A new family of quinoline and quinoxaline analogues of combretastatins

Pérez-Melero, Concepción; Maya, Ana B.S.; Rey, Benedicto del; Peláez, Rafael; Caballero, Esther; Medarde, Manuel

doi:10.1016/j.bmcl.2004.04.098

Cited by 72 publications

(27 citation statements)

References 10 publications

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“…Previous studies on combretastatin analogues have shown that replacement of the 3-hydroxy-4-methoxyphenyl moiety of CA-4 with heterocyclic groups such as quinoline, quinazoline and benzothiophene results in improved anti-cancer activity [11, 12, 33]. In the present work, we have synthesized a variety of heterocyclic ( Z )-cyanocombretastatin analogues that incorporate 2- and 3-indolyl, 2- and 3-benzofuranyl, 2-benzothiophenyl, and 2-benzothiazolyl moieties as replacements for the 3-fluoro-4-methoxyphenyl group in ( Z )-cyano CA-4 [9] (Fig.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, anticancer activity and molecular docking studies on a series of heterocyclic trans-cyanocombretastatin analogues as antitubulin agents

Penthala

Zong

Ketkar

et al. 2015

European Journal of Medicinal Chemistry

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A series of heterocyclic combretastatin analogues have been synthesized and evaluated for their anticancer activity against a panel of 60 human cancer cell lines. The most potent compounds were two 3,4,5-trimethoxy phenyl analogues containing either an (Z)-indol-2-yl (8) or (Z)-benzo[b]furan-2-yl (12) moiety; these compounds exhibited GI50 values of <10 nM against 74% and 70%, respectively, of the human cancer cell lines in the 60-cell panel. Compounds 8, and 12 and two previously reported compounds in the same structural class, i.e. 29 and 31, also showed potent anti-leukemic activity against leukemia MV4-11 cell lines with LD50 values = 44 nM, 47 nM, 18 nM, and 180 nM, respectively. From the NCI anti-cancer screening results and the data from the in vitro toxicity screening on cultured AML cells, seven compounds: 8, 12, 21, 23, 25, 29 and 31 were screened for their in vitro inhibitory activity on tubulin polymerization in MV4-11 AML cells; at 50 nM, 8 and 29 inhibited polymerization of tubulin by >50%. The binding modes of the three most active compounds (8, 12 and 29) to tubulin were also investigated utilizing molecular docking studies. All three molecules were observed to bind in the same hydrophobic pocket at the interface of α- and β-tubulin that is occupied by colchicine, and were stablized by van der Waals’ interactions with surrounding tubulin residues. The results from the tubulin polymerization and molecular docking studies indicate that compounds 8 and 29 are the most potent anti-leukemic compounds in this structural class, and are considered lead compounds for further development as anti-leukemic drugs.

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Section: Introductionmentioning

confidence: 99%

Synthesis, anticancer activity and molecular docking studies on a series of heterocyclic trans-cyanocombretastatin analogues as antitubulin agents

Penthala

Zong

Ketkar

et al. 2015

European Journal of Medicinal Chemistry

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“…A water soluble disodium phosphate derivative of CA-4 (CA-4P, fosbretabulin) has shown promising results in human cancer clinical trials [3,4], thus stimulating significant interest in a variety of CA-4 analogues [5]. Different analogs of combretastatins are obtained, including heterocombretastatins containing heterocyclic fragments as rings A or B [6][7][8][9][10][11][12]. A considerable cytotoxicity and antitubulin activity was revealed for heterocombretastatins containing a (4-methoxypyridin-3-yl)-or a (1-methyl-2-oxo-1,2-dihydropyridin-4-yl) ring B [6].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Cytotoxic Activity of a New Group of Heterocyclic Analogues of the Combretastatins

et al. 2014

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A series of new analogs of combretastatin A-4 (CA-4, 1) with the A or B-ring replaced by a 3-oxo-2,3-dihydrofurocoumarin or a furocoumarin residue have been designed and synthesized by employing a cross-coupling approach. All the compounds were evaluated for their cytotoxic activity with respect to model cancer cell lines (CEM-13, MT-4, U-937) using conventional MTT assays. Structure-activity relationship analysis reveals that compounds 2, 3, 6-8 in which the (Z)-styryl substituent was connected to the 2-position of the 3-oxo-2,3-dihydrofurocoumarin core, demonstrated increased potency compared to 3-(Z)-styrylfurocoumarins 4, 5, 9-11. The methoxy-, hydroxyl-and formyl-substitution on the aromatic ring of the (Z)-styryl moiety seems to play an important role in this class of compounds. Compounds 2 and 3 showed the best potency against the CEM-13 cell lines, with CTD 50 values ranging from 4.9 to 5.1 μM. In comparison with CA-4, all synthesized compounds presented moderate cytotoxic activity to the T-cellular human leucosis cells MT-4 and lymphoblastoid leukemia cells CEM-13, but most of them were active in the human monocyte cell lines U-937.

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“…Quinoxaline and quinoxaline 1,4-di- N -oxide are heterocycles that are often used in the synthesis of biologically active compounds [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31]. The former is described as a bioisoster of the quinoline, naphthyl, benzothienyl and other aromatic rings [32], and it can be found in the structure of anti-bacterial [1], anti-tuberculosis [5,6,7,9,10,11,13,14,16,22], anti-cancer [8,18,20,28], anti-malarial [12,24,26,29,30,31], anti-Chagas [15,25] and anti-inflammatory [19,27] drug candidates.…”

Section: Introductionmentioning

confidence: 99%

Unexpected Reduction of Ethyl 3-Phenylquinoxaline-2- carboxylate 1,4-Di-N-oxide Derivatives by Amines

et al. 2008

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The unexpected tendency of amines and functionalized hydrazines to reduce ethyl 3-phenylquinoxaline-2-carboxylate 1,4-di-N-oxide (1) to afford a quinoxaline 1c and mono-oxide quinoxalines 1a and 1b is described. The experimental conditions were standardized to the use of two equivalents of amine in ethanol under reflux for two hours, with the aim of studying the distinct reductive profiles of the amines and the chemoselectivity of the process. With the exception of hydrazine hydrate, which reduced compound 1 to a 3-phenyl-2-quinoxalinecarbohydrazide derivative, the amines only acted as reducing agents.

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A new family of quinoline and quinoxaline analogues of combretastatins

Cited by 72 publications

References 10 publications

Synthesis, anticancer activity and molecular docking studies on a series of heterocyclic trans-cyanocombretastatin analogues as antitubulin agents

Synthesis, anticancer activity and molecular docking studies on a series of heterocyclic trans-cyanocombretastatin analogues as antitubulin agents

Synthesis and Cytotoxic Activity of a New Group of Heterocyclic Analogues of the Combretastatins

Unexpected Reduction of Ethyl 3-Phenylquinoxaline-2- carboxylate 1,4-Di-N-oxide Derivatives by Amines

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