Conformational Restriction and/or Steric Hindrance in Medicinal Chemistry

Mann, André

doi:10.1016/b978-0-12-374194-3.00017-2

Cited by 67 publications

(51 citation statements)

References 48 publications

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“…Ms chloride provided the highest %conversion and %yield followed by Ns chloride and Ts chloride, respectively. This result was attributed to the small structure and less steric effect of methyl group of Ms [32,33]. Although the methyl group of Ms exhibited weakly electron donating property, it had relatively small structure and less steric interference to the electron attacking by lone pair electron of hydroxyl group of TPGS.…”

Section: Terminal Hydroxyl Derivatization Of Tpgs By Sulfonyl Derivatmentioning

confidence: 75%

Enhanced toxicity and cellular uptake of methotrexate-conjugated nanoparticles in folate receptor-positive cancer cells by decorating with folic acid-conjugated d -α-tocopheryl polyethylene glycol 1000 succinate

Junyaprasert

Dhanahiranpruk

Suksiriworapong

et al. 2015

Colloids and Surfaces B: Biointerfaces

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Section: Terminal Hydroxyl Derivatization Of Tpgs By Sulfonyl Derivatmentioning

confidence: 75%

Enhanced toxicity and cellular uptake of methotrexate-conjugated nanoparticles in folate receptor-positive cancer cells by decorating with folic acid-conjugated d -α-tocopheryl polyethylene glycol 1000 succinate

Junyaprasert

Dhanahiranpruk

Suksiriworapong

et al. 2015

Colloids and Surfaces B: Biointerfaces

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“…3,3-Dimethoxytetrahydro-2H-pyran (7). The compound 6 (96.8 g, 0.590 mol) was dissolved in absolute THF (450 mL).…”

Section: Methodsmentioning

confidence: 99%

“…[1][2][3][4][5] Apart from the widely accepted physicochemical parameters such as molecular weight or calculated LogP, 6 there is an enhanced interest in such properties as conformational restriction (measured as number of rotatable bonds), fractional sp 3 character (Fsp 3 ) and distribution of different heteroatom types. [3][4][5]7 In particular, it was shown by Fecher and Schmidt 5 that current combinatorial collections suffer from a low ratio of oxygen atoms to all heavy atoms compared with both drugs and natural compounds. In this view, saturated conformationally restricted oxygen-enriched building blocks of low molecular weight and lipophilicity are of particular interest.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of dihydro-2H-pyran-3(4H)-one

Mityuk¹,

Denisenko²,

Grygorenko³

et al. 2012

Arkivoc

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“…Niclosamide’s protonophore activity may be the mechanistic driver underlying its effects on ATP homeostasis and on oxidative phosphorylation. 44, 45 Thus, to improve the selectivity of Niclosamide-derived inhibitors, we interrogated a protonophore SAR model based on cLogP and pKa, 44 and used the principle of conformational restriction 46 to identify novel benzimidazole Wnt/β-catenin inhibitors with less effect on ATP cellular homeostasis than Niclosamide and greater selectivity for inhibition of Wnt/β-catenin.…”

Section: Introductionmentioning

confidence: 99%

Benzimidazole inhibitors from the Niclosamide chemotype inhibit Wnt/β-catenin signaling with selectivity over effects on ATP homeostasis

Mook

Ren

Wang

et al. 2017

Bioorganic & Medicinal Chemistry

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The Wnt signaling pathway plays a key role in organ and tissue homeostasis, and when dysregulated, can become a major underlying mechanism of disease, particularly cancer. We reported previously that the anthelmintic drug Niclosamide inhibits Wnt/β-catenin signaling and suppresses colon cancer cell growth in vitro and in vivo. To define Niclosamide’s mechanism of Wnt/β-catenin inhibition, and to improve its selectivity and pharmacokinetic properties as an anticancer treatment, we designed a novel class of benzimidazole inhibitors of Wnt/β-catenin signaling based on SAR studies of the Niclosamide salicylanilide chemotype. Niclosamide has multiple biological activities. To address selectivity in our design, we interrogated a protonophore SAR model and used the principle of conformational restriction to identify novel Wnt/β-catenin inhibitors with less effect on ATP cellular homeostasis. These studies led to the identification of 4-chloro-2-(5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl) phenol (4) and related derivatives with greater selectivity for Wnt/β-catenin signaling inhibition vs. differential effects on cellular ATP homeostasis. This is the first report that the Wnt signaling inhibitory activity of Niclosamide can be translated into a new chemical class and to show that its effects on ATP homeostasis can be separated from its inhibitory effects on Wnt signaling. These compounds could be useful tools to elucidate the mechanism of Niclosamide’s inhibition of Wnt signaling, and aid the discovery of inhibitors with improved pharmacologic properties to treat cancer and diseases in which Niclosamide has important biological activity.

show abstract

Conformational Restriction and/or Steric Hindrance in Medicinal Chemistry

Cited by 67 publications

References 48 publications

Enhanced toxicity and cellular uptake of methotrexate-conjugated nanoparticles in folate receptor-positive cancer cells by decorating with folic acid-conjugated d -α-tocopheryl polyethylene glycol 1000 succinate

Enhanced toxicity and cellular uptake of methotrexate-conjugated nanoparticles in folate receptor-positive cancer cells by decorating with folic acid-conjugated d -α-tocopheryl polyethylene glycol 1000 succinate

Synthesis of dihydro-2H-pyran-3(4H)-one

Benzimidazole inhibitors from the Niclosamide chemotype inhibit Wnt/β-catenin signaling with selectivity over effects on ATP homeostasis

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