Synthesis and evaluation of a series of quinolinyl trans-cyanostilbene analogs as anticancer agents

Penthala, Narsimha Reddy; Janganati, Venumadhav; Bommagani, Shobanbabu; Crooks, Peter A.

doi:10.1039/c4md00115j

Cited by 19 publications

(21 citation statements)

References 30 publications

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“…According to previous literature, base-catalyzed condensation of aryl/heteroaryl aldehydes with aryl/heteroaryl acetonitriles leads exclusively to the formation of the ( Z )-isomer. 14a–14c We confirmed the ( Z ) configuration of analogues 7a – 7g by carrying out carbon-proton coupling experiments to determine the magnitude of the coupling constant ( J CH ) of the CN carbon doublet that results from coupling with the adjacent olefinic proton. 14b …”

Section: Chemistrymentioning

confidence: 55%

“…1; structure D ); these compounds are potent anti-cancer agents which are not substrates for cellular P-glycoprotein. 14c In this respect, Ohsumi et al have reported that ( E )-substituted diarylacrylonitrile analogues structurally related to the combretastatins (Fig. 1; structure E ) are also effective anti-cancer agents against murine solid tumors.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis and evaluation of a series of resveratrol analogues as potent anti-cancer agents that target tubulin

et al. 2015

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A series of novel diarylacrylonitrile and trans-stilbene analogues of resveratrol has been synthesized and evaluated for their anticancer activities against a panel of 60 human cancer cell lines. The diarylacrylonitrile analogues 3b and 4a exhibited the most potent anticancer activity of all the analogues synthesized in this study, with GI50 values of < 10 nM against almost all the cell lines in the human cancer cell panel. Compounds 3b and 4a were also screened against the acute myeloid leukemia (AML) cell line, MV4-11, and were found to have potent cytotoxic properties that are likely mediated through inhibition of tubulin polymerization. Results from molecular docking studies indicate a common binding site for 4a and 3b on the 3,3-tubulin heterodimer, with a slightly more favorable binding for 3b compared to 4a; this is consistent with the results from the microtubule assays, which demonstrate that 4a is more potent than 3b in inhibiting tubulin polymerization in MV4-11 cells. Taken together, these data suggest that diarylacrylonitriles 3b and 4a may have potential as antitubulin therapeutics for treatment of both solid and hematological tumors.

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Section: Chemistrymentioning

confidence: 55%

Section: Introductionmentioning

confidence: 99%

Synthesis and evaluation of a series of resveratrol analogues as potent anti-cancer agents that target tubulin

et al. 2015

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“…We have recently reported on the synthesis and anti-cancer activities of a series of ( Z )-quinolinylcyano- ( V ) and ( E)- and ( Z ) - benzothiophene cyanocombretastatin analogues (Fig. 1, VI ) [11, 12], and have determined that such analogues (e.g. compound 29 , Fig.…”

Section: Introductionmentioning

confidence: 99%

“…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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“…17 Also, we have recently described the synthesis and potent anti-cancer activity of some cis - and trans -cyanostilbene analogs in which one of the phenyl moieties has been replaced with a heteroaromatic moiety such as benzothiophene 19 and quinoline. 20 …”

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Heteroaromatic analogs of the resveratrol analog DMU-212 as potent anti-cancer agents

Penthala¹,

Thakkar²,

Crooks³

2015

Bioorganic & Medicinal Chemistry Letters

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Heteroaromatic analogs of DMU-212 (8–15) have been synthesized and evaluated for their anticancer activity against a panel of 60 human cancer cell lines. These novel analogs contain a trans-3,4,5-trimethoxystyryl moiety attached to the C2 position of indole, benzofuran, benzothiazole or benzothiophene ring (8, 11, 13 and 14, respectively) and showed potent growth inhibition in 85% of the cancer cell lines examined, with GI50 values <1 µM. Interestingly, trans-3,4- and trans-3,5-dimethoxystyryl DMU-212 analogs 9, 10, 12 and 15 exhibited significantly less growth inhibition than their 3,4,5-trimethoxystyryl counterparts, suggesting that the trans-3,4,5-trimethoxystyryl moiety is an essential structural element for the potent anticancer activity of these heterocyclic DMU-212 analogs. Molecular modeling studies showed that the four most active compounds (8, 11, 13 and 14) all bind to the colchicine binding site on tubulin, and that their binding modes are similar to that of DMU-212.

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Synthesis and evaluation of a series of quinolinyl trans-cyanostilbene analogs as anticancer agents

Abstract: 2-Quinolyl- and 3-quinolyl-cyanocombretastatin analogs exhibit potent growth inhibition against a panel of 60 human cancer cell lines.

Cited by 19 publications

References 30 publications

Synthesis and evaluation of a series of resveratrol analogues as potent anti-cancer agents that target tubulin

Synthesis and evaluation of a series of resveratrol analogues as potent anti-cancer agents that target tubulin

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

Heteroaromatic analogs of the resveratrol analog DMU-212 as potent anti-cancer agents

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