Structure-Activity Relationship Studies of β-Lactam-azide Analogues as Orally Active Antitumor Agents Targeting the Tubulin Colchicine Site

Fu, Dong-Jun; Fu, Ling; Liu, Yingchao; Wang, Junwei; Wang, Yuqing; Han, Bing-Kai; Li, Xiaorui; Zhang, Chuang; Li, Feng; Song, Jian; Zhao, Bing; Mao, Ruo-Wang; Zhao, Ruo; Zhang, Sai‐Yang; Zhang, Li; Zhang, Yanbing; Liu, Hong‐Min

doi:10.1038/s41598-017-12912-4

Cited by 31 publications

(12 citation statements)

References 56 publications

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“…Previous studies have investigated different compounds containing the 3,4,5trimethoxyphenyl ring in order to understand its contribution to the biological activity [21]. For example, in a study performed by Dong-Jun et al, the authors showed that 3,4,5trimethoxyphenyl moiety at the N-1 position of the β-lactam-azide derivatives was crucial for the antiproliferative activity against MGC-803, MCF-7, and A549 cancer cell lines [22]. Furthermore, anticancer compounds such as colchicine, steganacin, phenstatin, podophyllotoxin, combretastatin, and other synthetic analogues of these compounds share a 3,4,5-trimethoxyphenyl moiety as a common structural feature [23].…”

Section: Structure-activity Relationship (Sar)mentioning

confidence: 99%

“…For this study, a series of 32 analogues of 1 (Scheme 1) were synthesized, preserving the (E)-3-(3,4,5-trimethoxyphenyl)-acryloyl moiety on cinnamic esters and amides and changing this moiety on benzoic esters by removing the ethylene group between carbons 2 and 3. Side-chain modi cations were also evaluated changing the radical R to methyl (5), ethyl (6), propyl (7), iPr (8), butyl (9), pentyl (10), decyl (11), 2-methoxyethyl (12), 4-methoxybenzyl (13), phenylethyl (14), 4-methylphenylethyl (15), carvacryl (16), CHPh 2 (17), furfuryl (18), eugenyl (19), (−)-bornyl (20) and piperonyl (21) on cinnamic esters, and butyl (22), N,N-diethyl (23), octyl (24), cyclohexyl (25) benzyl (26), pyrrolidyl (27), 4-methylbenzyl (28), 4-methoxybenzyl (29), 4-uorobenzyl (30), 4-chlorobenzyl (31), 4-bromobenzyl (32) 2,4-dimethoxybenzyl (33), and 3,4-dimethoxybenzyl (34) on amides. e benzoic esters synthetized were 2methoxyethyl-3,4,5-trimethoxybenzoate (35) and benzyl 3,4,5-trimethoxybenzoate (36) [8][9][10][11][12].…”

Section: Introductionmentioning

confidence: 99%

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Design, Antileishmanial Activity, and QSAR Studies of a Series of Piplartine Analogues

Nóbrega

Silva

Filho

et al. 2019

Journal of Chemistry

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Piplartine is an alkamide found in different Piper species and possesses several biological activities, including antiparasitic properties. Thus, the aim of the present study was to evaluate a series of 32 synthetic piplartine analogues against the Leishmania amazonensis promastigote forms and establish the structure-activity relationship and 3D-QSAR of these compounds. The antileishmanial effect of the compounds was determined using the MTT method. Most compounds were found to be active against L. amazonensis. Among 32 assayed derivatives, compound (E)-(−)-bornyl 3-(3,4,5-trimethoxyphenyl)-acrylate exhibited the most potent antileishmanial activity (IC50 = 0.007 ± 0.008 μM, SI > 10), followed by benzyl 3,4,5-trimethoxybenzoate (IC50 = 0.025 ± 0.009 μM, SI > 3.205) and (E)-furfuryl 3-(3,4,5-trimethoxyphenyl)-acrylate (IC50 = 0.029 ± 0.007 μM, SI > 2.688). It was found that the rigid substituents contribute to increasing antiparasitic activity against L. amazonensis promastigotes. The presence of the unsaturated heterocyclic substituent in the phenylpropanoid chemical structure (furfuryl group) resulted in a bioactive derivative. Molecular simplification of benzyl 3,4,5-trimethoxybenzoate by omitting the spacer group contributed to the bioactivity of this compound. Furthermore, bornyl radical appears to be important for antileishmanial activity, since (E)-(−)-bornyl 3-(3,4,5-trimethoxyphenyl)-acrylate exhibited the most potent antileishmanial activity. These results show that some derivatives studied would be useful as prototype molecules for the planning of new derivatives with profile of antileishmanial drugs.

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Section: Structure-activity Relationship (Sar)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Design, Antileishmanial Activity, and QSAR Studies of a Series of Piplartine Analogues

Nóbrega

Silva

Filho

et al. 2019

Journal of Chemistry

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“…However, because of extensive use, many bacteria have developed resistance to -lactam antibiotics. Additionally, the antiproliferative activity of compounds containing the -lactam (azetidin-2-one) ring structure has been investigated (Zhou et al 2018;Galletti et al 2014;Geesala et al, 2016;Arya et al, 2014;Fu et al, 2017). We have previously demonstrated the effectiveness of 1,4-diarylazetidin-2-ones in breast-cancer cell lines as tubulin-targeting antimitotic agents and selective estrogen-receptor modulators (SERMs;O'Boyle et al, 2014).…”

Section: Chemical Contextmentioning

confidence: 99%

Azetidin-2-ones: structures of antimitotic compounds based on the 1-(3,4,5-trimethoxyphenyl)azetidin-2-one core

Twamley¹,

O’Boyle²,

Meegan³

2020

Acta Crystallogr E Cryst Commun

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A series of related substituted 1-(3,4,5-trimethoxyphenyl)azetidin-2-ones have been characterized: 3-(4-fluorophenyl)-4-(4-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)azetidin-2-one, C25H24FNO5 (1), 3-(furan-2-yl)-4-(4-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)azetidin-2-one, C23H23NO6 (2), 4-(4-methoxyphenyl)-3-(naphthalen-1-yl)-1-(3,4,5-trimethoxyphenyl)azetidin-2-one, C29H27NO5 (3), 3-(3,4-dimethoxyphenyl)-4-(4-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)azetidin-2-one, C27H29NO7 (4) and 4,4-bis(4-methoxyphenyl)-3-phenyl-1-(3,4,5-trimethoxyphenyl)azetidin-2-one, C32H31NO6 (5). All of the compounds are racemic. The lactam and 3,4,5-trimethoxyphenyl rings are approximately co-planar and the orientation of the lactam and the 4-methoxyphenyl substituent is approximately orthogonal. The chiral centres, although eclipsed by geometry, have torsion angles ranging from −7.27 to 13.08° for the 3 position, and −8.69 to 13.76° for the 4 position of the β-lactam. The structures display intramolecular C—H...O bonding between the 3,4,5-trimethoxyphenyl ring and the lactam ketone. Further C—H...O interactions are observed and form either an opposing methoxy `buckle' to join two molecules together or a cyclic dimer.

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“…Small molecule tubulin polymerization inhibitors have been reported in which the cis double bond of CA-4 has been replaced by various heterocycles such as furan [25], indole[26,27], imidazole [28], isoxazole [29], triazole [30], tetrazole [31], benzoxepine [32], pyrazole [33], pyridine [34], benzimidazole [35] and related heterocycles [36]. While β-lactam antibiotics have occupied a central role in the treatment of pathogenic bacteria, the antiproliferative activity of compounds containing the β-lactam (azetidin-2-one) ring has also been investigated [37,38,39,40,41,42]. The synthesis and antitumour activity of a number of chiral β-lactam bridged CA-4 analogues have been reported [37,38].…”

Section: Introductionmentioning

confidence: 99%

3-Vinylazetidin-2-Ones: Synthesis, Antiproliferative and Tubulin Destabilizing Activity in MCF-7 and MDA-MB-231 Breast Cancer Cells

et al. 2019

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Microtubule-targeted drugs are essential chemotherapeutic agents for various types of cancer. A series of 3-vinyl-β-lactams (2-azetidinones) were designed, synthesized and evaluated as potential tubulin polymerization inhibitors, and for their antiproliferative effects in breast cancer cells. These compounds showed potent activity in MCF-7 breast cancer cells with an IC50 value of 8 nM for compound 7s 4-[3-Hydroxy-4-methoxyphenyl]-1-(3,4,5-trimethoxyphenyl)-3-vinylazetidin-2-one) which was comparable to the activity of Combretastatin A-4. Compound 7s had minimal cytotoxicity against both non-tumorigenic HEK-293T cells and murine mammary epithelial cells. The compounds inhibited the polymerisation of tubulin in vitro with an 8.7-fold reduction in tubulin polymerization at 10 M for compound 7s and were shown to interact at the colchicine-binding site on tubulin, resulting in significant G2/M phase cell cycle arrest. Immunofluorescence staining of MCF-7 cells confirmed that β-lactam 7s is targeting tubulin and resulted in mitotic catastrophe. A docking simulation indicated potential binding conformations for the 3-vinyl-β-lactam 7s in the colchicine domain of tubulin. These compounds are promising candidates for development as antiproiferative microtubule-disrupting agents.

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Structure-Activity Relationship Studies of β-Lactam-azide Analogues as Orally Active Antitumor Agents Targeting the Tubulin Colchicine Site

Cited by 31 publications

References 56 publications

Design, Antileishmanial Activity, and QSAR Studies of a Series of Piplartine Analogues

Design, Antileishmanial Activity, and QSAR Studies of a Series of Piplartine Analogues

Azetidin-2-ones: structures of antimitotic compounds based on the 1-(3,4,5-trimethoxyphenyl)azetidin-2-one core

3-Vinylazetidin-2-Ones: Synthesis, Antiproliferative and Tubulin Destabilizing Activity in MCF-7 and MDA-MB-231 Breast Cancer Cells

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