ChemInform Abstract: Structure‐Activity Relationships of a Series of Substituted Benzamides: Potent D2/5‐HT2 Antagonists and 5‐HT1a Agonists as Neuroleptic Agents.

Norman, Mark H.; Rigdon, Greg C.; Hall, William R.; Navas, Frank

doi:10.1002/chin.199627182

Cited by 5 publications

(5 citation statements)

References 1 publication

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“…The aqueous layer was washed with EtOAc (2 × 100 mL), the combined organics were dried (Na 2 SO 4 ), filtered, and concentrated. The crude residue was purified by crystallization (EtOAc) and rinsed with cold EtOAc and copious amounts of hexanes to provide 32 as an off-white solid in good yield (70%) …”

Section: Methodsmentioning

confidence: 99%

Structure–Activity Relationships for Vitamin D3-Based Aromatic A-Ring Analogues as Hedgehog Pathway Inhibitors

et al. 2014

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A structure-activity relationship study for a series of vitamin D3-based (VD3) analogues that incorporate aromatic A-ring mimics with varying functionality has provided key insight into scaffold features that result in potent, selective Hedgehog (Hh) pathway inhibition. Three analogue subclasses containing (1) a single substitution at the ortho or para position of the aromatic A-ring, (2) a heteroaryl or biaryl moiety, or (3) multiple substituents on the aromatic A-ring were prepared and evaluated. Aromatic A-ring mimics incorporating either single or multiple hydrophilic moieties on a six-membered ring inhibited the Hh pathway in both Hh-dependent mouse embryonic fibroblasts and cultured cancer cells (IC50 values 0.74-10 μM). Preliminary studies were conducted to probe the cellular mechanisms through which VD3 and 5, the most active analogue, inhibit Hh signaling. These studies suggested that the anti-Hh activity of VD3 is primarily attributed to the vitamin D receptor, whereas 5 affects Hh inhibition through a separate mechanism.

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Section: Methodsmentioning

confidence: 99%

Structure–Activity Relationships for Vitamin D3-Based Aromatic A-Ring Analogues as Hedgehog Pathway Inhibitors

et al. 2014

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“…The monobenzyl ester of isophthalic acid, 6b , was obtained in moderate yield following a published protocol . Protected carboxylic acids 7b – 8b were also generated in modest yield using standard conditions . Acids were coupled to 4 using standard esterification conditions followed by appropriate deprotection (Scheme ) to afford final analogues in good yields that were subsequently evaluated for their ability to selectively inhibit the Hh signaling pathway.…”

mentioning

confidence: 99%

Identification of Vitamin D3-Based Hedgehog Pathway Inhibitors That Incorporate an Aromatic A-Ring Isostere

DeBerardinis

Banerjee

Hadden

2013

ACS Med. Chem. Lett.

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Previous structure−activity relationship studies for vitamin D3 (VD3) inhibition of Hedgehog (Hh) signaling directed the design, synthesis, and evaluation of a series of VD3-based analogues that contain an aromatic A-ring mimic. Characterization of these compounds in a series of cellular assays demonstrated their ability to potently and selectively downregulate Hh pathway signaling. The most active of these, 17, inhibited pathway signaling in Hh-dependent mouse fibroblasts (IC 50 = 0.74 ± 0.1 μM) and cultured cancer cells (IC 50 values 3.8 ± 0.1 to 5.2 ± 0.2 μM). In addition, 17 demonstrated reduced activation of the vitamin D receptor (VDR) compared to VD3 in these cellular models. These results suggest that VD3-based analogues with an aromatic A-ring are a valid scaffold for the development of more selective and potent Hh pathway inhibitors and identify 17 as an intriguing lead from this class of compounds for further development. In addition, our analysis of Hh pathway inhibitors in cancer cells suggests that the murine basal cell carcinoma cell line ASZ001 and the human medulloblastoma cell line DAOY are appropriate in vitro cancer models for early stage evaluation of pathway inhibition.

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“…In agreement with the results reported above, when the Luche's reduction was performed on (Z)-7a-d, the spontaneous cyclization of intermediate alkoxyde to the functionalized 1,3oxazinane-2,4-dione (Z)-9a-d occurred. The 1,3-oxazinane-2,4-dione scaffold, being isoster of benzoxazine-2,4dione, may be exploited as central constrained core in the synthesis of potential drug candidates as psychotics (Mu et al 2002), anticancers (Norman et al 1996), and inhibitors of hepatitis C virus (Dong et al 2012).…”

Section: Reactivity Of -Methylene Amino Acid Deriving Alcohols (Z)-2a-dmentioning

confidence: 99%

Synthesis of α/β dipeptides containing linear or cyclic α-dehydro-β-amino acids as scaffolds for bioactive compounds

et al. 2019

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The synthesis of  dipeptides containing linear or cyclic -dehydro--amino acids has been performed starting from alkylidene acetacetamides deriving from -amino esters via Ir-catalyzed allylic amination. Differently hindered carbonates were synthesized via a protocol involving chemoselective Luche's reduction, acylation and allylic amination. Depending on the nature of the selected -amino acid, we observed strong influence on the product regiochemistry due to the carbonate size and the amino acid side chain. In particular complete regioselectivity was observed in the aminic allylation of carbonates deriving from amino acids possessing a methylene unit in -position. On the contrary, branched amino acid-deriving methyl carbonates afforded different results depending on the hindrance of the carbonate. Moreover spontaneous cyclization was observed for carbamate-containing intermediates, allowing to obtain peptidomimetic polyfunctionalized dihydropyrimidine-2,4-dione. Finally, by inverting the order of reduction/acylation steps on the starting alkylidene acetoacetamides, the formation of polyfunctionalized 1,3oxazinane-2,4-dione was obtained demonstrating the wide applications of these substrates for the preparation of bioactive peptidomimetics.

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ChemInform Abstract: Structure‐Activity Relationships of a Series of Substituted Benzamides: Potent D2/5‐HT2 Antagonists and 5‐HT1a Agonists as Neuroleptic Agents.

Cited by 5 publications

References 1 publication

Structure–Activity Relationships for Vitamin D3-Based Aromatic A-Ring Analogues as Hedgehog Pathway Inhibitors

Structure–Activity Relationships for Vitamin D3-Based Aromatic A-Ring Analogues as Hedgehog Pathway Inhibitors

Identification of Vitamin D3-Based Hedgehog Pathway Inhibitors That Incorporate an Aromatic A-Ring Isostere

Synthesis of α/β dipeptides containing linear or cyclic α-dehydro-β-amino acids as scaffolds for bioactive compounds

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