Vascular Disrupting Activity of Tubulin-Binding 1,5-Diaryl-1<i>H</i>-imidazoles

Bonezzi, Katiuscia; Taraboletti, Giulia; Borsotti, Patrizia; Bellina, Fabio; Rossi, Renzo; Giavazzi, Raffaella

doi:10.1021/jm900968s

Cited by 68 publications

(42 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Morphological changes to endothelial cells after treatment with VDAs, including membrane blebbing, have been observed in both in vitro and in vivo studies (Kanthou and Tozer, 2002;Yeung et al, 2007;Bonezzi et al, 2009), and the rounding-up and blebbing clearly apparent in HUVEC exposed to CYT997 (Fig. 1) are thus fully consistent with these literature data.…”

Section: Discussionsupporting

confidence: 87%

The Microtubule Depolymerizing Agent CYT997 Causes Extensive Ablation of Tumor Vasculature In Vivo

Burns¹,

Fantino²,

Powell³

et al. 2011

J Pharmacol Exp Ther

View full text Add to dashboard Cite

The orally active microtubule-disrupting agent (S)-1-ethyl-3-(2-methoxy-4-(5-methyl-4-((1-(pyridin-3-yl)butyl)amino)pyrimidin-2-yl)phenyl)urea (CYT997), reported previously by us (Bioorg Med Chem Lett 19:4639 -4642, 2009; Mol Cancer Ther 8:3036 -3045, 2009), is potently cytotoxic to a variety of cancer cell lines in vitro and shows antitumor activity in vivo. In addition to its cytotoxic activity, CYT997 possesses antivascular effects on tumor vasculature. To further characterize the vascular disrupting activity of CYT997 in terms of dose and temporal effects, we studied the activity of the compound on endothelial cells in vitro and on tumor blood flow in vivo by using a variety of techniques. In vitro, CYT997 is shown to potently inhibit the proliferation of vascular endothelial growth factor-stimulated human umbilical vein endothelial cells (IC 50 3.7 Ϯ 1.8 nM) and cause significant morphological changes at 100 nM, including membrane blebbing. Using the method of corrosion casting visualized with scanning electron microscopy, a single dose of CYT997 (7.5 mg/kg i.p.) in a metastatic cancer model was shown to cause destruction of tumor microvasculature in metastatic lesions. Furthermore, repeat dosing of CYT997 at 10 mg/kg and above (intraperitoneally, b.i.d.) was shown to effectively inhibit development of liver metastases. The time and dose dependence of the antivascular effects were studied in a DLD-1 colon adenocarcinoma xenograft model using the fluorescent dye Hoechst 33342. CYT997 demonstrated rapid and dose-dependent vascular shutdown, which persists for more than 24 h after a single oral dose. Together, the data demonstrate that CYT997 possesses potent antivascular activity and support continuing development of this promising compound.

show abstract

Section: Discussionsupporting

confidence: 87%

The Microtubule Depolymerizing Agent CYT997 Causes Extensive Ablation of Tumor Vasculature In Vivo

Burns¹,

Fantino²,

Powell³

et al. 2011

J Pharmacol Exp Ther

View full text Add to dashboard Cite

show abstract

“…The rationale of the design of active compounds was to retain the appropriate geometry of the two adjacent aryl groups required for potent bioactivity of chemically stable cis-restricted derivatives of CA-4. These were obtained by incorporating the olefinic double bond into vicinally diaryl-substituted fivemember aromatic heterocyclic rings (Table 1), such as pyrazole [67], imidazole [67][68][69], thiazole [70][71][72], furazan (1,2,5-oxadiazole) [73], furan [74,75], thiophene [76,77], isoxazole [78,79], oxazole [67,68,80,81], 1,2,3-thiadiazole [39], triazole [82,83,84,85], 1,2,3,4-tetrazole [70,86] and dioxolane [87]. Replacement of the olefinic bond with a five-member heterocyclic ring allowed the retention of the correct geometric orientation of the two phenyl rings of CA-4, placing them at an appropriate distance for efficient interaction with the colchicine-binding domain on tubulin [35].…”

Section: Other Synthetic Stilbene Derivatives As Tubulin-interactive mentioning

confidence: 99%

Tubulin-interactive stilbene derivatives as anticancer agents

Mikstacka

Stefański

Różański

2013

Cellular and Molecular Biology Letters

View full text Add to dashboard Cite

Microtubules are dynamic polymers that occur in eukaryotic cells and play important roles in cell division, motility, transport and signaling. They form during the process of polymerization of α- and β-tubulin dimers. Tubulin is a significant and heavily researched molecular target for anticancer drugs. Combretastatins are natural cis-stilbenes that exhibit cytotoxic properties in cultured cancer cells in vitro. Combretastatin A-4 (3′-hydroxy-3,4,4′, 5-tetramethoxy-cis-stilbene; CA-4) is a potent cytotoxic cis-stilbene that binds to β-tubulin at the colchicine-binding site and inhibits tubulin polymerization. The prodrug CA-4 phosphate is currently in clinical trials as a chemotherapeutic agent for cancer treatment. Numerous series of stilbene analogs have been studied in search of potent cytotoxic agents with the requisite tubulin-interactive properties. Microtubule-interfering agents include numerous CA-4 and transresveratrol analogs and other synthetic stilbene derivatives. Importantly, these agents are active in both tumor cells and immature endothelial cells of tumor blood vessels, where they inhibit the process of angiogenesis. Recently, computer-aided virtual screening was used to select potent tubulin-interactive compounds. This review covers the role of stilbene derivatives as a class of antitumor agents that act by targeting microtubule assembly dynamics. Additionally, we present the results of molecular modeling of their binding to specific sites on the α- and β-tubulin heterodimer. This has enabled the elucidation of the mechanism of stilbene cytotoxicity and is useful in the design of novel agents with improved anti-mitotic activity. Tubulin-interactive agents are believed to have the potential to play a significant role in the fight against cancer.

show abstract

“…Generally, introduction of N-containing 5-membered heterocycles as linkers between two aryl rings in CA4 analogues (Figure 1, III) resulted in potent cytotoxic compounds with antimitotic microtubule destabilizing mode of action. [11][12][13][14][15][16][17][18][19][20] Similarly, CA4 analogues with bicyclic triazolopyrimidine linker, halogen substituted triazolopyrimidines (Figure 1, IV), displayed cytotoxicity against human cancer cell lines with IC50 in nanomolar concentration range. 21 In the present study, polymethoxyhydroxy-substituted diaryltriazolopyrimidines 9 were found to be inactive up to 4 microMol concentration.…”

Section: Page 158mentioning

confidence: 99%

“…Spontaneous isomerization to the trans-double bond observed both in vitro and in vivo causes a dramatic decrease of biological activity. 10 To stabilize the active cis-conformation, several heteroaromatic rings, such as pyrazole, 11 imidazole, 11,12 thiazole, 11 isoxazole, 13,14 1,2,3-thiadiazole, 15 isomeric triazoles, 11,16,17 and tetrazole 11,[18][19][20] have been introduced as a nonisomerizable and metabolically stable isosteric equivalent of cis-double bond (Figure 1, III), resulting in highly active microtubule destabilizing antimitotic agents. Replacement of the double bond by triazolopyrimidine yielded diaryl-o-substituted-triazolopyrimidines (Figure 1, IV) with pronounced cytotoxicity against human cancer cells both in vitro and in mouse xenograft model.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and antimitotic properties of ortho-substituted polymethoxydiarylazolopyrimidines

Chernyshova¹,

Tsyganov²,

Khrustalev³

et al. 2017

Arkivoc

View full text Add to dashboard Cite

Ortho-substituted polymethoxydiarylazolopyrimidines were synthesized using polymethoxysubstituted benzaldehydes and acetophenones as starting material. X-ray crystallography data clearly confirmed that the subsequent cyclization of 3-amino-1,2,4-triazole with ketoaldehydes yielded polymethoxyphenylsubstituted 6,7-diaryl-[1,2,4]triazolo[1,5-a]pyrimidines as single isomers. All compounds were evaluated in vivo using phenotypic sea urchin embryo assay. 6-(4-Methoxyphenyl)-7-(3,4,5-trimethoxyphenyl)pyrazolo [1,5-a]pyrimidine showed antimitotic microtubule destabilizing activity. The importance of aryl rings substituents in diaryltriazolopyrimidines for their antiproliferative antitubulin effect has been suggested.

show abstract

Vascular Disrupting Activity of Tubulin-Binding 1,5-Diaryl-1H-imidazoles

Cited by 68 publications

References 19 publications

The Microtubule Depolymerizing Agent CYT997 Causes Extensive Ablation of Tumor Vasculature In Vivo

The Microtubule Depolymerizing Agent CYT997 Causes Extensive Ablation of Tumor Vasculature In Vivo

Tubulin-interactive stilbene derivatives as anticancer agents

Synthesis and antimitotic properties of ortho-substituted polymethoxydiarylazolopyrimidines

Contact Info

Product

Resources

About