Design, Synthesis, and Biological Evaluation of 1-Methyl-1,4-dihydroindeno[1,2-<i>c</i>]pyrazole Analogues as Potential Anticancer Agents Targeting Tubulin Colchicine Binding Site

Liu, Yanna; Wang, Jingjing; Ji, Ya-Ting; Zhao, Guodong; Tang, Liang‐Fu; Zhang, Chengmei; Guo, Xiu-Li; Liu, Zhaopeng

doi:10.1021/acs.jmedchem.6b00071

Cited by 76 publications

(54 citation statements)

References 52 publications

(103 reference statements)

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“…As the microtubule system plays a vital role in the maintenance of cell shape and basic cellular functions, an immunofluorescence staining assay was performed to study whether compound 28 could disrupt the microtubule dynamics in living cells 45 . 0.075 μM 28 moderately depolymerized interphase microtubules, whereas the depolymerization effect of 0.3 μM 28 is much stronger in MGC-803 cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

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

Liu

et al. 2017

Sci Rep

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We have synthesized a series of new β-lactam-azide derivatives as orally active anti-tumor agents by targeting tubulin colchicine binding site and examined their structure activity relationship (SAR). Among them, compound 28 exhibited the most potent antiproliferative activity against MGC-803 cells with an IC50 value of 0.106 μM by induction of G2/M arrest and apoptosis and inhibition of the epithelial to mesenchymal transition. 28 acted as a novel inhibitor of tubulin polymerization by its binding to the colchicine site. SAR analysis revealed that a hydrogen atom at the C-3 position of the β-lactam was required for the potent antiproliferative activity of β-lactam-azide derivatives. Oral administration of compound 28 also effectively inhibited MGC-803 xenograft tumor growth in vivo in nude mice without causing significant loss of body weight. These results suggested that compound 28 is a promising orally active anticancer agent with potential for development of further clinical applications.

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Section: Resultsmentioning

confidence: 99%

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

Liu

et al. 2017

Sci Rep

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“…The results of the experiment showed that the effects of MMAE (EC 50 = 1.426 µM) on tubulin were reduced when the N-terminus was modified with the linkers (Cys-11-Cys-15: EC 50 = 1.525-2.903 µM), but this effect was relatively limited (Figure 2). All of the tested Cys-linker-MMAE conjugates produced concentration-dependent inhibition of tubulin polymerization, providing a basis for developing ADCs with Cys-linker-MMAE as potent payloads [27]. In addition, the results also show that the effect of linker length on the activity of the conjugate is weak, and the insertion of the p-aminobenzyl alcohol (PAB) structure in the linker does not significantly reduce its activity.…”

Section: Tubulin Polymerization Inhibition Studymentioning

confidence: 90%

Antibody-Drug Conjugate Using Ionized Cys-Linker-MMAE as the Potent Payload Shows Optimal Therapeutic Safety

Wang¹,

Liu²,

Fan³

et al. 2020

Cancers

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Monomethyl auristatin E (MMAE) is the most popular and widely used cytotoxin in the development of antibody-drug conjugates (ADCs). However, current MMAE-based ADCs are all constructed using cleavable linkers, and this design concept still has insurmountable drawbacks. Their potential instabilities and lipophilic MMAE-induced “bystander effect” inevitably increase the toxicity to normal tissues. Herein, we overturn previous negative views of MMAE-based ADCs with non-cleavable linkers and propose using ionized L-Cysteine (Cys)-linker-MMAE as a novel payload, which can ingeniously enrich and enter tumor cells through receptor-mediated endocytosis of antibodies while its lower permeability helps to avoid further off-target toxicity. We demonstrate that Cys-linker-MMAE maintains high potency similar to free MMAE at the tubulin molecular level and can also be efficiently released in target cells. As a result, the preferred ADC (mil40-15) not only exhibits ideal plasma stability and maintains potent cytotoxicity as MMAE (IC50: 10−11 M), but also shows improved safety with lower bystander toxicity (IC50: 10−9 M), its maximum tolerated dose approaching the level of the naked antibody (160 mg/kg). This study indicated that Cys-linker-MMAE has the potential as a potent payload for ADCs, which is expected to provide novel strategies for the development of MMAE-based ADCs.

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“…DHPAC is a MTA that targets the colchicine binding site. 29 In previous studies, we did not investigate whether or not DHPAC can enter cells. In this study, we first used HPLC-MS/MS to assess whether DHPAC can enter cells.…”

Section: Dhpac Enters Cells and Inhibits Huvec Proliferationmentioning

confidence: 98%

“…DHPAC was obtained from the Institute of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University. 29 Combretastain A4 (CA4) was purchased from Meilun Biotechnology Co, Ltd (Dalian, China). DHPAC and CA4 ( Figure 1A1,A2) were dissolved in dimethyl sulfoxide (DMSO) and stored at −20°C.…”

Section: Compoundsmentioning

confidence: 99%

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DHPAC, a novel microtubule depolymerizing agent, suppresses angiogenesis and vasculogenic mimicry formation of human non‐small cell lung cancer

Gong

Wang

et al. 2020

J of Cellular Biochemistry

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Angiogenesis and vasculogenic mimicry (VM) are the main causes of tumor metastasis and recurrence. In this study, we investigated the antiangiogenesis and anti-VM formation of a novel microtubule depolymerizing agent, DHPAC, as well as combretastatin A4 (CA4, a combretastatin derivate) in non-small-cell lung cancer (NSCLC), subsequently elucidating the underlying mechanisms. In human umbilical vein endothelial cells (HUVECs), DHPAC could enter cells and inhibit proliferation, migration, and angiogenesis in the presence and absence of conditioned medium from H1299 cells. Interestingly, the inhibition was enhanced under the stimulation of the conditioned medium. Under hypoxia or normoxia, DHPAC suppressed signal transducer and activator of transcription 3 phosphorylation and reduced vascular endothelial growth factor (VEGF) expression and secretion from HUVECs, thus impeding the activation of the downstream signal transduction pathway of VEGF/VEGFR2. However, JNK inhibitors reversed the inhibitory effect of DHPAC on the angiogenesis, suggesting that DHPAC regulated angiogenesis through activating JNK. In H1299 cells, DHPAC could inhibit proliferation, migration, invasion, and the formation of VM. In addition, DHPAC inhibited the phosphorylation of FAK and AKT and decreased the expressions of VEGF, matrix metalloproteinase 2 (MMP2), MMP9 and Laminin 5, suggesting that DHPAC inhibited VM formation via the FAK/AKT signaling pathway. In addition, CA4 showed a similar effect as DHPAC against angiogenesis and VM formation. These new findings support the use of microtubule destabilizing agents as a promising strategy for cancer therapy.

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Design, Synthesis, and Biological Evaluation of 1-Methyl-1,4-dihydroindeno[1,2-c]pyrazole Analogues as Potential Anticancer Agents Targeting Tubulin Colchicine Binding Site

Cited by 76 publications

References 52 publications

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

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

Antibody-Drug Conjugate Using Ionized Cys-Linker-MMAE as the Potent Payload Shows Optimal Therapeutic Safety

DHPAC, a novel microtubule depolymerizing agent, suppresses angiogenesis and vasculogenic mimicry formation of human non‐small cell lung cancer

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