Structural interrogation of benzosuberene-based inhibitors of tubulin polymerization

Herdman, Christine A.; Devkota, Laxman; Lin, Chen; Niu, Haichan; Strecker, Tracy E.; Lopez, Ramona; Liu, Li; George, Clinton S.; Tanpure, Rajendra P.; Hamel, Ernest; Chaplin, David J.; Mason, Ralph P.; Trawick, Mary Lynn; Pinney, Kevin G.

doi:10.1016/j.bmc.2015.10.012

Cited by 20 publications

(33 citation statements)

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“…( A ) Natural products and combretastatin-inspired molecular structures found to be effective tubulin binding agents causing vascular disruption. Combretastatin A4 [ 15 ], AVE8062 [ 155 ], combretastatin A1P [ 14 ], ZD6126 [ 156 ], BNC105P [ 157 ], CKD-516 [ 158 ], OXi8007 [ 17 ], colchicine, KGP18 [ 144 ], OXi6916 [ 159 ] and SCB01A [ 160 ]. ( B ) Diverse molecular structures binding tubulin or causing vascular disruption: ABT-751 [ 143 ], EPC2407 [ 131 ], DMXAA [ 138 ], arsenic trioxide [ 161 ], paclitaxel [ 162 ], TZT-1027 [ 163 ], NPI-235 [ 124 ], MN-029 [ 39 ] and CYT997 [ 34 ].…”

Section: Figurementioning

confidence: 99%

Non-Invasive Evaluation of Acute Effects of Tubulin Binding Agents: A Review of Imaging Vascular Disruption in Tumors

et al. 2021

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Tumor vasculature proliferates rapidly, generally lacks pericyte coverage, and is uniquely fragile making it an attractive therapeutic target. A subset of small-molecule tubulin binding agents cause disaggregation of the endothelial cytoskeleton leading to enhanced vascular permeability generating increased interstitial pressure. The resulting vascular collapse and ischemia cause downstream hypoxia, ultimately leading to cell death and necrosis. Thus, local damage generates massive amplification and tumor destruction. The tumor vasculature is readily accessed and potentially a common target irrespective of disease site in the body. Development of a therapeutic approach and particularly next generation agents benefits from effective non-invasive assays. Imaging technologies offer varying degrees of sophistication and ease of implementation. This review considers technological strengths and weaknesses with examples from our own laboratory. Methods reveal vascular extent and patency, as well as insights into tissue viability, proliferation and necrosis. Spatiotemporal resolution ranges from cellular microscopy to single slice tomography and full three-dimensional views of whole tumors and measurements can be sufficiently rapid to reveal acute changes or long-term outcomes. Since imaging is non-invasive, each tumor may serve as its own control making investigations particularly efficient and rigorous. The concept of tumor vascular disruption was proposed over 30 years ago and it remains an active area of research.

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Section: Figurementioning

confidence: 99%

Non-Invasive Evaluation of Acute Effects of Tubulin Binding Agents: A Review of Imaging Vascular Disruption in Tumors

et al. 2021

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“…These analogues were prepared utilizing a synthetic strategy reminiscent of that employed for a variety of benzosuberene analogues developed in the Pinney Research Group. 10,11 The synthesis of each benzocyclooctene analogue was initiated with a Wittig olefination followed by catalytic hydrogenation to afford carboxylic acids 3 and 4 (Scheme 1). A Friedel-Crafts intramolecular annulation was accomplished using Eaton’s reagent (7.7 weight percent P 2 O 5 in CH 3 SO 3 H), 69 and the reaction was diluted and cooled in order to facilitate the construction of benzocyclooctanones 5 and 6 (Scheme 1).…”

Section: Resultsmentioning

confidence: 99%

“…Benzocyclooctanone 5 and indanone 11 bearing the ortho dimethoxy motif were each subjected to a selective demethylation 10,11,70 to afford phenolic analogues 13 and 15 , which were subsequently protected with TBS to yield 14 and 16 (Scheme 3). …”

Section: Resultsmentioning

confidence: 99%

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Synthesis and biological evaluation of benzocyclooctene-based and indene-based anticancer agents that function as inhibitors of tubulin polymerization

et al. 2016

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The natural products colchicine and combretastatin A-4 (CA4) have been inspirational for the design and synthesis of structurally related analogues and spin-off compounds as inhibitors of tubulin polymerization. The discovery that a water-soluble phosphate prodrug salt of CA4 (referred to as CA4P) is capable of imparting profound and selective damage to tumor-associated blood vessels paved the way for the development of a new therapeutic approach for cancer treatment utilizing small-molecule inhibitors of tubulin polymerization that also act as vascular disrupting agents (VDAs). Combination of salient structural features associated with colchicine and CA4 led to the design and synthesis of a variety of fused aryl-cycloalkyl and aryl-heterocyclic compounds that function as inhibitors of tubulin polymerization. Prominent among these compounds is a benzosuberene analogue (referred to as KGP18), which demonstrates sub-nM cytotoxicity against human cancer cell lines and functions (when administered as a water-soluble prodrug salt) as a VDA in mouse models. Structure activity relationship considerations led to the evaluation of benzocyclooctyl [6,8 fused] and indene [6,5 fused] ring systems. Four benzocyclooctene and four indene analogues were prepared and evaluated biologically. Three of the benzocyclooctene analogues were active as inhibitors of tubulin polymerization (IC50 < 5 μM), and benzocyclooctene phenol 23 was comparable to KGP18 in terms of potency. The analogous indene-based compound 31 also functioned as an inhibitor of tubulin polymerization (IC50 = 11 μM) with reduced potency. The most potent inhibitor of tubulin polymerization from this group was benzocyclooctene analogue 23, and it was converted to its water-soluble prodrug salt 24 to assess its potential as a VDA. Preliminary in vivo studies, which utilized the MCF7-luc-GFP-mCherry breast tumor in a SCID mouse model, demonstrated that treatment with 24 (120 mg/kg) resulted in significant vascular shutdown, as evidenced by bioluminescence imaging at 4 h post administration, and that the effect continued at both 24 and 48 h. Contemporaneous studies with CA4P, a clinically relevant VDA, were carried out as a positive control.

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“…tures found to be effective tubulin binding agents causing vascular disruption. Combretastatin A4 [15], AVE8062 [166], combretastatin A1P [14], ZD6126 [167], BNC105P [156], CKD-516 [168], OXi8007 [17], colchicine, KGP18 [141], OXi6916 [169] and SCB01A [170]. B) Diverse molecular structures binding tubulin or causing vascular disruption: ABT-751 [140], EPC2407 [130], DMXAA [136], arsenic trioxide [171], paclitaxel [172], TZT-1027 [173], NPI-235 [123], MN-029 [39] and CYT997 [34].…”

Section: Introductionmentioning

confidence: 99%

Non-Invasive Evaluation of Acute Effects of Tubulin Binding Agents: A Review of Imaging Vascular Disruption in Tumors

Liu¹,

O'Kelly²,

Schuetze³

et al. 2021

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Tumor vasculature proliferates rapidly, generally lacks pericyte coverage, and is uniquely frag-ile making it an attractive therapeutic target. A subset of small-molecule tubulin binding agents cause disaggregation of the endothelial cytoskeleton leading to enhanced vascular permeability generating increased interstitial pressure. The resulting vascular collapse and ischemia cause downstream hypoxia, ultimately leading to cell death and necrosis. Thus, local damage gener-ates massive amplification and tumor destruction. The tumor vasculature is readily accessed and potentially a common target irrespective of disease site in the body. Development of a therapeutic approach and particularly next generation agents benefits from effective non-invasive assays. Imaging technologies offer varying degrees of sophistication and ease of implementation. This review considers technological strengths and weaknesses with examples from our own laboratory. Methods reveal vascular extent and patency, as well as insights into tissue viability, proliferation and necrosis. Spatiotemporal resolution ranges from cellular mi-croscopy to single slice tomography and full three-dimensional views of whole tumors and measurements can be sufficiently rapid to reveal acute changes or long-term outcomes. Since imaging is non-invasive, each tumor may serve as its own control making investigations par-ticularly efficient and rigorous. The concept of tumor vascular disruption was proposed over 30 years ago and it remains an active area of research.

show abstract

Structural interrogation of benzosuberene-based inhibitors of tubulin polymerization

Cited by 20 publications

References 55 publications

Non-Invasive Evaluation of Acute Effects of Tubulin Binding Agents: A Review of Imaging Vascular Disruption in Tumors

Non-Invasive Evaluation of Acute Effects of Tubulin Binding Agents: A Review of Imaging Vascular Disruption in Tumors

Synthesis and biological evaluation of benzocyclooctene-based and indene-based anticancer agents that function as inhibitors of tubulin polymerization

Non-Invasive Evaluation of Acute Effects of Tubulin Binding Agents: A Review of Imaging Vascular Disruption in Tumors

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