- Synthesis, crystal structure and cytotoxic properties of nitrocombretastatins (E)- and (Z)-5-(4-methoxy-3-nitrostyryl)-1,2,3-trimethoxybenzene
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(Z)-5-(4-Methoxy-3-nitrostyryl)-1,2,3-trimethoxybenzene (2) is the key intermediate for the preparation of several anticancer agents, belonging to the group of aminocombretastatins (AC7739, AVE8062). Synthesis of the title compounds was achieved by a modified Wittig reaction under Boden's conditions using potassium carbonate as a base and 18-crown-6 as a phase transfer catalyst. Both π-diastereoisomers were characterized by single crystal X-ray diffraction analysis, 1H and 13C NMR spectroscopy. (E)-5-(4-Methoxy-3-nitrostyryl)-1,2,3-trimethoxybenzene (1) crystallizes in the orthorhombic space group Pbca (N° 61) with one molecule per asymmetric unit while (Z)-5-(4-methoxy-3-nitrostyryl)-1,2,3-trimethoxybenzene (2) crystallizes in the monoclinic space group P21/c (N° 14) also with one molecule per asymmetric unit. In both compounds no typical hydrogen bonding interactions could be located. The three-dimensional crystal structure is stabilized by C-H···O interactions. The cytotoxicity of synthesized nitrocombretastatins was also evaluated. The Z-stilbene 2 inhibited cell growth with IC50 of 0.15 and 0.11 μM following 72 h treatment in EA.hy926 and MG-63 cell lines.
- Gerova, Mariana S.,Encheva, Gergina R.,Nikolova, Rositsa P.,Chanev, Christo D.,Shivachev, Boris L.,Apostolova, Margarita D.,Petrov, Ognyan I.
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- Design, synthesis and biological evaluation of combretastatin A-4 sulfamate derivatives as potential anti-cancer agents
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A series of combretastatin A-4 (CA-4) sulfamate derivatives were synthesized and their structure-activity relationship on tubulin, arylsulfatase and tumor cell antiproliferation inhibition was studied. Among them, compound 16a showed excellent potency as well as CA-4 under the same conditions against six tumor cells including HTC-116, HeLa, HepG2, MGC803, MKN45 and MCF-7 cells, respectively. Molecular docking revealed that several important hydrogen bond interactions were formed between the sulfamate group of 16a and the colchicine binding site of tubulin and steroid sulfatase respectively. Although compound 16a was less active than CA-4 in regard to its in vitro activity as an inhibitor of tubulin polymerization, it was effective as an inhibitor of arylsulfatase. This novel combretastatin A-4 sulfamate derivative has the potential to be developed as a dual inhibitor of tubulin polymerization and arylsulfatase for cancer therapy.
- Huang, Jinwen,Huang, Leilei,Li, Yingzi,Nie, Hui,Song, Lixing,Wu, Fanhong
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supporting information
p. 1374 - 1380
(2021/09/30)
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- Compositions and Methods for Treatment of Cancer
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Resistance of randomly dispersed and oxygen-starved lung tumor cells to chemo- and radiotherapy constitutes the vast majority recurrences and death from lung cancer. We use sickle cells derived from humans with sickle cell anemia to target oxygen-deprived
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Paragraph 0054
(2020/12/17)
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- Prodrug Activation by a Viral Protease: Evaluating Combretastatin Peptide Hybrids to Selectively Target Infected Cells
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Infections with flaviviruses such as dengue virus (DENV) are prevalent throughout tropical regions worldwide. Replication of these viruses depends on tubulin, a host cell factor that can be targeted to obtain broad-spectrum antiviral agents. Targeting of tubulin does, however, require specific measures to avoid toxic side-effects. Herein, we report the synthesis and biological evaluation of combretastatin peptide hybrids that incorporate the cleavage site of the DENV protease to allow activation of the tubulin ligand within infected cells. The prodrug candidates have no effect on tubulin polymerization in vitro and are 20-2000-fold less toxic than combretastatin A-4. Several of the prodrug candidates were cleaved by the DENV protease in vitro with similar efficiency as the natural viral substrates. Selected compounds were studied in DENV and Zika virus replication assays and had antiviral activity at subcytotoxic concentrations.
- Richter, Michael,Leuthold, Mila M.,Graf, Dominik,Bartenschlager, Ralf,Klein, Christian D.
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p. 1115 - 1121
(2019/08/20)
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- Pt(IV) prodrugs containing microtubule inhibitors displayed potent antitumor activity and ability to overcome cisplatin resistance
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It is well-known that cisplatin exhibited a broad spectrum of anticancer activities against many solid tumors, but its severe toxicity and drug resistance have largely limited wider clinical applications. Various strategies have been tried to discover new Pt (II) drugs with at least equal activity as well as low toxicity compared to cisplatin, but the inherent problem remains unsolved. Here we report that Pt (IV) complexes comprising a CA-4 analogue, as dual-targeting Pt (IV) prodrug, were synthesized and evaluated for anti-proliferative activity using MTT assay. Among them, complex 19 displayed most potent activity against the tested cancer cell lines, and simultaneously exhibited better cell selectivity between cancer cells and normal cells than that of cisplatin. Mechanism studies revealed that complex 19 effectively induced cell cycle arrest at the G2/M phase and dramatically disrupted the microtubule organization. Moreover, complex 19 significantly induced cell apoptosis and decreased MMP. Importantly, complex 19 significantly inhibited tumor growth in SK-OV-3 xenograft model in vivo without apparent toxicity.
- Li, Lingxue,Huang, Xiaochao,Huang, Rizhen,Gou, Shaohua,Wang, Zhimei,Wang, Hengshan
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p. 666 - 679
(2018/07/29)
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- Design, Synthesis, and in vitro and in vivo Evaluations of (Z)-3,4,5-Trimethoxystyrylbenzenesulfonamides/sulfonates as Highly Potent Tubulin Polymerization Inhibitors
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Newer therapeutics can be developed in drug discovery by adopting the strategy of scaffold hopping of the privileged scaffolds from known bioactive compounds. This strategy has been widely employed in drug-discovery processes. Structure-based docking studies illustrate the basic underlying concepts and reveal that interactions of the sulfonamide group and hydrophobic interactions are crucial. On the basis of this strategy, over 60 synthetic analogues were synthesized and evaluated for their cytotoxicity against the NCI panel of 60 human cancer cell lines; the majority of these compounds exhibited promising cytotoxicity with GI50 values ranging between 18 and 50 nm. Among these compounds, (Z)-N-[2,3-dimethoxy-5-(3,4,5-trimethoxystyryl)phenyl]-4-methoxybenzenesulfonamide (7 a) and (Z)-N-[2-hydroxy-3-methoxy-6-(3,4,5-trimethoxystyryl)phenyl]-4-methoxybenzenesulfonamide (9 a) were found to be potent. Similar results were obtained against three human cancer cell lines with IC50 values ranging between 0.04 and 3.0 μm. Studies aimed at elucidating the mechanism of action of these new analogues revealed that they inhibited the in vitro polymerization of tubulin and disorganized the assembly of microtubules in HeLa and MCF-7cancer cells. Lead compounds 7 a and 9 a displayed notable in vivo antitumor activity in a HeLa tumor xenograft model. Our studies have resulted in the identification of a scaffold that can target tubulin polymerization, which should have significant potential toward the development of new antitumor drugs.
- Mahesh, Rasala,Nayak, Vadithe Lakshma,Babu, Korrapati Suresh,Riyaz, Syed,Shaik, Thokhir Basha,Kumar, Gajjela Bharth,Mallipeddi, Prema Latha,Reddy, Challa Ratna,Shekar, Kunta Chandra,Jose, Jedy,Nagesh, Narayana,Kamal, Ahmed
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p. 678 - 700
(2017/05/15)
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- Design, synthesis, and biological evaluation of water-soluble amino acid prodrug conjugates derived from combretastatin, dihydronaphthalene, and benzosuberene-based parent vascular disrupting agents
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Targeting tumor vasculature represents an intriguing therapeutic strategy in the treatment of cancer. In an effort to discover new vascular disrupting agents with improved water solubility and potentially greater bioavailability, various amino acid prodru
- Devkota, Laxman,Lin, Chen-Ming,Strecker, Tracy E.,Wang, Yifan,Tidmore, Justin K.,Chen, Zhi,Guddneppanavar, Rajsekhar,Jelinek, Christopher J.,Lopez, Ramona,Liu, Li,Hamel, Ernest,Mason, Ralph P.,Chaplin, David J.,Trawick, Mary Lynn,Pinney, Kevin G.
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p. 938 - 956
(2016/02/19)
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- Combretastatin A-4 and Derivatives: Potential Fungicides Targeting Fungal Tubulin
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Combretastatin A-4, first isolated from the African willow tree Combretum caffrum, is a tubulin polymerization inhibitor in medicine. It was first postulated as a potential fungicide targeting fungal tubulin for plant disease control in this study. Combretastatin A-4 and its derivatives were synthesized and tested against Rhizoctonia solani and Pyricularia oryzae. Several compounds have EC50 values similar to or better than that of isoprothiolane, which is widely used for rice disease control. Structure-activity relationship study indicated the the cis configuration and hydroxyl group in combretastatin A-4 are crucial to the antifungal effect. Molecular modeling indicated the binding sites of combretastatin A-4 and carbendazim on fungal tubulin are totally different. The bioactivity of combretastatin A-4 and its derivatives against carbendazim-resistant strains was demonstrated in this study. The results provide a new approach for fungicide discovery and fungicide resistance management.
- Ma, Zhong-Lin,Yan, Xiao-Jing,Zhao, Lei,Zhou, Jiu-Jiu,Pang, Wan,Kai, Zhen-Peng,Wu, Fan-Hong
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p. 746 - 751
(2016/02/10)
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- Design and Synthesis of Aminostilbene-Arylpropenones as Tubulin Polymerization Inhibitors
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A series of aminostilbene - arylpropenones were designed and synthesized by Michael addition and were investigated for their cytotoxic activity against various human cancer cell lines. Some of the investigated compounds exhibited significant antiproliferative activity against a panel of 60 human cancer cell lines of the US National Cancer Institute, with 50% growth inhibition (GI50) values in the range from 50 value of 50) values ranging from 0.011 to 8.56μM. A cell cycle assay revealed that these compounds arrested the G2/M phase of the cell cycle. Two compounds exhibited strong inhibitory effects on tubulin assembly with IC50 values of 0.71 and 0.79μM. Moreover, dot-blot analysis of cyclinB1 demonstrated that some of the congeners strongly induced cyclinB1 protein levels. Molecular docking studies indicated that these compounds occupy the colchicine binding site of tubulin.
- Kamal, Ahmed,Kumar, G. Bharath,Polepalli, Sowjanya,Shaik, Anver Basha,Reddy, Vangala Santhosh,Reddy, M. Kashi,Reddy, Ch. Ratna,Mahesh, Rasala,Kapure, Jeevak Sopanrao,Jain, Nishant
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p. 2565 - 2579
(2015/08/24)
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- Synthesis and biological evaluation of 1,2,3-triazole linked aminocombretastatin conjugates as mitochondrial mediated apoptosis inducers
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A series of 1,2,3-triazole linked aminocombretastatin conjugates were synthesized and evaluated for cytotoxicity, inhibition of tubulin polymerization and apoptosis inducing ability. Most of the conjugates exhibited significant anticancer activity against
- Kamal, Ahmed,Shaik, Bajee,Nayak, V. Lakshma,Nagaraju, Burri,Kapure, Jeevak Sopanrao,Shaheer Malik,Shaik, Thokhir Basha,Prasad
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p. 5155 - 5167
(2014/12/11)
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- CuI/1,10-phen/PEG promoted decarboxylation of 2,3-diarylacrylic acids: Synthesis of stilbenes under neutral and microwave conditions with an in situ generated recyclable catalyst
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A series of trans- or cis-stilbenes have been synthesized in good to excellent yields via a functional group-dependent decarboxylation process from the corresponding 2,3-diaryl acrylic acids in a neutral CuI/1,10-phen/PEG-400 system under microwave conditions. The in situ generation of the recyclable catalytic complex, the use of environmentally benign solvent PEG-400, the operational simplicity, the short reaction times, as well as the functional group-dependent chemo- and stereo-selectivity have made the decarboxylation process a highly efficient and applicable protocol.
- Zou, Yong,Huang, Qi,Huang, Tong-Kun,Ni, Qing-Chun,Zhang, En-Sheng,Xu, Tian-Long,Yuan, Mu,Li, Jun
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p. 6967 - 6974
(2013/10/08)
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- Synthesis and mechanistic studies of novel spin-labeled combretastatin derivatives as potential antineoplastic agents
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Two series (14a-d and 21a-h) of novel spin-labeled combretastatin derivatives were synthesized and evaluated for cytotoxicity against four tumor cell lines (K562, SGC-7901, Hela and HepG-2). Simultaneously, a representative compound 21a was selected to investigate the antitumor mechanisms of these synthetic compounds. The results indicated that some of the compounds showed significant cytotoxicity against four tumor cell lines in vitro and were more active than etoposide, a clinically available anticancer drug. Among the newly synthesized compounds, 21a, 21b and 21c displayed the greatest cytotoxicity against three tested tumor cell lines (HEPG-2, BGC-832 and Hela), with IC 50 values ranging from 0.15 to 1.05 μM, compared with values of 0.014-0.403 μM for 3-amino-deoxycombretastatin A-4 (3). In addition, the mechanistic analysis revealed that compound 21a effectively interfered with tubulin dynamics to prevent mitosis in cancer cells, leading to cell cycle arrest and, eventually, dose dependent apoptosis.
- Liu, Ying-Qian,Li, Xiao-Jing,Zhao, Chun-Yan,Nan, Xiang,Tian, Jing,Morris-Natschke, Susan L.,Zhang, Zhi-Jun,Yang, Xiao-Ming,Yang, Liu,Li, Lin-Hai,Zhou, Xing-Wen,Lee, Kuo-Hsiung
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p. 1248 - 1256
(2013/03/14)
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- METHOD FOR PREPARING COMBRETASTATIN
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The Invention relates to a method for preparing a combretastatin (A): formula (I) in the form of a base or of an addition salt with an acid, which comprises coupling, in the presence of a base and of T3P, the salt of the (Z)-amino compound of formula (II)
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Page/Page column 4-5
(2011/06/19)
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- Synthesis and biological evaluation of combretastatin analogs as cell cycle inhibitors of the G1 to S transition in Saccharomyces cerevisiae
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A series of Z and E combretastatin A-4 analogs bearing different substituents (OH, F, NO2, NH2, B(OH)2) in the 3′ position were synthesized. These derivatives and Z and E combretastatin A-1 were analysed by monitoring their ability to inhibit cell growth in Saccharomyces cerevisiae. Combretastatin A-1 (2a), A-4 (2b) and compound 2c were found to inhibit yeast growth. Moreover, combretatstatin A-4 (2b) and compound 2c induced a G1 arrest by affecting the synthesis of Clb5 protein, the principal S-phase cyclin. The G1 arrest is coincident with the activation of the stress activated kinase Snf1.
- Coccetti, Paola,Montano, Giuseppe,Lombardo, Alessandro,Tripodi, Farida,Orsini, Fulvia,Pagliarin, Roberto
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supporting information; experimental part
p. 2780 - 2784
(2010/08/19)
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- Synthesis of conjugates of amino-combretastatin with tuftsin derivatives as potential anticancer agents
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Novel 3′-N-(tuftsin or retro-tuftsin)-amino-combretastatin conjugates have been synthesized as potential anticancer compounds. We hope that the conjugation of immunomodulators like tuftsin derivatives with amino-combretastatin A-4 would improve the therap
- Dzierzbicka
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scheme or table
p. 81 - 85
(2009/08/08)
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- Design, synthesis, and biological evaluation of combretastatin nitrogen-containing derivatives as inhibitors of tubulin assembly and vascular disrupting agents
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A series of analogs with nitro or serinamide substituents at the C-2′-, C-5′-, or C-6′-position of the combretastatin A-4 (CA4) B-ring was synthesized and evaluated for cytotoxic effects against heart endothelioma cells, blood flow reduction to tumors in
- Monk, Keith A.,Siles, Rogelio,Hadimani, Mallinath B.,Mugabe, Benon E.,Ackley, J. Freeland,Studerus, Scott W.,Edvardsen, Klaus,Trawick, Mary Lynn,Garner, Charles M.,Rhodes, Monte R.,Pettit, George R.,Pinney, Kevin G.
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p. 3231 - 3244
(2007/10/03)
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- Synthesis and cytotoxic evaluation of combretafurazans
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Combretastatin A-4 is an antitumoral and antitubulin agent that is active only in its cis configuration. In the present manuscript, we have synthesized cis-locked combretastatins embodying a furazan ring (combretafurazans). To achieve this, we have developed a new strategy that exploits the dehydration of vicinal dioximes using the Mitsunobu reaction. Among the advantages of following such a strategy are the mild conditions used for the construction of the diarylfurazan derivatives, allowing for the presence of highly functionalized substrates and deactivated aromatic rings. Combretafurazans are more potent in vitro cytotoxic compounds compared to combretastatins in neuroblastoma cells, yet maintaining similar structure-activity relationship and pharmacodynamic profiles.
- Tron, Gian Cesare,Pagliai, Francesca,Del Grosso, Erika,Genazzani, Armando A.,Sorba, Giovanni
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p. 3260 - 3268
(2007/10/03)
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- Antineoplastic agents. 445. Synthesis and evaluation of structural modifications of (Z)- and (E)-combretastatin A-4
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A series of cis- and trans-stilbenes related to combretastatin A-4 (1a), with a variety of substituents at the 3′-position of the aryl B-ring, were synthesized and evaluated for inhibitory activity employing six human cancer cell lines (NCI-H460 lung carc
- Pettit, George R.,Rhodes, Monte R.,Herald, Delbert L.,Hamel, Ernest,Schmidt, Jean M.,Pettit, Robin K.
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p. 4087 - 4099
(2007/10/03)
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- Method for preparing Combretastatin
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The invention concerns novel methods for preparing Combretastatin by Wittig condensation between nitromethoxy-benzaldehyde and a trimethoxybenzyl phosphonium salt or inversely a nitromethoxybenzyl phosphonium salt with trimethoxybenzylaldehyde or further by a Wittig reaction on the same derivatives whereof the nitro function has been reduced into an amino group.
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Page/Page column 10-11
(2008/06/13)
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- Structural requirements for the interaction of combretastatins with tubulin: how important is the trimethoxy unit?
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A series of combretastatins possessing both a trimethoxy unit and other substituents on ring A has been synthesised and tested for cytotoxicity and their ability to interact with the protein tubulin. All previous studies have indicated that the trimethoxy
- Gaukroger, Keira,Hadfield, John A,Lawrence, Nicholas J,Nolan, Steven,McGown, Alan T
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p. 3033 - 3037
(2007/10/03)
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- Description anti-mitotic agents which inhibit tubulin polymerization
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Methoxy and ethoxy substituted 3-aroyl-2-arylbenzo[b]thiophenes and benzo[b]thiophene analogues are described for use in inhibiting tubulin polymerization. The compounds' use for treating tumor cells is also described. Additional aspects described here are certain diaryl ether benzo[b]thiophene derivatives. Also described are particular analogs derived from dihydronaphthalene which have proven particularly effective. Certain new benzofuran analogs are described, as well as certain sulfur oxide benzo[b]thiophene analogs. Important compounds described herein include the first nitrogen-containing derivatives of combretastatin. These include nitro, amino and azide combrdtastatin derivatives.
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Page column 33-34
(2010/02/05)
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- Synthesis and biological evaluation of aryl azide derivatives of combretastatin a-4 as molecular probes for tubulin
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Two new aryl azides, (Z)-1-(3'-azido-4'-methoxyphenyl)-2-(3'',4'',5''-trimethoxyphenyl)ethene 9 and (Z)-1-(4'-azido-3'-methoxyphenyl)-2-(3'',4'',5''-trimethoxyphenyl)ethene 5, modeled after the potent antitumor, antimitotic agent combretastatin A-4 (CA-4)
- Pinney, Kevin G.,Mejia, Maria P.,Villalobos, Victor M.,Rosenquist, Brent E.,Pettit, George R.,Verdier-Pinard, Pascal,Hamel, Ernest
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p. 2417 - 2425
(2007/10/03)
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- Novel combretastatin analogues effective against murine solid tumors: Design and structure-activity relationships
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A series of combretastatin A-4 (CA-4) analogues were synthesized, and their cytotoxic effects against murine Colon 26 adenocarcinoma and inhibitory activity on tubulin polymerization were evaluated. Since CA-4 has limited aqueous solubility, the target co
- Ohsumi, Koji,Nakagawa, Ryusuke,Fukuda, Yumiko,Hatanaka, Toshihiro,Morinaga, Yoshihiro,Nihei, Yukio,Ohishi, Kazuo,Suga, Yasuyo,Akiyama, Yukio,Tsuji, Takashi
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p. 3022 - 3032
(2007/10/03)
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