A novel class of trans-methylpyrazoline analogs of combretastatins: Synthesis and in-vitro biological testing

Lee, Megan; Brockway, Olivia; Dandavati, Armaan; Tzou, Samuel; Sjoholm, Robert; Satam, Vijay; Westbrook, Cara; Mooberry, Susan L.; Zeller, Mat­thias; Babu, Balaji; Lee, Moses

doi:10.1016/j.ejmech.2011.03.064

Cited by 35 publications

(12 citation statements)

References 21 publications

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“…We verify that the antiproliferative activity is, at least in part, due to microtubule depolymerization, and that they are binding at the colchicine site if they (or a structural analogue) competitively inhibit [ 3 H]colchicine binding. 15 Because this evidence for a CSI is the best available, and we have collected this data on multiple scaffolds (pyrrole analogues, combretastatin analogues, pyrimidine analogues and colchicine itself), 15–18,21–26 the training and internal test sets for this report – of 59 total compounds (see Table 1) – was thus restricted to compounds we have studied. The test set was 9 randomly selected compounds covering all three scaffolds other than colchicine, while the remaining 50 compounds comprised the training set.…”

Section: Resultsmentioning

confidence: 99%

“…We collected all antiproliferation (vs. MDA-MB-435 cancer cells) and microtubule depolymerization activity data for colchicine site agents from the several diverse scaffolds that have been tested in our laboratory. 15–18,21–26 As will be seen, there are a number of rather subtle but impactful features affecting activity, so we restricted our internal training and test sets set to these assay results to be certain that our analyses were not confounded by inter-laboratory variations.…”

Section: Introductionmentioning

confidence: 99%

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How to Deal with Low-Resolution Target Structures: Using SAR, Ensemble Docking, Hydropathic Analysis, and 3D-QSAR to Definitively Map the αβ-Tubulin Colchicine Site

Mooberry

Gupton

et al. 2013

J. Med. Chem.

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αβ-tubulin colchicine site inhibitors (CSIs) from four scaffolds that we previously tested for antiproliferative activity were modeled to better understand their effect on microtubules. Docking models, constructed by exploiting the SAR of a pyrrole subset and HINT scoring, guided ensemble docking of all 59 compounds. This conformation set and two variants having progressively less structure knowledge were subjected to CoMFA, CoMFA+HINT, and CoMSIA 3D-QSAR analyses. The CoMFA+HINT model (docked alignment) showed the best statistics: leave-one-out q2 of 0.616, r2 of 0.949 and r2pred (internal test set) of 0.755. An external (tested in other laboratories) collection of 24 CSIs from eight scaffolds were evaluated with the 3D-QSAR models, which correctly ranked their activity trends in 7/8 scaffolds for CoMFA+HINT (8/8 for CoMFA). The combination of SAR, ensemble docking, hydropathic analysis and 3D-QSAR provides an atomic-scale colchicine site model more consistent with a target structure resolution much higher than the ~3.6 Å available for αβ-tubulin.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

How to Deal with Low-Resolution Target Structures: Using SAR, Ensemble Docking, Hydropathic Analysis, and 3D-QSAR to Definitively Map the αβ-Tubulin Colchicine Site

Mooberry

Gupton

et al. 2013

J. Med. Chem.

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“…Lee’s group (158,159) developed a series of acetylated ( 198 ) and methylpyrazoline ( 199 , Fig. 15) analogs of CA-4 with the intention to improve solubility of the CA-4 analogs.…”

Section: Reported Cbsi In Preclinical Studiesmentioning

confidence: 99%

An Overview of Tubulin Inhibitors That Interact with the Colchicine Binding Site

et al. 2012

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Tubulin dynamics is a promising target for new chemotherapeutic agents. The colchicine binding site is one of the most important pockets for potential tubulin polymerization destabilizers. Colchicine binding site inhibitors (CBSI) exert their biological effects by inhibiting tubulin assembly and suppressing microtubule formation. A large number of molecules interacting with the colchicine binding site have been designed and synthesized with significant structural diversity. CBSIs have been modified as to chemical structure as well as pharmacokinetic properties, and tested in order to find a highly potent, low toxicity agent for treatment of cancers. CBSIs are believed to act by a common mechanism via binding to the colchicine site on tubulin. The present review is a synopsis of compounds that have been reported in the past decade that have provided an increase in our understanding of the actions of CBSIs.

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“…Thus, these scaffolds are also important from the standpoint of pharmaceutical and medicinal chemistry [6–11]. Not surprisingly, the construction of diverse heterocyclic cores including isoxazolines and pyrazolines has garnered much attention from synthetic chemists [12–15].…”

Section: Introductionmentioning

confidence: 99%

Hypervalent iodine-mediated Ritter-type amidation of terminal alkenes: The synthesis of isoxazoline and pyrazoline cores

Park¹,

Kim²,

Song³

et al. 2018

Beilstein J. Org. Chem.

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Hypervalent iodine-mediated olefin functionalization provides a rapid gateway towards accessing both various heterocyclic cores and functional groups. In this regard, we have developed a Ritter-type alkene functionalization utilizing a PhI(OAc)2 ((diacetoxyiodo)benzene, PIDA)/Lewis acid combination in order to access isoxazoline and pyrazoline cores. Based on allyl ketone oximes and allyl ketone tosylhydrazones, we have developed an alkene oxyamidation and amido-amidation protocol en route to accessing both isoxazoline and pyrazoline cores. Additionally, acetonitrile serves as both the solvent and an amine source in the presence of this PIDA/Lewis acid combination. This operationally straightforward and metal-free protocol provides an easy access to isoxazoline and pyrazoline derivatives.

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A novel class of trans-methylpyrazoline analogs of combretastatins: Synthesis and in-vitro biological testing

Cited by 35 publications

References 21 publications

How to Deal with Low-Resolution Target Structures: Using SAR, Ensemble Docking, Hydropathic Analysis, and 3D-QSAR to Definitively Map the αβ-Tubulin Colchicine Site

How to Deal with Low-Resolution Target Structures: Using SAR, Ensemble Docking, Hydropathic Analysis, and 3D-QSAR to Definitively Map the αβ-Tubulin Colchicine Site

An Overview of Tubulin Inhibitors That Interact with the Colchicine Binding Site

Hypervalent iodine-mediated Ritter-type amidation of terminal alkenes: The synthesis of isoxazoline and pyrazoline cores

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