Steroidomimetic Tetrahydroisoquinolines for the Design of New Microtubule Disruptors

Leese, Mathew P.; Jourdan, Fabrice; Döhle, Wolfgang; Kimberley, Meriel R.; Thomas, Mark; Bai, Ruoli; Hamel, Ernest; Ferrandis, Eric; Potter, Barry V. L.

doi:10.1021/ml200232c

Cited by 33 publications

(47 citation statements)

References 20 publications

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“…Preliminary results obtained with such conformationally restrained THIQ-based systems have been reported elsewhere. [15] …”

Section: Resultsmentioning

confidence: 99%

“…The N -2 site offers an achiral, tractable point for elaboration and could also conceivably allow the products to be salified to promote formulation of any active compounds discovered. We have reported preliminary data from this approach [15] and now disclose full details of, in particular, our exploration of the optimal linkage between the THIQ core and the aryl group and the nature of the decorating H-bond acceptor. In addition, derivatives with a polymethoxylated aryl group are described and their differential SAR indicate a chimeric nature.…”

Section: Introductionmentioning

confidence: 99%

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Tetrahydroisoquinolinone‐Based Steroidomimetic and Chimeric Microtubule Disruptors

et al. 2013

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A SAR translation strategy was used for the discovery of tetrahydroisoquinoline (THIQ)-based steroidomimetic and chimeric microtubule disruptors based upon a steroidal starting point. A steroid A,B-ring-mimicking THIQ core was connected to methoxy aryl D-ring ring mimics through methylene, carbonyl and sulfonyl linkers to afford a number of steroidomimetic hits (e.g. 20c GI50 2.1 μM). Optimisation and control experiments demonstrate the complementary SAR of this series and the steroid derivatives that inspired its design. Linkage of the THIQ-based A,B-mimic with the trimethoxy aryl motif prevalent in colchicine site binding microtubule disruptors delivered a series of chimeric molecules whose activity (to GI50 40 nM) surpasses that of the parent steroid derivatives. Validation of this strategy was obtained from the excellent oral activity of 20z relative to a benchmark steroidal bis-sulfamate in an in vivo model of multiple myeloma.

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“…Preliminary results obtained with such conformationally restrained THIQ-based systems have been reported elsewhere. [15] …”

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Tetrahydroisoquinolinone‐Based Steroidomimetic and Chimeric Microtubule Disruptors

et al. 2013

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“…In parallel work, we also applied the same THIQ core to generate steroidomimetic microtubule disruptors that exhibit a distinct structure–activity relationship (SAR) to the chimeras, yet share their favourable physicochemical properties. [10] In the present study, we explore optimisation of our chimeric system through modification of the trimethoxyaryl component, knowing that in some colchicine site binding microtubule disruptor series replacement of this motif with alternate trisubstituted systems can have a dramatic effect on potency. [11] We therefore synthesised candidate chimeric microtubule disruptors in which one or more of the methoxy groups are exchanged for an alternate functionality.…”

Section: Introductionmentioning

confidence: 99%

Optimisation of Tetrahydroisoquinoline‐Based Chimeric Microtubule Disruptors

et al. 2014

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Tetrahydroisoquinoline (THIQ)-based “chimeric” microtubule disruptors were optimised through modification of the N-benzyl motif, in concert with changes at C3 and C7, resulting in the identification of compounds with improved in vitro antiproliferative activities (e.g. 15: GI50 20 nM in DU-145). The broad anticancer activity of these novel structures was confirmed in the NCI 60-cell line assay, with 12e,f displaying MGM values in the 40 nM region. In addition, their profiles as inhibitors of tubulin polymerisation and colchicine binding to tubulin were confirmed. Compound 15, for example, inhibited tubulin polymerisation with an IC50 of 1.8 μM, close to that of the clinical drug combretastatin A-4, and also proved effective at blocking colchicine binding. Additionally, compound 20b was identified as the only phenol in the series to date showing both better in vitro antiproliferative properties than its corresponding sulfamate and excellent antitubulin data (IC50 = 1.6 μM). Compound 12f was selected for in vivo evaluation at the NCI in the hollow fibre assay and showed very good activity and wide tissue distribution, illustrating the value of this template for further development.

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“…Tetrahydroisoquinolines incorporating conformationally restricted side chains as the replacement of the amonoethoxy residue of E 2 , typical of SERMs were reported exhibiting binding affinity to ER-α and antagonistic properties [23]. More recently, new steroidomimetic tetrahydroquinolines were reported which act as microtubule disruptors [24]. …”

Section: Introductionmentioning

confidence: 99%

Synthesis and Pharmacological Evolution of Tetrahydroisoquinolines as Anti Breast Cancer Agents

2014

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Breast cancer is leading cause of mortality among women, resulting in more than half a million deaths worldwide each year. Unfortunately, the recovery rate of advanced breast cancer by current available drug treatment is till unacceptably low. Chemotherapy is the main stay of cancer treatment and most of the drugs cause general toxicity to any non-proliferating cells, which can severely limit the therapeutic values of these drugs. Tetrahydroisoqinoline derivatives (THIQs) were identified as subtype selective estrogen receptor antagonists/agonists hence, potential therapeutic agents for breast cancer. Substituted THIQs were synthesized and well characterized. Antiproliferative activity against human ER (+) MCF-7 (Breast), ER(−) MDA-MB-231 (breast) and Ishikawa (endometrial) cancer cell lines were studied after 72 hours drug exposure employing CellTiter-Glo assay at concentrations ranging from 0.01–100,000 nM. The activities of these compounds were compared with Tamoxifen (TAM). In-vitro results indicated that most of the compounds showed better activity than TAM. The most active compounds obtained in this study were 6a, 6b, 6d and 6j (IC50=0.63, 0.23; 0.93, 0.21; 043, 0.01; 0.7, 0.02 μg/ml) against MCF-7 and Ishikawa cell lines, in comparison to Tamoxifen activity (IC50=5.14, 4.55 μg/ml). The newly synthesized molecules were docked in the active sites of the ER-α (PDB: 3ERT) and ER-β (PDB: 3ERT) crystal structures and probable binding modes of this class of molecules were determined.

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Steroidomimetic Tetrahydroisoquinolines for the Design of New Microtubule Disruptors

Cited by 33 publications

References 20 publications

Tetrahydroisoquinolinone‐Based Steroidomimetic and Chimeric Microtubule Disruptors

Tetrahydroisoquinolinone‐Based Steroidomimetic and Chimeric Microtubule Disruptors

Optimisation of Tetrahydroisoquinoline‐Based Chimeric Microtubule Disruptors

Synthesis and Pharmacological Evolution of Tetrahydroisoquinolines as Anti Breast Cancer Agents

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