N-(1′-naphthyl)-3,4,5-trimethoxybenzohydrazide as microtubule destabilizer: Synthesis, cytotoxicity, inhibition of cell migration and in vivo activity against acute lymphoblastic leukemia

Salum, Lívia B.; Mascarello, Alessandra; Canevarolo, Rafael Renatino; Altei, Wanessa Fernanda; Laranjeira, Angelo Brunelli Albertoni; Neuenfeldt, Patrícia D.; Stumpf, Taisa Regina; Chiaradia-Delatorre, Louise Domeneghini; Vollmer, Laura L.; Daghestani, Hikmat N.; Melo, Carolina Pereira de Souza; Silveira, André B.; Leal, Paulo César; Frederico, Marisa Jádna Silva; Nascimento, Leandro F.; Santos, Adair R.S.; Andricopulo, Adriano D.; Day, Billy W.; Yunes, Rosendo A.; Vogt, Andreas; Yunes, José Andrés; Nunes, Ricardo José

doi:10.1016/j.ejmech.2015.02.041

Cited by 36 publications

(31 citation statements)

References 34 publications

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“…Simultaneous removal of the methoxy groups on both rings results in dramatic potency losses . Replacement of the hydroxy group at the 3 position of the B ring by an amino group maintains the potency, but substitution of the p‐ methoxy group by methyl, amino, or acetamido groups decreases cytotoxicity . The trimethoxyphenyl ring is required in combretastatins for high cytotoxicity but for diarylsulfonamides it can be successfully replaced by 2‐acetamido‐ or 2‐ethylureido‐phenyl groups, structurally more akin to ABT‐751…”

Section: The Sulfonamidesmentioning

confidence: 99%

Antitubulin sulfonamides: The successful combination of an established drug class and a multifaceted target

Vicente‐Blázquez

González

Álvarez

et al. 2018

Medicinal Research Reviews

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Tubulin, the microtubules and their dynamic behavior are amongst the most successful antitumor, antifungal, antiparasitic, and herbicidal drug targets. Sulfonamides are exemplary drugs with applications in the clinic, in veterinary and in the agrochemical industry. This review summarizes the actual state and recent progress of both fields looking from the double point of view of the target and its drugs, with special focus onto the structural aspects. The article starts with a brief description of tubulin structure and its dynamic assembly and disassembly into microtubules and other polymers. Posttranslational modifications and the many cellular means of regulating and modulating tubulin's biology are briefly presented in the tubulin code. Next, the structurally characterized drug binding sites, their occupying drugs and the effects they induce are described, emphasizing on the structural requirements for high potency, selectivity, and low toxicity. The second part starts with a summary of the favorable and highly tunable combination of physical-chemical and biological properties that render sulfonamides a prototypical example of privileged scaffolds with representatives in many therapeutic areas. A complete description of tubulin-binding sulfonamides is provided, covering the different species and drug sites. Some of the antimitotic sulfonamides have met with very successful Med Res Rev. 2019;39:775-830. wileyonlinelibrary.com/journal/med © 2018 Wiley Periodicals, Inc. | 775applications and others less so, thus illustrating the advances, limitations, and future perspectives of the field.All of them combine in a mechanism of action and a clinical outcome that conform efficient drugs. K E Y W O R D S molecular mechanisms, sulfonamides, tubulin binding drugs, tubulin binding sites 1 | INTRODUCTION Drugs targeting tubulin and the microtubules (tubulin binding drugs [TBDs]) are amongst the most successful antitumor, antifungal, antiparasitic, and herbicidal agents with applications in the clinic, in veterinary and in the agrochemical industry. Recently, the combination of computational methods, medicinal chemistry, biochemistry, structural biology, and cell biology is starting to unravel the intricacies of tubulin binding drugs and of the microtubules themselves, thus paving the way towards new and better TBDs. New methodological advances such as the high resolution cryo-electron microscopy, the imaging of individual microtubule dynamics, and the achievement of recombinant tubulin, altogether with more established methodologies for the study of the microtubules have combined to provide a sharper view of the structure and function of these essential cell components and their interactions with clinically important drugs. The sulfonamides are a prototypical example of privileged scaffolds, with representatives in many therapeutic areas, due to a combination of favorable and highly tunable physical-chemical and biological properties. The early discovery of the dinitroaniline herbicides, and mainly the seminal discovery o...

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Section: The Sulfonamidesmentioning

confidence: 99%

Antitubulin sulfonamides: The successful combination of an established drug class and a multifaceted target

Vicente‐Blázquez

González

Álvarez

et al. 2018

Medicinal Research Reviews

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“…Hydrazone is another biologically active pharmacophore group. N -(1′-Naphthyl)-3,4,5-trimethoxybenzohydrazide has been reported as a potential anti-leukemia agent acting as a microtubule destabilizer [11]. 2- N -Heteroaryl caffeine hydrazones demonstrated high activity toward T-lymphoblastic leukemia cells and inhibited both RNA and DNA synthesis and mitosis [12].…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis and Evaluation of Antiproliferative Activity of New Benzimidazolehydrazones

et al. 2016

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Abstract:The synthesis and antiproliferative activity of new benzimidazole derivatives bearing an hydrazone mojety at the 2-position is described. The new N 1 -(4-arylidene)-1H-benzo[d]imidazole-2-carbohydrazides were evaluated for their cytostatic activity toward the murine leukemia (L1210), human T-cell leukemia (CEM), human cervix carcinoma (HeLa) and human pancreas carcinoma cells (Mia Paca-2). A preliminary structure-activity relationship could be defined. Some of the compounds possess encouraging and consistent antiproliferative activity, having IC 50 values in the low micromolar range.

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“…Further work will be required to derivatize the lead structures in order to gain greater potency, to assess molecular targets in detail, and determine if these compounds can affect the tubulin colchicine site, which could provide a means of overcoming multidrug resistance, in particular to taxanes (24). …”

Section: Discussionmentioning

confidence: 99%

Substituted Tetrahydroisoquinolines as Microtubule-destabilizing Agents in Triple Νegative Human Breast Cancer Cells

Gangapuram

Jean

Mazzio

et al. 2016

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Triple-negative breast cancer (TNBC) occurs in greater frequency amongst African-Americans, and is characterized by the absence of estrogen receptor (ER), progesterone receptor (PR) and human epidermal receptor 2 (HER2). TNBC is often invasive and typically treated with cytostatic agents such as taxanes in combination with anthracyclines or platinum-based drugs. In this study, we synthesized a number of tetrahydroisoquinoline moieties by N-amination of substituted isoquinolines by O-mesytelene sulfonylhydroxylamine followed by ylide formation and reduction, which yielded the desired, substituted tetrahydroisoquinolines (THIQs) in moderate to good yield. Using a differential scatter plot to identify potential selective ER-modulating drugs in ER-positive control cells (MCF-7) driven by estradiol vs. TNBC (MDA-MB-231) cells, the in vitro data showed an absence of effects on the ER (compared to 4-hydroxy-tamoxifen and raloxifene). In contrast, two lead compounds halted proliferation (cytostatic) in MDA-MB-231 TNBC cells at a potency level below 2.5 µM concomitant with mitotic arrest, attenuated replicative DNA synthesis, halted microtubule nucleation/stunted tubulin polymerization, abnormal expansive cytoskeletal tubulin and actin morphologies with multinucleation of cells. The most effective cytostatic compounds GM-4-53 and GM-3-121 blocked replicative processes at the G2 growth phase. These findings suggest that specific THIQs work independently of the ER, by holding static the microtubule network thereby preventing mitosis. Future work will be required to establish the safety and efficacy of these drugs and their potential adjunct therapeutic gain in the presence of taxanes in TNBC.

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N-(1′-naphthyl)-3,4,5-trimethoxybenzohydrazide as microtubule destabilizer: Synthesis, cytotoxicity, inhibition of cell migration and in vivo activity against acute lymphoblastic leukemia

Cited by 36 publications

References 34 publications

Antitubulin sulfonamides: The successful combination of an established drug class and a multifaceted target

Antitubulin sulfonamides: The successful combination of an established drug class and a multifaceted target

Design, Synthesis and Evaluation of Antiproliferative Activity of New Benzimidazolehydrazones

Substituted Tetrahydroisoquinolines as Microtubule-destabilizing Agents in Triple Νegative Human Breast Cancer Cells

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