Pyridine Based Antitumour Compounds Acting at the Colchicine Site

Álvarez, Raquel; Aramburu, Laura; Puebla, Pilar; Caballero, Esther; González, Myriam; Vicente, Alba; Medarde, Manuel; Peláez, Rafael

doi:10.2174/092986732311160420104823

Cited by 42 publications

(21 citation statements)

References 241 publications

(311 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The first pocket contacts both the α (B5‐H5 loop) and β subunits (H10‐B9 loop, H8, and B9), the central one is located at the C‐terminus of the central H7, over B8, B9 ,and B10 and covered by the displaced H10‐B9 loop and H8, while the third pocket is more buried in the β subunit, passing behind H8 towards the sheet formed by B1, B4, B5, and B6 and covered by H1 and the middle part of H7. Currently, most of the colchicine‐domain drugs structurally characterized bind only to two contiguous pockets out of the available three, with the exception of the sulfonamide ABT‐751 and the pyrimidine lexibulin which binds completely to two of them but also partially occupy the third one …”

Section: Tubulin As a Targetmentioning

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

View full text Add to dashboard Cite

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...

show abstract

Section: Tubulin As a Targetmentioning

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

View full text Add to dashboard Cite

show abstract

“…Another important property is the polarity which can be used as a mean of reducing the lipophilic character, improving water solubility and oral absorption. 24 The quinoline motif is frequently found in natural alkaloids that exhibit a wide range of biological activities. The quinoline ring system-containing drugs, such as quinine, chloroquine, mefloquine and amodiaquine, are used as efficient treatments of malaria.…”

Section: Introductionmentioning

confidence: 99%

Discovery of Novel Quinoline–Chalcone Derivatives as Potent Antitumor Agents with Microtubule Polymerization Inhibitory Activity

Wen

et al. 2018

J. Med. Chem.

View full text Add to dashboard Cite

A series of novel quinoline-chalcone derivatives were designed, synthesized and evaluated for their antiproliferative activity. Among them, compound 24d exhibited the most potent activity with IC50 values ranging from 0.009 to 0.016 μM in a panel of cancer cell lines. Compound 24d also displayed a good safety profile with LD50 value of 665.62 mg/kg by intravenous injection, and its hydrochloride salt 24d-HCl significantly inhibited tumor growth in H22 xenograft models without observable toxic effects, which was more potent than that of CA-4. Mechanism studies demonstrated that 24d bound to the colchicine site of tubulin, arrested cell cycle at the G2/M phase, induced apoptosis, depolarized mitochondria and induced reactive oxidative stress (ROS) generation in K562 cells. Moreover, 24d has potent in vitro anti-metastasis, in vitro and in vivo anti-vascular activities. Collectively, our findings suggest that 24d deserves to be further investigated as a potent and safe anti-tumor agent for cancer therapy.

show abstract

“…The replacement of the 3-hydroxy-4-methoxyphenyl ring of combretastatins, isocombretastatins and phenstatins by indoles [11,12,13,14,20,21], naphthalenes [13], and 4-dimethylaminophenyl rings [15,16,22], results in potent tubulin inhibitory and cytotoxic compounds, but require further elaboration in order to achieve improved water solubility [10,23]. An alternative to prodrug formation is the introduction of polar functions, which has been attempted by replacing the phenyl rings of combretastatins, isocombretastatins, and related compounds, with pyridine rings, yielding better results as A than as B rings [15,22,24,25,26]. This likely reflects the more hydrophobic nature of the pocket, and the energy penalty associated with the desolvation of these polar groups.…”

Section: Discussionmentioning

confidence: 99%

The Masked Polar Group Incorporation (MPGI) Strategy in Drug Design: Effects of Nitrogen Substitutions on Combretastatin and Isocombretastatin Tubulin Inhibitors

et al. 2019

View full text Add to dashboard Cite

Colchicine site ligands suffer from low aqueous solubility due to the highly hydrophobic nature of the binding site. A new strategy for increasing molecular polarity without exposing polar groups—termed masked polar group incorporation (MPGI)—was devised and applied to nitrogenated combretastatin analogues. Bulky ortho substituents to the pyridine nitrogen hinder it from the hydrophobic pocket while increasing molecular polarity. The resulting analogues show improved aqueous solubilities and highly potent antiproliferative activity against several cancer cell lines of different origin. The more potent compounds showed moderate tubulin polymerization inhibitory activity, arrested the cell cycle of treated cells at the G2/M phase, and subsequently caused apoptotic cell death represented by the cells gathered at the subG0/G1 population after 48 h of treatment. Annexin V/Propidium Iodide (PI) double-positive cells observed after 72 h confirmed the induction of apoptosis. Docking studies suggest binding at the colchicine site of tubulin in a similar way as combretastatin A4, with the polar groups masked by the vicinal substituents. These results validate the proposed strategy for the design of colchicine site ligands and open a new road to increasing the aqueous solubility of ligands binding in apolar environments.

show abstract

Pyridine Based Antitumour Compounds Acting at the Colchicine Site

Cited by 42 publications

References 241 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

Discovery of Novel Quinoline–Chalcone Derivatives as Potent Antitumor Agents with Microtubule Polymerization Inhibitory Activity

The Masked Polar Group Incorporation (MPGI) Strategy in Drug Design: Effects of Nitrogen Substitutions on Combretastatin and Isocombretastatin Tubulin Inhibitors

Contact Info

Product

Resources

About