker AMX 200 ( 1 H, 13 C and 19 F) or with a Bruker Avance 300…”

“…[16] In view of the establishment of structure-activity relationships (SARs) we have reported that it was allowed to reduce the ethylene double bond (isoerianin derivatives) [17] and to replace the 1,1-ethylene double bond of such drugs by a N-Me function (isoazaerianin derivatives) [18] with no loss of anti-cancer efficiency. Later, by structural modifications on the A-ring of isoCA-4, we have synthesized a series of highly potent cytotoxic isocombretaquinazolines (isoCoQs) [19] and isocombretaQuinolines (isoCoQuines) [20] demonstrating for the first time, that the 3,4,5-trimethoxyphenyl A-ring present in CA-4 and isoCA-4 can be replaced in these structures by various nitrogen-containing heterocyclic systems.…”