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Investigational New Drugs
Published in: Investigational New Drugs 4/2010

01-08-2010 | PRECLINICAL STUDIES

Evaluation Of 5-hydroxy-2,3-diaryl (substituted)-cyclopent-2-en-1-ones as cis-restricted analogues of combretastatin A-4 as novel anti angiogenic and anticancer agents

Authors: Vinod Kumar Sanna, Manu Jaggi, Vadlapudi Kumar, Anand C. Burman

Published in: Investigational New Drugs | Issue 4/2010

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Summary

Two potent cis-restricted CA-4 analogues 11 and 42 belonging to 2,3-diaryl-5-hydroxycyclopent-2-en-1-one class were evaluated for anticancer and anti angiogenic activity. The compound 42 displayed potent cytotoxic activity (IC50 < 1 μM) against a panel of human cancer cell lines viz PTC, MDA.MB.453, PA1, SKOV3, DU145 and Miapaca2, whereas compound 11 displayed cytotoxicity activity (IC50 < 1 μM) only in Miapaca2. Both the compounds inhibit growth factor stimulated endothelial cell proliferation, migration and capillary tube formation. In all the above parameter compound 42 was superior to 11. Based on the above results compound 42 was assessed for inhibition of vasculature in vivo and showed significant inhibition at 25 mg/kg dose. Further it was evaluated for in vivo anti tumor activity in athymic mice bearing DU145 and SKVO3 tumor xenograft and showed regression in tumor volume (T/C) of 23.8% (CA-4), 50.1% (compound 42) and 23.5% (CA-4), 56% (compound 42) respectively at a dose of 20 mg/kg (i.v.) daily for 14 days.
Literature
1.
2.
3.
4.
Carlsson J, Stalnacke CG, Acker H (1979) The influence of oxygen on viability and proliferation in cellular spheroids. Int J Radiat Oncol Biol Phys 5:2011–2020PubMed
5.
Blood CN, Zetter BR (1990) Tumor interactions with the vasculature: angiogenesis and tumor metastasis. Biochim Biophys Acta 1032:89–118PubMed
6.
7.
Paku S, Paweletz N (1991) First steps of tumor-related angiogenesis. Lab Invest 65:334–346PubMed
8.
Hobson B, Denekamp J (1984) Endothelial proliferation in tumors and normal tissues continuous labeling studies. Br J Cancer 49:405–414PubMed
9.
10.
Belotti D, Vergani V, Drudis T et al (1996) The microtubule-affecting drug paclitaxel has antiangiogenic activity. Clin Cancer Res 2:1843–1849PubMed
11.
Klauber N, Parangi S, Flynn E et al (1997) Inhibition of angiogenesis and breast cancer in mice by the microtubule inhibitors 2-methoxyestradiol and Taxol. Cancer Res 57:81–86PubMed
12.
Sweeney CJ, Miller KD, Sissons SE, Nozaki S et al (2001) The antiangiogenic property of docetaxel is synergistic with a recombinant humanized monoclonal antibody against vascular endothelial growth factor or 2-methoxyestradiol but antagonized by endothelial growth factors. Cancer Res 61:3369–3372PubMed
13.
Ettenson DS, Gotlieb AI (1992) Centrosomes, microtubules, and microfilaments in the reendothelialization and remodeling of double-sided in vitro wounds. Lab Invest 66:722–733PubMed
14.
15.
16.
Liou JP, Chang YL, Kuo FM, Chang CW et al (2004) Concise synthesis and structure-activity relationships of combretastatin A-4 analogues, 1-aroylindoles and 3-aroylindoles, as novel classes of potent antitubulin agents. J Med Chem 47:4247–4257. doi:10.​1021/​jm049802l CrossRefPubMed
17.
Vincent L, Kermani P, Young LM et al (2005) Combretastatin A4 phosphate induces rapid regression of tumor neovessels and growth through interference with vascular endothelial-cadherin signaling. J Clin Invest 115(11):2992–3006. doi:10.​1172/​JCI24586 CrossRefPubMed
18.
Gurjar MK, Wakharkar RD, Singh AT et al (2007) Synthesis and evaluation of 4/5-hydroxy-2, 3-diaryl (substituted)-cyclopent-2-en-1-ones as cis-restricted analogues of combretastatin A-4 as novel anticancer agents. J Med Chem 50(8):1744–1753. doi:10.​1021/​jm060938o CrossRefPubMed
19.
20.
Carmichael J, DeGraff WG, Gazdar AF et al (1987) Evaluation of a tetrazolium-based semiautomated colorimetric assay: assessment of chemosensitivity testing. Cancer Res 47:936–942PubMed
21.
22.
Park JG, Kramer BS, Steinberg SM et al (1987) Chemosensitivity testing of human colorectal carcinoma cell lines using a tetrazolium-based colorimetric assay. Cancer Res 47:5875–5879PubMed
23.
Hotchkiss KA, Ashton AW, Mahmood R et al (2002) Inhibition of endothelial cell function in vitro and angiogensis in vivo by docetaxel (Taxotere): association with impaired repositioning of the microtuble organizing center. Mol Cancer Ther 1(13):1191–1200PubMed
24.
25.
Isaji M, Miyata H, Ajisawa Y et al (1997) Tranilast inhibits the proliferation, chemotaxis and tube formation of human microvascular endothelial cells in vitro and angiogenesis in vivo. Br J Pharmacol 122(6):1061–1066. doi:10.​1038/​sj.​bjp.​0701493 CrossRefPubMed
26.
27.
Plowman J (1997) Human tumour xenograft models in NCI drug development. In: Teicher B (ed) Anticancer drug development guide: preclinical screening, clinical trials, and approval. Totowa, NJ, Humana, pp 101–125
28.
29.
Kanthou C, Greco O, Stratford A et al (2004) The tubulin-binding agent combretastatin A-4-phosphate arrests endothelial cells in mitosis and induces mitotic cell death. Am J Pathol 165(4):1404–1411
Metadata
Title
Evaluation Of 5-hydroxy-2,3-diaryl (substituted)-cyclopent-2-en-1-ones as cis-restricted analogues of combretastatin A-4 as novel anti angiogenic and anticancer agents
Authors
Vinod Kumar Sanna
Manu Jaggi
Vadlapudi Kumar
Anand C. Burman
Publication date
01-08-2010
Publisher
Springer US
Published in
Investigational New Drugs / Issue 4/2010
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI
https://doi.org/10.1007/s10637-009-9256-2

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