Effects of the Tumor‐Vasculature‐Disrupting Agent Verubulin and Two Heteroaryl Analogues on Cancer Cells, Endothelial Cells, and Blood Vessels

Abstract

Two analogues of the discontinued tumor vascular-disrupting agent verubulin (Azixa®, MPC-6827, 1) featuring benzo-1,4-dioxan-6-yl (compound 5 a) and N-methylindol-5-yl (compound 10) residues instead of the para-anisyl group on the 4-(methylamino)-2-methylquinazoline pharmacophore, were prepared and found to exceed the antitumor efficacy of the lead compound. They were antiproliferative with single-digit nanomolar IC50 values against a panel of nine tumor cell lines, while not affecting nonmalignant fibroblasts. Indole 10 surpassed verubulin in seven tumor cell lines including colon, breast, ovarian, and germ cell cancer cell lines. In line with docking studies indicating that compound 10 may bind the colchicine binding site of tubulin more tightly (Ebind =-9.8 kcal mol(-1) ) than verubulin (Ebind =-8.3 kcal mol(-1) ), 10 suppressed the formation of vessel-like tubes in endothelial cells and destroyed the blood vessels in the chorioallantoic membrane of fertilized chicken eggs at nanomolar concentrations. When applied to nude mice bearing a highly vascularized 1411HP germ cell xenograft tumor, compound 10 displayed pronounced vascular-disrupting effects that led to hemorrhages and extensive central necrosis in the tumor.

The chicken chorioallantoic membrane model in biology, medicine and bioengineering

“…Disruption of small blood vessels, as well as hemorrhages as a result of leaking or broken vessels were observed shortly after administration of VDAs, e.g. verubulin [162], or the microtubule-depolymerizing agent C9 [163]. Moreover, the growth of solid tumors on the surface of the CAM was successfully inhibited by VDAs, e.g.…”

IsoCombretaQuinazolines: Potent Cytotoxic Agents with Antitubulin Activity

“…[20,24] Interestingly,i nt he isoCA-4 analogues 1-3,s ubstitution of the 3,4,5-trimethoxy-phenylAring with heterocyclic structures has received very little attention. [25][26][27] In 2007, Cai and colleagues [25,26] reported the discovery of MPC-6827, whichc ontainsaquinazolinen ucleus, as ap otent cytotoxic (GI 50 :6 n m towardH CT cellsa mong others) and apoptosis-inducing small molecule (EC 50 :2n m)t hat prevents microtubule formationw ith potencye qual to that of vinblastin. Given the structural similarities between MPC-6827 and azaisoerianin derivatives 3,w epreparedaseries of novel derivatives 4,a sisoCA-4a nalogues,i nw hich aq uinazoline ring replaces the "traditional" 3,4,5-trimethoxyphenyl unit.…”

Current advances of tubulin inhibitors as dual acting small molecules for cancer therapy

“…Verubulin (MPC‐6827) ( 30 ) is a quinazoline derivative that showed potent antineoplastic activities against diverse tumors and promoted apoptosis in both sensitive and MDR cancer cell phenotypes . Other verubulin analogs have been developed in an attempt to maintain potency and avoid resistance, and these compounds have reported vascular disrupting activities and low IC 50 values against various cancer cells . Mahal et al reported an analog of verubulin bearing an indole moiety N ‐(methylindolyl)aminoquinazoline10 ( 37 ), which showed good vascular disrupting effects with low nanomolar IC 50 values ranging from 0.4 to 5.8 nM against several cell lines.…”

“…Other verubulin analogs have been developed in an attempt to maintain potency and avoid resistance, and these compounds have reported vascular disrupting activities and low IC 50 values against various cancer cells . Mahal et al reported an analog of verubulin bearing an indole moiety N ‐(methylindolyl)aminoquinazoline10 ( 37 ), which showed good vascular disrupting effects with low nanomolar IC 50 values ranging from 0.4 to 5.8 nM against several cell lines. Additionally, some other tetrahydroquinoline analogs of verubulin 1b ( 38 ) were designed and synthesized by Wang’s group .…”

“…119 Other verubulin analogs have been developed in an attempt to maintain potency and avoid resistance, and these compounds have reported vascular disrupting activities and low IC 50 values against various cancer cells. 120 derivative of indanone and a selective inducer of apoptosis to stationary multidrug-resistant cancer cells. One approach to eradicate tumor cells involved combination therapy with indanocine, which was selectively cytotoxic to noncycling, multidrug-resistant cells, and other chemotherapeutic drugs, which targeted abnormalities of cell cycle tumors.…”